WO2026032421A1 - Compositions contre le surdosage et leurs utilisations - Google Patents

Compositions contre le surdosage et leurs utilisations

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Publication number
WO2026032421A1
WO2026032421A1 PCT/CN2025/113562 CN2025113562W WO2026032421A1 WO 2026032421 A1 WO2026032421 A1 WO 2026032421A1 CN 2025113562 W CN2025113562 W CN 2025113562W WO 2026032421 A1 WO2026032421 A1 WO 2026032421A1
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WIPO (PCT)
Prior art keywords
glp
agonist
pharmaceutical composition
subject
dnp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/113562
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English (en)
Inventor
Shiyi ZHANG
Linan YANG
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Polykleitos Pharmaceuticals LLC
Original Assignee
Polykleitos Pharmaceuticals LLC
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Publication date
Application filed by Polykleitos Pharmaceuticals LLC filed Critical Polykleitos Pharmaceuticals LLC
Publication of WO2026032421A1 publication Critical patent/WO2026032421A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • anti-overdosing compositions and uses thereof.
  • anti-overdosing pharmaceutical compositions comprising a mitochondrial uncoupler and a GLP-1R agonist and uses thereof as well as methods for preventing overdosing of the uncoupler.
  • Such pharmaceutical compositions can be useful for treating diseases, such as but not limited to NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , and Alzheimer’s disease and related dementias (AD/ADRD) .
  • Mitochondrial uncouplers have long been recognized for their potential in promoting weight loss and treating various metabolic disorders, including obesity and fatty liver diseases. These compounds work by disrupting the mitochondrial proton gradient, leading to increased energy expenditure and fat loss. Despite their promising effects, early concerns about toxicity significantly impeded their therapeutic development during the 1930s. There exists a general believe that the higher dose of a weight-loss medication that a patient is administered, the better the weight loss effect that the patient should observe. As such, the risk of patients overdosing weight-loss medications and the resulting consequence of the overdose is very serious and becoming more common in the public.
  • DNP 2-dinitrophenol
  • Typical overdose symptoms include hyperthermia, tachycardia, diaphoresis, and tachypnea.
  • overdose symptoms include hyperthermia, tachycardia, diaphoresis, and tachypnea.
  • 4-DNP can induce dangerously increased heart and respiratory rates and hyperthermia.
  • WO2015031756A1 the inventors wanted to address the need of treating NAFLD and other diseases and disorders. They used a coated extended-release formulation of DNP (ERDNP) which can administer a very low dose continuous infusion of DNP without any associated hyperthermia and systemic toxicities when DNP was not overdosed. This formulation aimed to increase the no observed adverse effect level (NOAEL) .
  • NOAEL no observed adverse effect level
  • DNP prodrugs such as 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) and 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) have been designed to minimize rapid absorption and high peak blood concentrations of DNP, thereby providing a wider therapeutic index and improved safety profile.
  • these modifications only improve the NOAEL and do not address the potential hyperthermia or systemic toxicity risks associated with DNP when DNP is overdosed.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) a mitochondrial uncoupler; and (ii) a GLP-1R agonist; wherein the pharmaceutical composition is formulated to provide a dose of the GLP-1R agonist to the subject that is sufficient to trigger vomiting of the subject when a dose of the mitochondrial uncoupler administered to the subject exceeds a threshold to prevent the overdose of mitochondrial uncoupler.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) a mitochondrial uncoupler; and (ii) a GLP-1R agonist; wherein the pharmaceutical composition protects the subject from an unacceptable toxicity resulted from overdosing an amount of the mitochondrial uncoupler by triggering vomiting of the subject when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) an amount of a mitochondrial uncoupler; and (ii) an amount of a GLP-1R agonist; wherein the pharmaceutical composition comprises the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist at a predetermined ratio such that when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold, then the dose of the GLP-1R agonist administered to the subject is sufficient to trigger vomiting of the subject.
  • the present disclosure provides a method for preventing or treating a disease comprising insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease and related dementias (AD/ADRD) , or any combination thereof in a subject in need thereof, comprising a
  • the present disclosure provides a use of the pharmaceutical composition of the present disclosure in the preparation of a medicament for preventing or treating a disease comprising insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease and related dementias (AD/ADRD)
  • the present disclosure provides a method for preventing an unacceptable toxicity resulted from overdosing an amount of a mitochondrial uncoupler in a subject, comprising orally administering to the subject an amount of the mitochondrial uncoupler and an amount of a GLP-1R agonist at a predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist, such that when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold, then the dose of the GLP-1R agonist administered to the subject is sufficient to trigger vomiting of the subject to prevent the unacceptable toxicity resulted from overdosing of the amount of the mitochondrial uncoupler.
  • FIG. 1 shows the latency to the first vomiting induced by danuglipron. The results demonstrate that the latency period was less than 3 hours;
  • FIG. 2 shows the incidence of vomiting induced by danuglipron across three animal models. The results indicate a high incidence of vomiting across these models;
  • FIG. 3 shows the incidence of vomiting induced by various GLP-1R agonists in the ferret model. The results suggest that different GLP-1R agonists can trigger vomiting in this model;
  • FIG 4. shows the incidence of vomiting induced by various GLP-1R agonists in the tree shrew model. The results indicate that different GLP-1R agonists are capable of inducing vomiting in this model;
  • FIG. 5 shows the incidence of vomiting induced by various GLP-1R agonists in the beagle dog model. The results reveal that different GLP-1R agonists can induce vomiting in this model;
  • FIG. 6 shows the lethal or unacceptably toxic doses of various mitochondrial uncouplers in rats and mice
  • FIG. 7 shows the effect of the combination of mitochondrial uncouplers with GLP-1R agonists on body weight in a DIO mice model. The results indicated that the combination treatment resulted in greater weight loss effect compared to either the mitochondrial uncoupler or GLP-1R agonist alone;
  • FIG. 8 shows the effect of the combination of mitochondrial uncouplers with GLP-1R agonists on fat mass in DIO mice model. The results showed that the combination treatment was more effective in reducing fat mass than either the mitochondrial uncoupler or GLP-1R agonist alone;
  • FIG. 9 shows the effect of the combination of mitochondrial uncouplers with GLP-1R agonists on lean mass in DIO mice model. The results indicated that the reduction in lean mass with the combination treatment was less pronounced compared to GLP-1R agonist alone.
  • GLP-1 receptor agonists involve the gastrointestinal tract, including nausea, vomiting, constipation, and diarrhea.
  • NCT04707313 danuglipron
  • a potential hypothesis from the analysis may include:
  • the vomiting event (s) may potentially help excrete the mitochondrial uncoupler, thereby avoid the systemic toxicity associated with its overdose.
  • compositions and uses thereof as well as methods for preventing overdosing.
  • the following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) a mitochondrial uncoupler; and (ii) a GLP-1R agonist; wherein the pharmaceutical composition is formulated to provide a dose of the GLP-1R agonist to the subject that is sufficient to trigger vomiting of the subject when a dose of the mitochondrial uncoupler administered to the subject exceeds a threshold.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) a mitochondrial uncoupler; and (ii) a GLP-1R agonist; wherein the pharmaceutical composition protects the subject from an unacceptable toxicity resulted from overdosing an amount of the mitochondrial uncoupler by triggering vomiting of the subject when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold.
  • the present disclosure provides a pharmaceutical composition for oral administration to a subject in need thereof, comprising: (i) an amount of a mitochondrial uncoupler; and (ii) an amount of a GLP-1R agonist; wherein the pharmaceutical composition comprises the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist at a predetermined ratio such that when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold, then the dose of the GLP-1R agonist administered to the subject is sufficient to trigger vomiting of the subject.
  • the mitochondrial uncoupler comprises at least one mitochondrial uncoupler. In some embodiments, the mitochondrial uncoupler comprises two or more different mitochondrial uncouplers. In some embodiments, the mitochondrial uncoupler comprises two different mitochondrial uncouplers. In some embodiments, the mitochondrial uncoupler comprises one mitochondrial uncoupler. In some embodiments, the GLP-1R agonist comprises at least one GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises two or more different GLP-1R agonists. In some embodiments, the GLP-1R agonist comprises two different GLP-1R agonists.
  • the GLP-1R agonist comprises one GLP-1R agonist.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a protonophore and a non-protonophore mitochondrial uncoupler.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof. In some embodiments, the GLP-1R agonist comprises a peptide-based GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises both a peptide-based GLP-1R agonist and a small molecule GLP-1R agonist.
  • the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject. In some embodiments, the maximum dose can be administered to the subject without causing an unacceptable toxicity. In some embodiments, the maximum dose can be administered to the subject without causing a fatal toxicity. In some embodiments, the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing a fatal toxicity in the subject.
  • the threshold is from about 10%to about 95%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 90%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 85%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 80%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 10%to about 75%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 70%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 65%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 60%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 10%to about 55%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 20%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 30%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 40%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 10%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 15%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 20%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 25%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 30%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 95%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 90%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 85%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 80%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 75%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 70%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 65%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 60%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 55%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 45%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 35%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 30%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 25%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 20%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 15%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 10%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 5%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 100 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 20 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 4 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.1 mg/kg to about 2 mg/kg, or about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.01 mg/kg to about 1 mg/kg or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 0.1 mg/kg to about 2 mg/kg for the subject. In some embodiments, the maximum dose is about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 100 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 20 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.1 mg/kg to about 2 mg/kg, or about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.01 mg/kg to about 1 mg/kg or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 0.1 mg/kg to about 2 mg/kg for the subject. In some embodiments, the threshold is about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the unacceptable toxicity is not selected from a gastrointestinal side effect.
  • the fatal toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is a systemic toxicity.
  • the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, or 24 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, or 12 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, or 6 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, or 2 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, or 1 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, or 45 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, 15 min, or 30 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min, 10 min, or 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 10 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold such that the unacceptable toxicity is ameliorated. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold such that the unacceptable toxicity is prevented. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 10 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 20 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 30 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 40 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 50 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 60 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 10 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 20 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 30 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 40 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 50 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 5 min to about 60 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 2 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 3 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 4 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 5 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 6 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 7 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 8 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 9 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 h to about 10 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 2 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 3 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 4 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 5 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 6 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 7 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 8 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 9 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested between about 1 min to about 10 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 10 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 30 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 45 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 1 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 2 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 3 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 4 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 5 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 6 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 7 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 8 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 9 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 10 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 11 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 12 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 14 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the pharmaceutical composition that the subject has ingested no later than 24 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises one or more mitochondrial uncouplers disclosed in the following publications: US20220117920A1, US20220175704A1, US20240066001A1, US20220055985, WO2017070576A1, WO2017201313A1, WO2018217757A1, WO2019204813A1, WO2019204816A1, WO2019204819A1, WO2019226490A1, WO2020168290A1, WO2021042080A1, WO2022173750A1, WO2022246039A1, WO2023150759A1, WO2023150767A1, WO2024054766A2, WO2024112663A1, US11136290B2, US11365177B2, US11708376B2, US11896591B2, US11945825B2, US20190359565A1, US20200317613A1, US20210186918A1, US20210253538A1, US20210253594A1, US20220017537A1,
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile (OPC-163493) ; MB-X01Y03; 6- [ [4- (trifluoromethoxy) phenyl] amino] - [1, 2, 5] oxadiazolo [3, 4-b] pyrazin-5 (3H) -one (SHS4121705) ; or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • TLC-1235 2, 4-fluorophenyl) 6- [ (2
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the mitochondrial uncoupler is a DNP analog.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the isomer of DNP is 2, 6-dinitrophenol.
  • the DNP analog comprises a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the derivative of DNP is DNP-methyl ether (DNPME) .
  • the prodrug of DNP comprises 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , and 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the BAM 15 derivative comprises N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • DNPME DNP-methyl
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the mitochondrial uncoupler is DNP.
  • the mitochondrial uncoupler is 2, 6-dinitrophenol.
  • the mitochondrial uncoupler is DNP-methyl ether (DNPME) .
  • the mitochondrial uncoupler is 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) .
  • the mitochondrial uncoupler is 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) .
  • the mitochondrial uncoupler is TLC-6740.
  • the mitochondrial uncoupler is N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) .
  • the mitochondrial uncoupler causes an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler causes a fatal toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the unacceptable toxicity is not selected from a gastrointestinal side effect. In some embodiments, the fatal toxicity is not selected from a gastrointestinal side effect. In some embodiments, the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the unacceptable toxicity is a systematic toxicity. In some embodiments, the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the mitochondrial uncoupler causes an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler causes a fatal toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler. In some embodiments, the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises both a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4DNP) , a
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile (OPC-163493) ; MB-X01Y03; 6- [ [4- (trifluoromethoxy) phenyl] amino] - [1, 2, 5] oxadiazolo [3, 4-b] pyrazin-5 (3H) -one (SHS4121705) ; or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • TLC-1235 2, 4-fluorophenyl) 6- [ (2
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof. In some embodiments, mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof. In some embodiments, mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the mitochondrial uncoupler is a DNP analog.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the isomer of DNP is 2, 6-dinitrophenol.
  • the DNP analog comprises a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the derivative of DNP is DNP-methyl ether (DNPME) .
  • the prodrug of DNP comprises 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , and 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the BAM 15 derivative comprises N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • mitochondrial uncoupler comprises2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • DNP 4-dinitrophenol
  • DNPME DNP-methyl ether
  • mitochondrial uncoupler comprises2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the mitochondrial uncoupler is DNP.
  • the mitochondrial uncoupler is 2, 6-dinitrophenol.
  • the mitochondrial uncoupler is DNP-methyl ether (DNPME) .
  • mitochondrial uncoupler is 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) .
  • the mitochondrial uncoupler is 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) .
  • the mitochondrial uncoupler is TLC-6740.
  • the mitochondrial uncoupler is N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) .
  • the mitochondrial uncoupler is (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) .
  • 2, 4-dinitrophenol (DNP) 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof, causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) ,
  • 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof administered to the subject exceeds the threshold.
  • the DNP analog causes a fatal toxicity when the dose of the DNP analog administered to the subject exceeds the threshold.
  • the unacceptable toxicity is not selected from a gastrointestinal side effect.
  • the fatal toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is a systematic toxicity.
  • the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 80 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 60 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 20 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 80 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 60 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 60 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 30 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 5 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 40 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 30 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 5 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 2 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 30 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 5 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 5 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 2 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 100 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 80 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 60 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 40 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 30 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 10 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 5 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 2 mg/kg/day.
  • the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 1 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 0.1 mg/kg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 0.01 mg/kg/day.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIPR dual agonist, a peptide GLP-1R/GCGR dual agonist, a peptide GLP-1R/GLP-2R dual agonist, a peptide GLP-1R/AMYR dual agonist, a peptide GLP-1R/GCGR/GIPR tri-specific agonist, a peptide GLP-1R/GCGR/FGF21 tri-specific agonist, a peptide GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIPR dual agonist, a peptide GLP-1R/GCGR dual agonist, a peptide GLP-1R/GLP-2R dual agonist, a peptide GLP-1R/AMYR dual agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GCGR/GIPR tri-specific agonist, a peptide GLP-1R/GCGR/FGF21 tri-specific agonist, a peptide GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIP dual agonist, a peptide GLP-1R/GCGRA, a peptide GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, TG103, VK2735, AMG 133, BGM0504, HRS9531, CT-388, HS-20094, tirzepatide, HZ010, HZ012, DR10627,
  • the peptide-based GLP-1R agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, DR10627, P29, XW015, TE-8105, GSBR-3rd Gen, GSBR-2nd Gen, CY-5, Next Gen GSBR, SPN007, PP18,
  • the peptide-based GLP-1R agonist is a peptide GLP-1R single agonist.
  • the peptide GLP-1R single agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, DR10627, P29, XW015, TE-8105, GSBR-3
  • the peptide GLP-1R single agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, or any combination thereof.
  • the peptide GLP-1R single agonist comprises DR10627, P29, XW015, TE-8105, GSBR-3rd Gen, GSBR-2nd Gen, CY-5, Next Gen GSBR, SPN007, PP18, DR10601, SAR441255, RAY001, HM-15211, cagriSema, QL1005, peptide 3b, DR10625, DR10619, ZT007, HR17031, or any combination thereof.
  • the peptide GLP-1R single agonist comprises DR10627, P29, XW015, TE-8105, GSBR-3rd Gen, GSBR-2nd Gen, CY-5, Next Gen GSBR, SPN007, or any combination thereof.
  • the peptide GLP-1R single agonist comprises PP18, DR10601, SAR441255, RAY001, HM-15211, cagriSema, QL1005, peptide 3b, DR10625, DR10619, ZT007, HR17031, or any combination thereof.
  • the peptide GLP-1R single agonist is semaglutide.
  • the peptide-based GLP-1R agonist is a peptide GLP-1R/GIPR dual agonist.
  • the peptide GLP-1R/GIPR dual agonist comprises tirzepatide, HRS9531, HS-20094, CT-388, CT-868, BGM0504, AMG 133, VK2735, RAY1225, NN9541, GMA106, HZ010, LY3493269, SCO-094, HZ012, THDBH120, HDM1005, NN9542, NN9650, NBB-T007, or any combination thereof.
  • the peptide GLP-1R/GIPR dual agonist is tirzepatide.
  • the peptide-based GLP-1R agonist is a peptide GLP-1R/GCGR dual agonist.
  • the peptide GLP-1R/GCGR dual agonist comprises mazdutide, survodutide, efinoprgdutide, pemvidutide, cotadutide, pegapamodutide, PB-718, AZD9550, DD01, G3215, SHR-1816, TB001, DA-1726, Bamadutide, NBB-C007, NN1177, or any combination thereof.
  • the peptide GLP-1R/GCGR dual agonist comprises mazdutide, survodutide, efinoprgdutide, pemvidutide, cotadutide, pegapamodutide, or any combination thereof.
  • the peptide-based GLP-1R agonist is a peptide GLP-1R/GLP-2R dual agonist.
  • the peptide GLP-1R/GLP-2R dual agonist comprises dapiglutide, PG-102, or any combination thereof.
  • the peptide GLP-1R/GLP-2R dual agonist is dapiglutide.
  • the peptide GLP-1R/GLP-2R dual agonist is PG-102. In some embodiments, the peptide-based GLP-1R agonist is a peptide GLP-1R/AMYR dual agonist. In some embodiments, the peptide GLP-1R/AMYR dual agonist is amycretin (NN9487) . In some embodiments, the peptide-based GLP-1R agonist is a peptide GLP-1R/GCGR/GIPR tri-specific agonist.
  • the peptide GLP-1R/GCGR/GIPR tri-specific agonist comprises retatrutide, efocipegtrutide, MWN101, UBT251, ZX2021, or any combination thereof. In some embodiments, the peptide GLP-1R/GCGR/GIPR tri-specific agonist comprises retatrutide, efocipegtrutide, or any combination thereof. In some embodiments, the peptide GLP-1R agonist is a peptide GLP-1R/GCGR/FGF21 tri-specific agonist. In some embodiments, the peptide GLP-1R/GCGR/FGF21 tri-specific agonist is DR10624.
  • the peptide GLP-1R agonist is a peptide GLP-1R/GCGR/AMYR tri-specific agonist. In some embodiments, the peptide GLP-1R/GCGR/AMYR tri-specific agonist is ZP2929. In some embodiments, the peptide GLP-1R agonist is a peptide GLP-1R/FGF21 dual agonist. In some embodiments, the peptide GLP-1R/FGF21 dual agonist comprises HEC88473, AP026, YH2572, or any combination thereof. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist suitable for oral formulation.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist suitable for oral administration. In some embodiments, the peptide-based GLP-1R agonist is suitable for oral formulation. In some embodiments, the peptide-based GLP-1R agonist is suitable for oral administration. In some embodiments, the GLP-1R agonist is orally administered to the subject. In some embodiments, the peptide-based GLP-1R agonist is orally administered to the subject. The following table lists some examples of peptide-based GLP-1R agonist structures.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises exenatide (byetta) , lixisenatide (adlyxin) , liraglutide (victoza) , dulaglutide (Trulicity) , semaglutide (ozempic) , or any combination thereof.
  • the GLP-1R agonist comprises AC-3174, liraglutide, semaglutide, or any combination thereof.
  • the GLP-1R agonist comprises liraglutide, albiglutide, exenatide (byetta) , taspoglutide, lixisenatide, dulaglutide, semaglutide, N, N-9924, TTP-054, YH-25723 (YH-25724; YH-22241) , efruxifermin (AKR-001) , or any combination thereof.
  • the GLP-1R agonist comprises ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382) , SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, semaglutide, or any combination thereof.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, an IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, an IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist is a small molecule GLP-1R agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIPR dual agonist, a small molecule GLP-1R/GCGR dual agonist, a small molecule GLP-1R/GLP-2R dual agonist, a small molecule GLP-1R/AMYR dual agonist, a small molecule GLP-1R/GCGR/GIPR tri-specific agonist, a small molecule GLP-1R/GCGR/FGF21 tri-specific agonist, a small molecule GLP-1R/GCGR/AMYR tri-specific agonist, a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combinations thereof.
  • the GLP-1R agonist is a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIP dual agonist, a small molecule GLP-1R/GCGRA, a small molecule GLP-1R/GIPR/GCGRA tri-specific agonist, a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the small molecule GLP-1R agonist comprises one or more of the small molecule GLP-1R agonists in the following publications: WO2021197464A1, WO2021259309A1, WO2022078152A1, WO2022078407A1, WO2022109182A1, WO2022111624A1, WO2022192430A1, WO2022202864A1, WO2022199458A1, WO201155841A1, WO2023011539A1, WO2019/239371, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284, WO2021/096304, WO2021/112538, WO2021/154796, WO2021/160127, WO2021/187886, WO2021/197464, CN113480534, WO2021/219019, WO2021/244645,
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, a IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, a IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist is a small molecule GLP-1R agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIPR dual agonist, a small molecule GLP-1R/GCGR dual agonist, a small molecule GLP-1R/GLP-2R dual agonist, a small molecule GLP-1R/AMYR dual agonist, a small molecule GLP-1R/GCGR/GIPR tri-specific agonist, a small molecule GLP-1R/GCGR/FGF21 tri-specific agonist, a small molecule GLP-1R/GCGR/AMYR tri-specific agonist, a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combinations thereof.
  • the GLP-1R agonist is a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIP dual agonist, a small molecule GLP-1R/GCGRA, a small molecule GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, TT-OAD2, GSBR-1290, GSBR Next Gen, ID110521156, HDM1002, HRS-7535, RGT-075, TTP273, MDR-001, K-833, VCT220, K-757, CT-996, ECC5004, XW014, SAL0112, THDBH110, HSK34890, BEBT-808, YGX1, MWN109, HPG-5119, NA-931, TERN-601, APH01727, Aleniglipron, HS-10501, GS-4571, ASC30, ZY01, Boc5, HS-10535, RT001, V-0219, CT-859, DD14, DD15, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, TT-OAD2, GSBR-1290, GSBR Next Gen, ID110521156, HDM1002, HRS-7535, RGT-075, TTP273, MDR-001, K-833, VCT220, K-757, CT-996, ECC5004, XW014, SAL0112, HSK34890, BEBT-808, HPG-5119, NA-931, TERN-601, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, GSBR-1290, GSBR Next Gen, HDM1002, HRS-7535, THDBH110, YGX1, MWN109, HPG-5119, NA-931, TERN-601, APH01727, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, THDBH110, YGX1, MWN109, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HDM1002, HRS-7535, HPG-5119, NA-931, TERN-601, APH01727, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, HDM1002, HRS-7535, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, NA-931, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, TERN-601, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR Next Gen, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR Next Gen, HPG-5119, NA-931, TERN-601, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, NA-931, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HDM1002, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HRS-7535, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist is danuglipron. In some embodiments, the small molecule GLP-1R agonist is orforglipron. In some embodiments, the small molecule GLP-1R agonist is GSBR-1290. In some embodiments, the small molecule GLP-1R agonist is HDM1002. In some embodiments, the small molecule GLP-1R agonist is HRS-7535. In some embodiments, the small molecule GLP-1R agonist is GSBR Next Gen.
  • the small molecule GLP-1R agonist is HPG-5119 In some embodiments, the small molecule GLP-1R agonist is NA-931. In some embodiments, the small molecule GLP-1R agonist is TERN-601. The following table lists some examples of small molecule GLP-1R agonist structures.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from 0.01 mg/kg to 20 mg/kg.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose of about 0.01 mg/kg, about 0.1 mg/kg, about 0.16 mg/kg, about 0.3 mg/kg, about 1.12 mg/kg, about 1.2 mg/kg, about 1.6 mg/kg, about 3.2 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg.
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from 0.01 mg/kg to 20 mg/kg. In some embodiments, the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose of about 0.01 mg/kg, about 0.1 mg/kg, about 0.16 mg/kg, about 0.3 mg/kg, about 1.12 mg/kg, about 1.2 mg/kg, about 1.6 mg/kg, about 3.2 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg.
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from 0.01 mg/kg to 20 mg/kg. In some embodiments, the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose of about about 0.01 mg/kg, 0.1 mg/kg, about 0.16 mg/kg, about 0.3 mg/kg, about 1.12 mg/kg, about 1.2 mg/kg, about 1.6 mg/kg, about 3.2 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once every 28 days to about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 1000 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once every 28 days to about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 1000 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg to about 1000 mg and dosed from about once every 28 days to about once a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 1000 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 200 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 10 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 5 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 200 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 10 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 5 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 200 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 10 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 5 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg to about 600 mg, about 0.25 mg to about 5 mg, or about 1 mg to about 20 mg.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg to about 600 mg and dosed once every 28 days, about 10 mg to about 200 mg and dosed once every 14 days, about 0.25 mg to about 5 mg and dosed once every 7 days, or about 1 mg to about 20 mg and dosed once a day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days, about 10 mg/14 days to about 200 mg/14 days, about 0.25 mg/7 days to about 5 mg/7 days, or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days, about 0.25 mg/7 days to about 5 mg/7 days, or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 10 mg/14 days to about 200 mg/14 days, about 0.25 mg/7 days to about 5 mg/7 days or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 0.25 mg/7 days to about 5 mg/7 days or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 10 mg/14 days to about 200 mg/14 days.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 0.25 mg/7 days to about 5 mg/7 days.
  • the GLP-1R agonist comprises a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/three times a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about twice or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/day.
  • the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/day. In some embodiments, the GLP-1R agonist comprises a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/day.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 7000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 6000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 5000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 7000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 6000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 5000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 4000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 3000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 50: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 3000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 2000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 50: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 4000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 3000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 2000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 50:1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 3000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 2000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 50: 1. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 5000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 4000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 3000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 500: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 4000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 3000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 500: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is about 50: 1 to 1: 100. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is about 40: 1, about 30: 1, about 20: 1, about 10: 1, about 1: 1, about 1: 10, about 1: 20, about 1: 30, about 1: 40, about 1: 50, about 1: 60, about 1: 70, about 1: 80, about 1: 90, or about 1: 100.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 2000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 1000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 500: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 500: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 10: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 2000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 1000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 500: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 1000: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 500: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 10: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 20: 1.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined molar ratio. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 2000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 200: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 2000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 1000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 100: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 2000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 600: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 200: 1. the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 2000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 200: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 600: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 50: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 50: 1.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined molar ratio. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 200: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 50: 1. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 200: 1
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 20: 1.
  • the pharmaceutical composition is formulated for provision of an immediate or burst release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the pharmaceutical composition is formulated for provision of an immediate release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the pharmaceutical composition is formulated for provision of a burst release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h.
  • the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h, or at least 24h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h.
  • the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h.
  • the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the pharmaceutical composition is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler for at least a period of time. In some embodiments, pharmaceutical composition is formulated for provision of a sustained release of the mitochondrial uncoupler for at least a period of time. In some embodiments, pharmaceutical composition is formulated for provision of a controlled release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h.
  • the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h, or at least 24h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h.
  • the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h.
  • the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the pharmaceutical composition produces a body weight-lowering effect when administered to the subject.
  • the pharmaceutical composition produces a body weight-lowering effect when administered to a subject in need thereof and the body weight-lowering effect of the pharmaceutical composition is greater than a body weight-lowering effect produced when either the mitochondrial uncoupler or the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a body weight-lowering effect when administered to a subject in need thereof and the body weight-lowering effect of the pharmaceutical composition is synergistic as compared to a body weight-lowering effect produced when either the mitochondrial uncoupler or the GLP-1R agonist is administered to the subject alone.
  • the mitochondrial uncoupler is present in an amount that is sufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, the mitochondrial uncoupler is present in an amount that is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, the GLP-1R agonist is present in an amount that is sufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, the GLP-1R agonist is present in an amount that is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone.
  • each of the mitochondrial uncoupler and the GLP-1R agonist are present in an amount that is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, each of the mitochondrial uncoupler and the GLP-1R agonist are present in an amount that is sufficient to produce a body weight-lowering effect in the subject when administered to the subject alone.
  • the pharmaceutical composition produces a reduction in fat mass in the subject when administered to the subject. In some embodiments, the pharmaceutical composition produces a lower reduction in muscle mass or lean mass than the reduction in muscle mass or lean mass produced by the GLP-1R agonist alone. In some embodiments, the pharmaceutical composition produces lower reduction in muscle mass or lean mass than the reduction in muscle mass or lean mass produced by either the mitochondrial uncoupler or the GLP-1R agonist alone.
  • the pharmaceutical composition produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone. In some embodiments, the pharmaceutical composition produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the mitochondrial uncoupler or the GLP-1R agonist is administered to the subject alone.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%or 80%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, or 35%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, or 25%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, or 20%. In some embodiments, the reduction in fat mass is at least 5%, 10%, or 15%. In some embodiments, the reduction in fat mass is at least 5%or 10%. In some embodiments, the reduction in fat mass is at least 5%. In some embodiments, the reduction in fat mass ranges from about 5%to about 80%. In some embodiments, the reduction in fat mass ranges from about 5%to about 75%. In some embodiments, the reduction in fat mass ranges from about 5%to about 70%.
  • the reduction in fat mass ranges from about 5%to about 65%. In some embodiments, the reduction in fat mass ranges from about 5%to about 60%. In some embodiments, the reduction in fat mass ranges from about 5%to about 55%. In some embodiments, the reduction in fat mass ranges from about 5%to about 50%. In some embodiments, the reduction in fat mass ranges from about 5%to about 45%. In some embodiments, the reduction in fat mass ranges from about 5%to about 40%. In some embodiments, the reduction in fat mass ranges from about 5%to about 35%. In some embodiments, the reduction in fat mass ranges from about 5%to about 30%. In some embodiments, the reduction in fat mass ranges from about 5%to about 25%.
  • the reduction in fat mass ranges from about 5%to about 20%. In some embodiments, the reduction in fat mass ranges from about 5%to about 15%. In some embodiments, the reduction in fat mass ranges from about 5%to about 10%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, 30%, or 35%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, or 30%.
  • the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, or 25%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, or 20%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, or 20%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, or 15%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%or 10%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%. In some embodiments, the reduction in muscle mass or lean mass is no more than 10%.
  • the reduction in muscle mass or lean mass is no more than 15%. In some embodiments, the reduction in muscle mass or lean mass is no more than 20%. In some embodiments, the reduction in muscle mass or lean mass is no more than 25%. In some embodiments, the reduction in muscle mass or lean mass is no more than 30%. In some embodiments, the reduction in muscle mass or lean mass is no more than 35%. In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 40%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 35%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 30%.
  • the reduction in muscle mass or lean mass ranges from about 5%to about 25%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 20%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 15%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 10%.
  • the pharmaceutical composition produces a reduction in fat mass in the subject when administered to the subject. In some embodiments, the pharmaceutical composition produces a lower reduction in muscle mass or lean mass than the reduction in muscle mass or lean mass produced by the GLP-1R agonist alone. In some embodiments, the pharmaceutical composition produces lower reduction in muscle mass or lean mass than the reduction in muscle mass or lean mass produced by either the mitochondrial uncoupler or the GLP-1R agonist alone.
  • the pharmaceutical composition produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone. In some embodiments, the pharmaceutical composition produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the mitochondrial uncoupler or the GLP-1R agonist is administered to the subject alone.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%or 80%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, or 35%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, or 25%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, or 20%. In some embodiments, the reduction in fat mass is at least 5%, 10%, or 15%. In some embodiments, the reduction in fat mass is at least 5%or 10%. In some embodiments, the reduction in fat mass is at least 5%. In some embodiments, the reduction in fat mass ranges from about 5%to about 80%. In some embodiments, the reduction in fat mass ranges from about 5%to about 75%. In some embodiments, the reduction in fat mass ranges from about 5%to about 70%.
  • the reduction in fat mass ranges from about 5%to about 65%. In some embodiments, the reduction in fat mass ranges from about 5%to about 60%. In some embodiments, the reduction in fat mass ranges from about 5%to about 55%. In some embodiments, the reduction in fat mass ranges from about 5%to about 50%. In some embodiments, the reduction in fat mass ranges from about 5%to about 45%. In some embodiments, the reduction in fat mass ranges from about 5%to about 40%. In some embodiments, the reduction in fat mass ranges from about 5%to about 35%. In some embodiments, the reduction in fat mass ranges from about 5%to about 30%. In some embodiments, the reduction in fat mass ranges from about 5%to about 25%.
  • the reduction in fat mass ranges from about 5%to about 20%. In some embodiments, the reduction in fat mass ranges from about 5%to about 15%. In some embodiments, the reduction in fat mass ranges from about 5%to about 10%.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 40%, 30%, 25%, 20%, 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%or 90%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 30%, 25%, 20%, 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 25%, 20%, 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or 70%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 20%, 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 60%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, 30%, or 40%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, 25%, or 30%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, 20%, or 25%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, 15%, or 20%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when administered to the subject and/or the reduction in muscle mass or lean mass produced by the administration of the pharmaceutical composition to the subject is 5%, 10%, or 15%lower than the reduction in muscle mass or lean mass produced when the GLP-1R agonist is administered to the subject alone.
  • the pharmaceutical composition does not result in an unacceptable toxicity or an unacceptable increase in body temperature. In some embodiments, the pharmaceutical composition does not result in a fatal toxicity or an unacceptable increase in body temperature. In some embodiments, the unacceptable toxicity is not selected from a gastrointestinal side effect. In some embodiments, the fatal toxicity is not selected from a gastrointestinal side effect. In some embodiments, the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • an unacceptable toxicity is a fatal toxicity.
  • the pharmaceutical composition does not result in an unacceptable toxicity or an unacceptable increase in body temperature when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition does not result in an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition does not result in an unacceptable increase in body temperature when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the unacceptable toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, or any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable increase in body temperature is an increase in body temperature ranging from greater than or equal to 5°C to less than or equal to 15 °C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature ranging from greater than or equal to 5°C to less than or equal to 10°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 10°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 9°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 8°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 7°C.
  • the unacceptable increase in body temperature is an increase in body temperature of greater than 6°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 5 °C. In some embodiments, the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, less than or equal to 0.5 °C or less than or equal to 0.25 °C.
  • the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, less than or equal to 0.5 °C or less than or equal to 0.25 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, or less than or equal to 0.5 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, or less than or equal to 1 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, or less than or equal to 1.5 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, or less than or equal to 2°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C or less than or equal to 4°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature of less than or equal to 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the pharmaceutical composition results in an increase in body temperature ranging from about 0.25°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature ranging from about 0.5°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature ranging from about 1°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature ranging from about 1.5°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the pharmaceutical composition results in an increase in body temperature ranging from about 2°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature ranging from about 3°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the pharmaceutical composition results in an increase in body temperature ranging from about 4°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the unit dosage form comprises from about 0.01 mg to about 1 g, about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.01 mg to about 1 g, about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.5 mg to about 100 mg or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.5 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.2 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.05 mg to about 750 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 1 g of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 500 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 750 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.1 mg to about 1 g of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 750 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 100 ⁇ g to about 500 mg, about 100 ⁇ g to about 400 mg, about 100 ⁇ g to about 300 mg, about 100 ⁇ g to about 200 mg, or about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 600 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist.
  • the unit dosage form comprises an amount of the GLP-1R agonist that is greater than or equal an emetic dose of the GLP-1R that when administered to the subject causes significant and/or severe vomiting.
  • the unit dosage form comprises from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, or about 2 mg to about 200 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, or about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, or about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg or about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 2 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist.
  • the GLP-1R agonist is present in an amount that is sufficient to produce an emetic effect in the subject when administered to the subject. In some embodiments, the GLP-1R agonist is present in an amount that is greater than or equal to the amount required to produce an emetic effect in the subject when administered to the subject. In some embodiments, the GLP-1R agonist is present in an amount that is greater than the amount required to produce an emetic effect in the subject when administered to the subject. In some embodiments, the amount is from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the amount is from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the amount is from about 100 mg to about 1000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is in the form of a unit dosage form.
  • the unit dosage form comprises an amount of the GLP-1R agonist that is greater than or equal an emetic dose of the GLP-1R that when administered to the subject causes significant and/or severe vomiting.
  • the unit dosage form comprises from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, or about 2 mg to about 200 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, or about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, or about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg or about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 2 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist.
  • the pharmaceutical composition is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler and meanwhile an immediate or burst release of the GLP-1R agonist for at least a period of time.
  • the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h.
  • the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h or at least 24h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h. In some embodiments, the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the pharmaceutical composition is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler and a sustained or controlled release of the GLP-1R agonist for at least a period of time. In some embodiments, the pharmaceutical composition is formulated for provision of a sustained or controlled release of the GLP-1R agonist for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h.
  • the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h or at least 24h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h.
  • the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h.
  • the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the mitochondrial uncoupler and the GLP-1R agonist are present as one dosage form or are respectively present as a separate dosage form in the pharmaceutical composition. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as one dosage form in the pharmaceutical composition. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as a separate dosage form in the pharmaceutical composition.
  • composition for a Composition of the Disclosure, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers.
  • the subject is a mammal. In some embodiments, the mammal is a human.
  • the pharmaceutical composition is for use in therapy.
  • the pharmaceutical composition is for use in preventing or treating a disease.
  • the disease is selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, medical complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease and
  • the disease is selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, medical complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease (AD) , and any combination thereof.
  • T1D type 1 diabetes
  • T2D type 2 diabetes
  • D diabetic neuropathy
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease and related dementias (AD/ADRD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease (AD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is selected from the group consisting of overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is NASH. In some embodiments, the disease is overweight. In some embodiments, the disease is obesity. In some embodiments, the disease is medical complications related to overweight or obesity. In some embodiments, the disease is type 2 diabetes (T2D) . In some embodiments, the disease is Alzheimer’s disease and related dementias (AD/ADRD) . In some embodiments, the disease is Alzheimer’s disease (AD) . In some embodiments, the disease is Alzheimer’s related dementias (ADRD) .
  • the present disclosure provides a method for preventing or treating a disease selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease and related dementias (AD/ADRD) , and any combination thereof in a subject
  • the disease is selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, medical complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease (AD) , and any combination thereof.
  • T1D type 1 diabetes
  • T2D type 2 diabetes
  • D diabetic neuropathy
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease and related dementias (AD/ADRD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease (AD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is selected from the group consisting of overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is NASH. In some embodiments, the disease is overweight. In some embodiments, the disease is obesity. In some embodiments, the disease is medical complications related to overweight or obesity. In some embodiments, the disease is type 2 diabetes (T2D) . In some embodiments, the disease is Alzheimer’s disease and related dementias (AD/ADRD) . In some embodiments, the disease is Alzheimer’s disease (AD) . In some embodiments, the disease is Alzheimer’s related dementias (ADRD) .
  • the present disclosure provides use of a Composition of the Disclosure in the preparation of a medicament for preventing or treating a disease selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease and related dementias (AD/
  • the disease is selected from the group consisting of insulin resistance, pre-diabetes, hyperglycemia, impaired glucose tolerance, type 1 diabetes (T1D) , type 2 diabetes (T2D) , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, overweight, obesity, medical complications related to overweight or obesity, eating disorders, adipocyte dysfunction, visceral adipose deposition, nonalcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH) , hepatic steatosis, hepatic fibrosis, liver cirrhosis, hepatocellular carcinoma, sclerosing choleangitis, lipodystrophy, dyslipidemia, hypertriglyceridemia, metabolic syndrome, hypertension, cardiovascular disease, nephropathy, neuropathy, Alzheimer’s disease (AD) , and any combination thereof.
  • T1D type 1 diabetes
  • T2D type 2 diabetes
  • D diabetic neuropathy
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease and related dementias (AD/ADRD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , Alzheimer’s disease (AD) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, type 2 diabetes (T2D) , and any combination thereof.
  • the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is selected from the group consisting of NASH, overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is selected from the group consisting of overweight, obesity, medical complications related to overweight or obesity, and any combination thereof. In some embodiments, the disease is NASH. In some embodiments, the disease is overweight. In some embodiments, the disease is obesity. In some embodiments, the disease is medical complications related to overweight or obesity. In some embodiments, the disease is type 2 diabetes (T2D) . In some embodiments, the disease is Alzheimer’s disease and related dementias (AD/ADRD) . In some embodiments, the disease is Alzheimer’s disease (AD) . In some embodiments, the disease is Alzheimer’s related dementias (ADRD) .
  • the present disclosure provides a kit comprising a Composition of the Disclosure and a package insert including instructions for use thereof in a packaging material.
  • the present disclosure provides a method for preventing an unacceptable toxicity resulted from overdosing an amount of a mitochondrial uncoupler in a subject, comprising orally administering to the subject an amount of the mitochondrial uncoupler and an amount of a GLP-1R agonist at a predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist, such that when the dose of the mitochondrial uncoupler administered to the subject exceeds a threshold, then the dose of the GLP-1R agonist administered to the subject is sufficient to trigger vomiting of the subject to prevent the unacceptable toxicity resulted from overdosing of the amount of the mitochondrial uncoupler.
  • the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject. In some embodiments, the maximum dose can be administered to the subject without causing an unacceptable toxicity. In some embodiments, the maximum dose can be administered to the subject without causing a fatal toxicity. In some embodiments, the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing a fatal toxicity in the subject.
  • the threshold is from about 10%to about 95%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 90%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 85%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 80%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 10%to about 75%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 70%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 65%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 60%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 10%to about 55%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 10%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 20%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is from about 30%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is from about 40%to about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 10%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 15%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 20%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 25%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 30%to about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 95%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 90%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 85%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 80%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 75%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 70%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 65%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 60%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 55%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 50%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 45%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 40%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 35%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 30%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 25%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 20%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 15%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject. In some embodiments, the threshold is about 10%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the threshold is about 5%below a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 100 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 20 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 4 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the maximum dose is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.1 mg/kg to about 2 mg/kg, or about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.01 mg/kg to about 1 mg/kg or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the maximum dose is about 0.1 mg/kg to about 2 mg/kg for the subject. In some embodiments, the maximum dose is about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the maximum dose is about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 200 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 100 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 20 mg/kg, or about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 20 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 4 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 20 mg/kg, about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg, about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 1 mg/kg to about 4 mg/kg, about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.1 mg/kg to about 2 mg/kg, or about 0.01 mg/kg to about 1 mg/kg, or about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the threshold is about 0.1 mg/kg to about 2 mg/kg or about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.01 mg/kg to about 1 mg/kg or about 0.001 mg/kg to about 0.1 mg/kg for the subject. In some embodiments, the threshold is about 0.1 mg/kg to about 2 mg/kg for the subject. In some embodiments, the threshold is about 0.01 mg/kg to about 1 mg/kg for the subject. In some embodiments, the threshold is about 0.001 mg/kg to about 0.1 mg/kg for the subject.
  • the unacceptable toxicity is not selected from a gastrointestinal side effect.
  • the fatal toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is a systemic toxicity.
  • the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, or 24 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, or 12 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, or 6 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, or 2 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, 45 min, or 1 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, 30 min, or 45 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, 15 min, or 30 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min, 10 min, or 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 10 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold such that the unacceptable toxicity is ameliorated.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold such that the unacceptable toxicity is prevented. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncouplerthat the subject has ingested between about 1 min to about 10 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 20 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 30 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 40 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 50 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 60 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 10 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 20 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 30 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 40 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 50 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 5 min to about 60 min, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 2 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 3 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 4 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 5 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 6 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 7 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 8 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 9 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 h to about 10 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 2 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 3 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 4 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 5 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 6 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 7 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 8 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 9 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested between about 1 min to about 10 h, after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 10 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 15 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 30 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 45 min after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 1 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 2 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 3 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 4 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 5 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 6 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 7 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 8 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 9 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 10 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 11 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 12 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 14 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold. In some embodiments, the subject will vomit up at least part of the amount of the mitochondrial uncoupler that the subject has ingested no later than 24 h after the dose of the mitochondrial uncoupler administered to the subject has exceeded the threshold.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises the mitochondrial uncouplers in the following publications: US20220117920A1, US20220175704A1, US20240066001A1, US20220055985, WO2017070576A1, WO2017201313A1, WO2018217757A1, WO2019204813A1, WO2019204816A1, WO2019204819A1, WO2019226490A1, WO2020168290A1, WO2021042080A1, WO2022173750A1, WO2022246039A1, WO2023150759A1, WO2023150767A1, WO2024054766A2, WO2024112663A1, US11136290B2, US11365177B2, US11708376B2, US11896591B2, US11945825B2, US20190359565A1, US20200317613A1, US20210186918A1, US20210253538A1, US20210253594A1, US20220017537A1, WO201608
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof.
  • the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile (OPC-163493) ; MB-X01Y03; 6- [ [4- (trifluoromethoxy) phenyl] amino] - [1, 2, 5] oxadiazolo [3, 4-b] pyrazin-5 (3H) -one (SHS4121705) ; or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • TLC-1235 2, 4-fluorophenyl) 6- [ (2
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the mitochondrial uncoupler is a DNP analog.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the isomer of DNP is 2, 6-dinitrophenol.
  • the DNP analog comprises a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the derivative of DNP is DNP-methyl ether (DNPME) .
  • the prodrug of DNP comprises 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , and 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the BAM 15 derivative comprises N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • DNPME DNP-methyl
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the mitochondrial uncoupler is DNP.
  • the mitochondrial uncoupler is 2, 6-dinitrophenol.
  • the mitochondrial uncoupler is DNP-methyl ether (DNPME) .
  • the mitochondrial uncoupler is 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) .
  • the mitochondrial uncoupler is 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) .
  • the mitochondrial uncoupler is TLC-6740.
  • the mitochondrial uncoupler is N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) .
  • the mitochondrial uncoupler is (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) .
  • the mitochondrial uncoupler causes an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler causes a fatal toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the unacceptable toxicity is not selected from a gastrointestinal side effect. In some embodiments, the fatal toxicity is not selected from a gastrointestinal side effect. In some embodiments, the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the unacceptable toxicity is a systematic toxicity. In some embodiments, the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the mitochondrial uncoupler causes an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler causes a fatal toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler, a non-protonophore mitochondrial uncoupler, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises a protonophore mitochondrial uncoupler. In some embodiments, the mitochondrial uncoupler comprises a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises both a protonophore and a non-protonophore mitochondrial uncoupler.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4DNP) , a
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; 1, 3-bis (dichlorophenyl) urea (CR4) ; ethyl (E) -5- (4-chlorophenyl) -2- (3, 5-dibromo-4-hydroxybenzylidene) -7-methyl-3-oxo-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (CZ5) ; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof; TLC-1235; (2-fluorophenyl) 6- [ (2-fluorophenyl) amino] (1, 2, 5-oxadiazolo [3, 4-e] pyrazin-5-yl) amine (BAM 15) ; a BAM 15 derivative; TLC-6740; 4- (5-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) -1H-1, 2, 3-triazole-5-carbonitrile (OPC-163493) ; MB-X01Y03; 6- [ [4- (trifluoromethoxy) phenyl] amino] - [1, 2, 5] oxadiazolo [3, 4-b] pyrazin-5 (3H) -one (SHS4121705) ; or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • TLC-1235 2, 4-fluorophenyl) 6- [ (2
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a DNP analog, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof. In some embodiments, the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the mitochondrial uncoupler is a DNP analog.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the DNP analog comprises a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof.
  • the isomer of DNP is 2, 6-dinitrophenol.
  • the DNP analog comprises a derivative of DNP, a prodrug of DNP, or any combination thereof.
  • the derivative of DNP is DNP-methyl ether (DNPME) .
  • the prodrug of DNP comprises 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , and 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the BAM 15 derivative comprises N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof.
  • DNP 2, 4-dinitrophenol
  • DNPME DNP-methyl
  • the mitochondrial uncoupler comprises 2, 4-dinitrophenol (DNP) , 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , or any combination thereof.
  • the mitochondrial uncoupler is DNP.
  • the mitochondrial uncoupler is 2, 6-dinitrophenol.
  • the mitochondrial uncoupler is DNP-methyl ether (DNPME) .
  • the mitochondrial uncoupler is 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) .
  • the mitochondrial uncoupler is 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) .
  • the mitochondrial uncoupler is TLC-6740.
  • the mitochondrial uncoupler is N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) .
  • the mitochondrial uncoupler is (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) .
  • 2, 4-dinitrophenol (DNP) , the DNP analog, or any combination thereof causes an unacceptable toxicity when the dose of 2, 4-dinitrophenol (DNP) , the DNP analog, or any combination thereof administered to the subject exceeds the threshold.
  • 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof causes an unacceptable toxicity when the dose of 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, or any combination thereof administered to the subject exceeds the threshold.
  • 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof causes an unacceptable toxicity when the dose of 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, or any combination thereof administered to the subject exceeds the threshold.
  • the DNP analog causes an unacceptable toxicity when the dose of the DNP analog administered to the subject exceeds the threshold.
  • 2, 4-dinitrophenol (DNP) 2, 6-dinitrophenol, DNP-methyl ether (DNPME) , 5- [ (2, 4-dinitrophenoxy) methyl] -1-methyl-2-nitroimidazole (HU6) , 2, 4-dinitrophenyl morpholine-4-carboxylate (MP-201) , TLC-6740, N 5 - (2-fluorophenyl) -N 6 - (3-fluorophenyl) - [1, 2, 5] oxadiazolo- [3, 4-b] pyrazine-5, 6-diamine (SHC517) , (N- [2-fluoro-4- [trifluoromethoxy] phenyl] -5-methoxy-2- [trifluoromethyl] -1H-imidazo [4, 5-b] pyrazine-6-amine) (SHD865) , or any combination thereof, causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) ,
  • 2, 4-dinitrophenol (DNP) , the DNP analog, and any combination thereof causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) , the DNP analog, and any combination thereof administered to the subject exceeds the threshold.
  • 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, and any combination thereof causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) , a salt of DNP, a solvate of DNP, an isomer of DNP, and any combination thereof administered to the subject exceeds the threshold.
  • 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, and any combination thereof causes a fatal toxicity when the dose of 2, 4-dinitrophenol (DNP) , a derivative of DNP, a prodrug of DNP, and any combination thereof administered to the subject exceeds the threshold.
  • the DNP analog causes a fatal toxicity when the dose of the DNP analog administered to the subject exceeds the threshold.
  • the unacceptable toxicity is not selected from a gastrointestinal side effect.
  • the fatal toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is a systematic toxicity.
  • the fatal toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, and any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 80 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 60 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 20 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 80 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 60 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 100 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 80 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 60 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.2 mg/kg/day and less than or equal to 30 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.5 mg/kg/day and less than or equal to 5 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 40 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 30 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 5 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.1 mg/kg/day and less than or equal to 2 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 40 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 30 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 10 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 5 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 5 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of greater than or equal to 0.01 mg/kg/day and less than or equal to 2 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 100 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 80 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 60 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 40 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 30 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 10 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 5 mg/kg/day.
  • the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 2 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 1 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 0.1 mg/kg/day. In some embodiments, the amount of the mitochondrial uncoupler is formulated for administration of the mitochondrial uncoupler at a dose of less than or equal to 0.01 mg/kg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIPR dual agonist, a peptide GLP-1R/GCGR dual agonist, a peptide GLP-1R/GLP-2R dual agonist, a peptide GLP-1R/AMYR dual agonist, a peptide GLP-1R/GCGR/GIPR tri-specific agonist, a peptide GLP-1R/GCGR/FGF21 tri-specific agonist, a peptide GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIPR dual agonist, a peptide GLP-1R/GCGR dual agonist, a peptide GLP-1R/GLP-2R dual agonist, a peptide GLP-1R/AMYR dual agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GCGR/GIPR tri-specific agonist, a peptide GLP-1R/GCGR/FGF21 tri-specific agonist, a peptide GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises a peptide GLP-1R single agonist, a peptide GLP-1R/GIP dual agonist, a peptide GLP-1R/GCGRA, a peptide GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the peptide-based GLP-1R agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, TG103, VK2735, AMG 133, BGM0504, HRS9531, CT-388, HS-20094, tirzepatide, HZ010, HZ012, DR10627,
  • the peptide-based GLP-1R agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, DR10627, P29, XW015, TE-810 5, GSBR-3rd Ge n, GSBR-2nd Gen, CY-5, Next Gen GSBR, SPN007, PP
  • the peptide-based GLP-1R agonist is a peptide GLP-1R single agonist.
  • the peptide GLP-1R single agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, DR10627, P29, XW015, TE-810 5, GSBR-3
  • the peptide GLP-1R single agonist comprises semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, albiglutide, efpegleatide, beinaglutide, ecnoglutide, efsubaglutide alfa, GZR18, PEG loxenatide, GL0034, GLP-1 (7-36) , exendin-4, noiigliutide, glutazumab, supaglutide, PB-119, HB1085, JY09, SHR-2042, E-2-HSA, SPN009, FY002, ZT002, XW004, GMA102, KN056, E4F4, HL08, aibennatai, or any combination thereof.
  • the peptide GLP-1R single agonist comprises DR10627, P29, XW015, TE-8105, GSBR-3rd Gen, GSBR-2nd Gen, CY-5, Next Gen GSBR, SPN007, PP18, DR10601, SAR441255, RAY001, HM-15211, cagriSema, QL1005, peptide 3b, DR10625, DR10619, ZT007, HR17031, or any combination thereof.
  • the peptide-based GLP-1R agonist is a peptide GLP-1R/GCGR dual agonist.
  • the peptide GLP-1R/GCGR dual agonist comprises mazdutide, survodutide, efinoprgdutide, pemvidutide, cotadutide, pegapamodutide, PB-718, AZD9550, DD01, G3215, SHR-1816, TB001, DA-1726, or any combination thereof.
  • the peptide GLP-1R/GCGR dual agonist comprises mazdutide, survodutide, efinoprgdutide, pemvidutide, cotadutide, pegapamodutide, or any combination thereof.
  • the peptide-based GLP-1R agonist is a peptide GLP-1R/GLP-2R dual agonist.
  • the peptide GLP-1R/GLP-2R dual agonist comprises dapiglutide, PG-102, or any combination thereof.
  • the peptide GLP-1R/GLP-2R dual agonist is dapiglutide.
  • the peptide GLP-1R/GCGR/GIPR tri-specific agonist comprises retatrutide, efocipegtrutide, MWN101, UBT251, ZX2021, or any combination thereof. In some embodiments, the peptide GLP-1R/GCGR/GIPR tri-specific agonist comprises retatrutide, efocipegtrutide, or any combination thereof. In some embodiments, the peptide GLP-1R agonist is a peptide GLP-1R/GCGR/FGF21 tri-specific agonist. In some embodiments, the peptide GLP-1R/GCGR/FGF21 tri-specific agonist is DR10624.
  • the peptide GLP-1R agonist is a peptide GLP-1R/GCGR/AMYR tri-specific agonist. In some embodiments, the peptide GLP-1R/GCGR/AMYR tri-specific agonist is ZP2929. In some embodiments, the peptide GLP-1R agonist is a peptide GLP-1R/FGF21 dual agonist. In some embodiments, the peptide GLP-1R/FGF21 dual agonist comprises HEC88473, AP026, YH2572, or any combination thereof. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist suitable for oral formulation.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist suitable for oral administration. In some embodiments, the peptide-based GLP-1R agonist is suitable for oral formulation. In some embodiments, the peptide-based GLP-1R agonist is suitable for oral administration. In some embodiments, the GLP-1R agonist is orally administered to the subject. In some embodiments, the peptide-based GLP-1R agonist is orally administered to the subject.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises exenatide (byetta) , lixisenatide (adlyxin) , liraglutide (victoza) dulaglutide (Trulicity) , semaglutide (ozempic) , or any combination thereof.
  • the GLP-1R agonist comprises AC-3174, liraglutide, semaglutide, or any combination thereof.
  • the GLP-1R agonist comprises liraglutide, albiglutide, exenatide (byetta) , taspoglutide, lixisenatide, dulaglutide, semaglutide, N, N-9924, TTP-054, YH-25723 (YH-25724; YH-22241) , efruxifermin (AKR-001) , or any combination thereof.
  • the GLP-1R agonist comprises ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382) , SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, semaglutide, or any combination thereof.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the GLP-1R agonist is a small molecule GLP-1R agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIPR dual agonist, a small molecule GLP-1R/GCGR dual agonist, a small molecule GLP-1R/GLP-2R dual agonist, a small molecule GLP-1R/AMYR dual agonist, a small molecule GLP-1R/GCGR/GIPR tri-specific agonist, a small molecule GLP-1R/GCGR/FGF21 tri-specific agonist, a small molecule GLP-1R/GCGR/AMYR tri-specific agonist, or any combinations thereof.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIP dual agonist, a small molecule GLP-1R/GCGRA, a small molecule GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the small molecule GLP-1R agonist comprises the small molecule GLP-1Ragonists in the following publications: WO2021197464A1, WO2021259309A1, WO2022078152A1, WO2022078407A1, WO2022109182A1, WO2022111624A1, WO2022192430A1, WO2022202864A1, WO2022199458A1, WO2023011539A1, WO2019/239371, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284, WO2021/096304, WO2021/112538, WO2021/154796, WO2021/160127, WO2021/187886, WO2021/197464, CN113480534, WO2021/219019, WO2021/244645, WO2021/249494949
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, a small molecule GLP-1R agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIPR dual agonist, a GLP-1R/GCGR dual agonist, a GLP-1R/GLP-2R dual agonist, a GLP-1R/AMYR dual agonist, a GLP-1R/GCGR/GIPR tri-specific agonist, a GLP-1R/GCGR/FGF21 tri-specific agonist, a GLP-1R/GCGR/AMYR tri-specific agonist, a IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist comprises a GLP-1R single agonist, a GLP-1R/GIP dual agonist, a GLP-1R/GCGRA, a GLP-1R/GIPR/GCGRA tri-specific agonist, , a IGF-1/GLP-1/GIP/Glucagon quadruple agonist, or any combination thereof.
  • the GLP-1R agonist is a small molecule GLP-1R agonist.
  • the small molecule GLP-1R agonist comprises a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIPR dual agonist, a small molecule GLP-1R/GCGR dual agonist, a small molecule GLP-1R/GLP-2R dual agonist, a small molecule GLP-1R/AMYR dual agonist, a small molecule GLP-1R/GCGR/GIPR tri-specific agonist, a small molecule GLP-1R/GCGR/FGF21 tri-specific agonist, a small molecule GLP-1R/GCGR/AMYR tri-specific agonist, a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist, and any combinations thereof.
  • the GLP-1R agonist is a small molecule IGF-1/GLP-1/GIP/Glucagon quadruple agonist.
  • the small molecule GLP-1R agonist is selected from a group consisting of a small molecule GLP-1R single agonist, a small molecule GLP-1R/GIP dual agonist, a small molecule GLP-1R/GCGRA, a small molecule GLP-1R/GIPR/GCGRA tri-specific agonist, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, TT-OAD2, GSBR-1290, GSBR Next Gen, ID110521156, HDM1002, HRS-7535, RGT-075, TTP273, MDR-001, K-833, VCT220, K-757, CT-996, ECC5004, XW014, SAL0112, THDBH110, HSK34890, BEBT-808, YGX1, MWN109, HPG-5119, NA-931, TERN-601, APH01727, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, TT-OAD2, GSBR-1290, GSBR Next Gen, ID110521156, HDM1002, HRS-7535, RGT-075, TTP273, MDR-001, K-833, VCT220, K-757, CT-996, ECC5004, XW014, SAL0112, HSK34890, BEBT-808, HPG-5119, NA-931, TERN-601, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, THDBH110, YGX1, MWN109, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, lotiglipron, orforglipron, GSBR-1290, GSBR Next Gen, HDM1002, HRS-7535, THDBH110, YGX1, MWN109, HPG-5119, NA-931, TERN-601, APH01727, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HDM1002, HRS-7535, HPG-5119, NA-931, TERN-601, APH01727, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, HDM1002, HRS-7535, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, NA-931, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR Next Gen, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR Next Gen, HPG-5119, NA-931, TERN-601, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, TERN-601, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, NA-931, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HPG-5119, NA-931, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, HPG-5119, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, GSBR Next Gen, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, GSBR-1290, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HDM1002, or any combination thereof.
  • the small molecule GLP-1R agonist comprises danuglipron, orforglipron, HRS-7535, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist comprises danuglipron, orforglipron, or any combination thereof. In some embodiments, the small molecule GLP-1R agonist is danuglipron. In some embodiments, the small molecule GLP-1R agonist is orforglipron. In some embodiments, the small molecule GLP-1R agonist is GSBR-1290. In some embodiments, the small molecule GLP-1R agonist is HDM1002. In some embodiments, the small molecule GLP-1R agonist is HRS-7535.
  • the small molecule GLP-1R agonist is GSBR Next Gen. In some embodiments, the small molecule GLP-1R agonist is HPG-5119 In some embodiments, the small molecule GLP-1R agonist is NA-931. In some embodiments, the small molecule GLP-1R agonist is TERN-601.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once every 28 days to about once a day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 1000 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once every 28 days to about once a day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 1000 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg to about 1000 mg.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg to about 1000 mg and dosed from about once every 28 days to about once a day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 1000 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 600 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 400 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 200 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 100 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 60 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 20 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 10 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/28 days to about 5 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 600 mg/day.
  • amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 400 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 200 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 100 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 60 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 20 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 10 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/28 days to about 5 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 600 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 400 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 200 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 100 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 60 mg/day.
  • the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 20 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 10 mg/day. In some embodiments, the amount of the GLP-1R agonist is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/28 days to about 5 mg/day. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg to about 600 mg, about 0.25 mg to about 5 mg, or about 1 mg to about 20 mg.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg to about 600 mg and dosed once every 28 days, about 10 mg to about 200 mg and dosed once every 14 days, about 0.25 mg to about 5 mg and dosed once every 7 days, or about 1 mg to about 20 mg and dosed once a day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days, about 10 mg/14 days to about 200 mg/14 days, about 0.25 mg/7 days to about 5 mg/7 days, or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days, about 0.25 mg/7 days to about 5 mg/7 days, or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 10 mg/14 days to about 200 mg/14 days, about 0.25 mg/7 days to about 5 mg/7 days or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 0.25 mg/7 days to about 5 mg/7 days or about 1 mg/day to about 20 mg/day.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days or about 1 mg/day to about 20 mg/day. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 6 mg/28 days to about 600 mg/28 days.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 10 mg/14 days to about 200 mg/14 days.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 0.25 mg/7 days to about 5 mg/7 days.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the amount of the peptide-based GLP-1R agonist is formulated for administration of the peptide-based GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about four times a day. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/four times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/four times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/four times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about three times a day. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/three times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/three times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/three times a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/three times a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/three times a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about twice or more a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day to about twice a day. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/twice a day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/twice a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 5 mg/twice a day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg to about 1000 mg and dosed about once a day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg to about 1000 mg and dosed about once a day. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.01 mg/day to about 1000 mg/day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 0.1 mg/day to about 1000 mg/day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 1 mg/day to about 1000 mg/day.
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the pharmaceutical composition is formulated for administration of the small molecule GLP-1R agonist at a dose from about 5 mg/day to about 1000 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 100 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.01 mg/day to about 5 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 100 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 0.1 mg/day to about 5 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 400 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 60 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 10 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 1 mg/day to about 5 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 600 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 400 mg/day.
  • the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 200 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 100 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 60 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 20 mg/day. In some embodiments, the pharmaceutical composition is formulated for administration of the GLP-1R agonist at a dose from about 5 mg/day to about 10 mg/day.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 7000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 6000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 5000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 4000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 7000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 6000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 5000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 7000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 6000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 5000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 4000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 3000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist is less than or equal to 50: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 3000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 2000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 50: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 4000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 3000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 2000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 50:1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 4000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 3000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 2000: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 1000: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 500: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the GLP-1R agonist is a peptide-based GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the peptide-based GLP-1R agonist ranges from about 1: 10 to about 50: 1. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 5000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 4000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 3000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 500: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 4000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 3000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 500: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 2000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 1000: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 500: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 500: 1.
  • the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the predetermined weight ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 10: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 500: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 2000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 1000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 500: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist ranges from about 1: 10 to about 100: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 2000: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 1000: 1.
  • the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 500: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of the mitochondrial uncoupler and the small molecule GLP-1R agonist is less than or equal to 10: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof, the GLP-1R agonist is a small molecule GLP-1R agonist, and the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 10 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined weight ratio of DNP, a DNP analog or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 20: 1.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined molar ratio. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 2000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 1000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 600: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 200: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 100: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 2000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 2000 to about 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 1000 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 2000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 400: 1. the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 2000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 600: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 50: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 2000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 50: 1.
  • the GLP-1R agonist is a peptide-based GLP-1R agonist.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 2000 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 1000 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist ranges from about 1: 600 to about 50: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 2000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 1000: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 200: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a peptide-based GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the peptide-based GLP-1R agonist is less than or equal to 50: 1.
  • the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined weight ratio or a predetermined molar ratio. In some embodiments, the predetermined ratio of the mitochondrial uncoupler and the GLP-1R agonist is a predetermined molar ratio. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is greater than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is less than or equal to the emetic dose of the GLP-1R agonist.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist provides (i) an amount of the mitochondrial uncoupler that is less than or equal to the maximum dose of the mitochondrial uncoupler and (ii) an amount of the GLP-1R agonist that is greater than or equal to the emetic dose of the GLP-1R agonist.
  • the maximum dose is a maximum dose of the mitochondrial uncoupler that can be administered to the subject without causing an unacceptable toxicity in the subject.
  • the maximum dose is a toxic dose.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 1000: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 400: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 100 to about 200: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist ranges from about 1: 50 to about 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 1000: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 800: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 600: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 400: 1.
  • the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 200: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 100: 1. In some embodiments, the predetermined molar ratio of the mitochondrial uncoupler and the GLP-1R agonist is less than or equal to 50: 1. In some embodiments, the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 200: 1
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 100 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 200: 1
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist ranges from about 1: 50 to about 20: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 600: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 400: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 200: 1
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 100: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 60: 1.
  • the mitochondrial uncoupler is DNP, a DNP analog, or any combination thereof
  • the GLP-1R agonist is a small molecule GLP-1R agonist
  • the predetermined molar ratio of DNP, a DNP analog, or any combination thereof and the small molecule GLP-1R agonist is less than or equal to 20: 1.
  • the amount of the mitochondrial uncoupler is formulated for provision of an immediate or burst release of the mitochondrial uncoupler. In some embodiments, the amount of the mitochondrial uncoupler is formulated for provision of an immediate or burst release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the amount of the mitochondrial uncoupler is formulated for provision of an immediate release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the amount of the mitochondrial uncoupler is formulated for provision of a burst release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h.
  • the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h, or at least 24h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h.
  • the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h. In some embodiments, the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the amount of the mitochondrial uncoupler is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler. In some embodiments, the amount of the mitochondrial uncoupler is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler for at least a period of time. In some embodiments, amount of the mitochondrial uncoupler is formulated for provision of a sustained release of the mitochondrial uncoupler for at least a period of time. In some embodiments, amount of the mitochondrial uncoupler is formulated for provision of a controlled release of the mitochondrial uncoupler for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h.
  • the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h, or at least 24h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h.
  • the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h. In some embodiments, the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the method produces a body weight-lowering effect when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject. In some embodiments, the method produces a body weight-lowering effect when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to a subject in need thereof and the body weight-lowering effect of the method is greater than a body weight-lowering effect produced when either the amount of the mitochondrial uncoupler or the amount of GLP-1R agonist is administered to the subject alone.
  • the method produces a body weight-lowering effect when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to a subject in need thereof and the body weight-lowering effect of the method is synergistic as compared to a body weight-lowering effect produced when either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is administered to the subject alone.
  • the amount of the mitochondrial uncoupler is sufficient to produce a body weight-lowering effect in the subject when administered to the subject alone.
  • the amount of the mitochondrial uncoupler is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone.
  • the amount of the GLP-1R agonist is sufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, the amount of the GLP-1R agonist is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone. In some embodiments, either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is insufficient to produce a body weight-lowering effect in the subject when administered to the subject alone.
  • the method produces a reduction in fat mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject. In some embodiments, the method produces a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is administered to the subject alone.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%or 80%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, or 35%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, or 25%.
  • the reduction in fat mass is at least 5%, 10%, 15%, or 20%. In some embodiments, the reduction in fat mass is at least 5%, 10%, or 15%. In some embodiments, the reduction in fat mass is at least 5%or 10%. In some embodiments, the reduction in fat mass is at least 5%. In some embodiments, the reduction in fat mass ranges from about 5%to about 80%. In some embodiments, the reduction in fat mass ranges from about 5%to about 75%. In some embodiments, the reduction in fat mass ranges from about 5%to about 70%. In some embodiments, the reduction in fat mass ranges from about 5%to about 65%. In some embodiments, the reduction in fat mass ranges from about 5%to about 60%.
  • the reduction in fat mass ranges from about 5%to about 55%. In some embodiments, the reduction in fat mass ranges from about 5%to about 50%. In some embodiments, the reduction in fat mass ranges from about 5%to about 45%. In some embodiments, the reduction in fat mass ranges from about 5%to about 40%. In some embodiments, the reduction in fat mass ranges from about 5%to about 35%. In some embodiments, the reduction in fat mass ranges from about 5%to about 30%. In some embodiments, the reduction in fat mass ranges from about 5%to about 25%. In some embodiments, the reduction in fat mass ranges from about 5%to about 20%. In some embodiments, the reduction in fat mass ranges from about 5%to about 15%.
  • the reduction in fat mass ranges from about 5%to about 10%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, 30%, or 35%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, or 25%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, 20%, or 25%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, or 20%.
  • the reduction in muscle mass or lean mass is no more than 5%, 10%, 15%, or 20%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%, 10%, or 15%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%or 10%. In some embodiments, the reduction in muscle mass or lean mass is no more than 5%. In some embodiments, the reduction in muscle mass or lean mass is no more than 10%. In some embodiments, the reduction in muscle mass or lean mass is no more than 15%. In some embodiments, the reduction in muscle mass or lean mass is no more than 20%. In some embodiments, the reduction in muscle mass or lean mass is no more than 25%.
  • the reduction in muscle mass or lean mass is no more than 30%. In some embodiments, the reduction in muscle mass or lean mass is no more than 35%. In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 40%. In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 35%. In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 30%. In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 25%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 20%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 15%. In some embodiments, In some embodiments, the reduction in muscle mass or lean mass ranges from about 5%to about 10%.
  • the method produces a reduction in fat mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject. In some embodiments, the method produces a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in fat mass and a reduction in muscle mass or lean mass in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject, but the reduction in muscle mass or lean mass is lower than the reduction in muscle mass or lean mass produced when either the amount of the mitochondrial uncoupler or the amount of the GLP-1R agonist is administered to the subject alone.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%or 80%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%.
  • the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, 30%, or 35%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, 25%, or 30%. In some embodiments, the reduction in fat mass is at least 5%, 10%, 15%, 20%, or 25%.
  • the reduction in fat mass is at least 5%, 10%, 15%, or 20%. In some embodiments, the reduction in fat mass is at least 5%, 10%, or 15%. In some embodiments, the reduction in fat mass is at least 5%or 10%. In some embodiments, the reduction in fat mass is at least 5%. In some embodiments, the reduction in fat mass ranges from about 5%to about 80%. In some embodiments, the reduction in fat mass ranges from about 5%to about 75%. In some embodiments, the reduction in fat mass ranges from about 5%to about 70%. In some embodiments, the reduction in fat mass ranges from about 5%to about 65%. In some embodiments, the reduction in fat mass ranges from about 5%to about 60%.
  • the reduction in fat mass ranges from about 5%to about 55%. In some embodiments, the reduction in fat mass ranges from about 5%to about 50%. In some embodiments, the reduction in fat mass ranges from about 5%to about 45%. In some embodiments, the reduction in fat mass ranges from about 5%to about 40%. In some embodiments, the reduction in fat mass ranges from about 5%to about 35%. In some embodiments, the reduction in fat mass ranges from about 5%to about 30%. In some embodiments, the reduction in fat mass ranges from about 5%to about 25%. In some embodiments, the reduction in fat mass ranges from about 5%to about 20%. In some embodiments, the reduction in fat mass ranges from about 5%to about 15%.
  • the reduction in fat mass ranges from about 5%to about 10%.
  • the method produces a reduction in muscle mass or lean mass of no more than 40%, 30%, 25%, 20%, 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%or 90%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 30%, 25%, 20%, 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 30%, 25%, 20%, 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, or 80%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 25%, 20%, 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or 70%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 20%, 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 60%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, 30%, or 40%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, 25%, or 30%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, 20%, or 25%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, 15%, or 20%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method produces a reduction in muscle mass or lean mass of no more than 15%, 10%, or 5%in the subject when the amount of the mitochondrial uncoupler and the amount of the GLP-1R agonist are administered to the subject and/or the reduction in muscle mass or lean mass produced by the method is 5%, 10%, or 15%lower than the reduction in muscle mass or lean mass produced when the amount of the GLP-1R agonist is administered to the subject alone.
  • the method does not result in an unacceptable toxicity or an unacceptable increase in body temperature. In some embodiments, the method does not result in a fatal toxicity or an unacceptable increase in body temperature. In some embodiments, for a Composition of the Disclosure, the unacceptable toxicity is not selected from a gastrointestinal side effect. In some embodiments, the fatal toxicity is not selected from a gastrointestinal side effect. In some embodiments, the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof. In some embodiments, the unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • an unacceptable toxicity is a fatal toxicity.
  • the method does not result in an unacceptable toxicity or an unacceptable increase in body temperature when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method does not result in an unacceptable toxicity when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method does not result in an unacceptable increase in body temperature when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the unacceptable toxicity is a systemic toxicity.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, or any combination thereof.
  • the systemic toxicity is not selected from a gastrointestinal side effect.
  • the gastrointestinal side effect is selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the systemic toxicity is selected from the group consisting of consistent fever, hyperthemia, tachycardia, palpitations, myocardial injury, tachypnoea, dyspnea, acidosis, agitation, confusion, delirium, cerebral edema, hepatic injury, pancreatic injury, renal failure, hemorrhage, hematopenia, multi-organ system dysfunction, multi-organ system failure, death, and any combination thereof; and is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable increase in body temperature is an increase in body temperature ranging from greater than or equal to 5°C and less than or equal to 15°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature ranging from greater than or equal to 5°C and less than or equal to 10°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 10°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 9°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 8°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 7°C.
  • the unacceptable increase in body temperature is an increase in body temperature of greater than 6°C. In some embodiments, the unacceptable increase in body temperature is an increase in body temperature of greater than 5 °C. In some embodiments, the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, less than or equal to 0.5 °C or less than or equal to 0.25 °C.
  • the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, less than or equal to 0.5 °C or less than or equal to 0.25 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, less than or equal to 1 °C, or less than or equal to 0.5 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, less than or equal to 1.5 °C, or less than or equal to 1 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, less than or equal to 2°C, or less than or equal to 1.5 °C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature of less than or equal to 5°C, less than or equal to 4°C, less than or equal to 3°C, or less than or equal to 2°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method results in an increase in body temperature of less than or equal to 5°C or less than or equal to 4°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature of less than or equal to 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 0.25°Cto about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 0.5°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the method results in an increase in body temperature ranging from about 1°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 1.5°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 2°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 3°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold. In some embodiments, the method results in an increase in body temperature ranging from about 4°C to about 5°C when the dose of the mitochondrial uncoupler administered to the subject exceeds the threshold.
  • the mitochondrial uncoupler and the GLP-1R agonist are present as a unit dosage form.
  • the unit dosage form comprises from about 0.01 mg to about 1 g, about 0.01 mg to about 750 mg, about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, or about 0.01 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.1 mg to about 1 g, about 0.1 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.1 mg to about 250 mg, about 0.1 mg to about 100 mg, or about 0.1 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.01 mg to about 1 g, about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.01 mg to about 1 g, about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.05 mg to about 750 mg, about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg, about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.2 mg to about 250 mg, about 0.5 mg to about 100 mg, or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.5 mg to about 100 mg or about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.5 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.2 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.05 mg to about 750 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 1 g of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 500 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.01 mg to about 750 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 0.1 mg to about 1 g of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 75 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 100 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 250 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 500 mg of the mitochondrial uncoupler. In some embodiments, the unit dosage form comprises from about 0.1 mg to about 750 mg of the mitochondrial uncoupler.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 100 ⁇ g to about 500 mg, about 100 ⁇ g to about 400 mg, about 100 ⁇ g to about 300 mg, about 100 ⁇ g to about 200 mg, or about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 600 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist.
  • the unit dosage form comprises an amount of the GLP-1R agonist that is greater than or equal an emetic dose of the GLP-1R that when administered to the subject causes significant and/or severe vomiting.
  • the unit dosage form comprises from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, or about 2 mg to about 200 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, or about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, or about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg or about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 2 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist.
  • the GLP-1R agonist is present in an amount that is sufficient to produce an emetic effect in the subject when administered to the subject. In some embodiments, the GLP-1R agonist is present in an amount that is greater than or equal to the amount required to produce an emetic effect in the subject when administered to the subject. In some embodiments, the GLP-1R agonist is present in an amount that is greater than the amount required to produce an emetic effect in the subject when administered to the subject. In some embodiments, the amount is from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the amount is from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the amount is from about 100 mg to about 1000 mg of the GLP-1R agonist. In some embodiments, the amount is from about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the amount is in the form of a unit dosage form.
  • the unit dosage form comprises an amount of the GLP-1R agonist that is greater than or equal an emetic dose of the GLP-1R that when administered to the subject causes significant and/or severe vomiting.
  • the unit dosage form comprises from about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, or about 100 mg to about 1000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 1 mg to about 300 mg, about 2 mg to about 200 mg, about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 100 mg, about 100 mg to about 1000 mg, or about 1000 mg to 2000 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, about 2 mg to about 200 mg, or about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, about 1 mg to about 300 mg, or about 2 mg to about 200 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, about 500 ⁇ g to about 400 mg, or about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg, about 200 ⁇ g to about 500 mg, or about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg or about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 200 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 500 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 1 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 2 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 100 ⁇ g to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 100 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 100 ⁇ g to about 600 mg of the GLP-1R agonist.
  • the unit dosage form comprises from about 5 mg to about 500 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 400 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 300 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 200 mg of the GLP-1R agonist. In some embodiments, the unit dosage form comprises from about 5 mg to about 100 mg of the GLP-1R agonist.
  • the mitochondrial uncoupler and the GLP-1R agonist are formulated for provision of a sustained or controlled release of the mitochondrial uncoupler and meanwhile an immediate or burst release of the GLP-1R agonist for at least a period of time.
  • the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h. In some embodiments, the period of time ranges from about 0.5h to about 8h.
  • the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h or at least 24h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h.
  • the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h.
  • the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the pharmaceutical composition is formulated for provision of a sustained or controlled release of the mitochondrial uncoupler and a sustained or controlled release of the GLP-1R agonist for at least a period of time. In some embodiments, the pharmaceutical composition is formulated for provision of a sustained or controlled release of the GLP-1R agonist for at least a period of time. In some embodiments, the period of time ranges from about 0.5h to about 24h. In some embodiments, the period of time ranges from about 0.5h to about 20h. In some embodiments, the period of time ranges from about 0.5h to about 16h. In some embodiments, the period of time ranges from about 0.5h to about 12h.
  • the period of time ranges from about 0.5h to about 8h. In some embodiments, the period of time ranges from about 0.5h to about 6h. In some embodiments, the period of time ranges from about 0.5h to about 4h. In some embodiments, the period of time ranges from about 0.5h to about 2h. In some embodiments, the period of time ranges from about 0.5h to about 1h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, at least 20h or at least 24h.
  • the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, at least 16h, or at least 20h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, at least 12h, or at least 16h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, at least 4h, at least 6h, at least 8h, or at least 12h.
  • the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, at least 6h, or at least 8h. In some embodiments, the period of time is at least 0.5 h, at least 1h, at least 2h, at least 4h, or at least 6h. In some embodiments, the period of time is at least 0.5h, at least 1h, at least 2h, or at least 4h. In some embodiments, the period of time is at least 0.5h, at least 1h, or at least 2h. In some embodiments, the period of time is at least 0.5 h or at least 1h. In some embodiments, the period of time is about 24h. In some embodiments, the period of time is about 20h.
  • the period of time is about 16h. In some embodiments, the period of time is about 12h. In some embodiments, the period of time is about 8h. In some embodiments, the period of time is about 6h. In some embodiments, the period of time is about 4h. In some embodiments, the period of time is about 2h. In some embodiments, the period of time is about 1h. In some embodiments, the period of time is about 0.5h.
  • the mitochondrial uncoupler and the GLP-1R agonist are present as one dosage form or are respectively present as a separate dosage form. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as one dosage form. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as the same dosage form. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as a separate dosage form. In some embodiments, the mitochondrial uncoupler and the GLP-1R agonist are present as a different dosage form.
  • the subject is a mammal. In some embodiments, the mammal is a human. Definitions
  • mitochondrial uncoupler and “mitochondrial protonophore” are used interchangeably, and refer to an agent which dissociates the reactions of ATP synthesis from the electron transport chain.
  • an unacceptable toxicity is, within the scope of sound medical judgment, an unwanted side effect of an agent (e.g., mitochondrial uncoupler) that is not commensurate with a reasonable benefit/risk ratio as to the administration of the agent and is characterized by excessive toxicity, irritation, allergic response, or other problem or complication.
  • an unacceptable toxicity is not a gastrointestinal side effect .
  • an unacceptable toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • the unacceptable toxicity is a fatal toxicity.
  • the fatal toxicity is not a gastrointestinal side effect. In some embodiments, the fatal toxicity is not a gastrointestinal side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, anorexia, vomiting, and any combination thereof.
  • GLP-1R agonist refers to an agent which agonizes glucagon-like peptide-1 receptor in vitro and/or in vivo.
  • the term “consistent fever” means that a fever lasts for at least 3 days. In some embodiments, the term “consistent fever” means that a fever lasts for at least 2 days.
  • the term “subject” refers to a human as well as a non-human mammal (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like) .
  • the subject is a human (e.g., male child, female child, male adolescent, female adolescent, male adult, female adult) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • the term “asubject in need thereof” refers to a subject that suffers from, or is at risk for, a pathology to be preventively or therapeutically treated with a mitochondrial uncoupler, a GLP-1R agonist, a combination thereof or a pharmaceutical composition as described in the present disclosure.
  • administer As used in the specification and the appended claims, the terms “administer” , “administered” , “administers” and “administering” are defined as providing a mitochondrial uncoupler, a GLP-1R agonist, a combination thereof or a pharmaceutical composition as described in the present disclosure to a subject in need thereof via a suitable route known in the art. In some embodiments, an oral route of administration is used.
  • the term “prevent” , “prevention” or “preventing” as related to a disease or condition may refer to a mitochondrial uncoupler, a GLP-1R agonist, a combination thereof or a pharmaceutical composition as described in the present disclosure that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treat refers to an approach for obtaining beneficial or desired results (i.e., therapeutic benefits) with respect to a disease or condition.
  • treat, treatment or treating involves administering a mitochondrial uncoupler, a GLP-1R agonist, a combination thereof or a pharmaceutical composition as described in the present disclosure to a subject.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease, disorder, or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a subject.
  • a therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. In some embodiments, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and other animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, excipient, or vehicle which is used for the preparation of the pharmaceutical compositions or medicaments in accordance with the present disclosure.
  • Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical compositions or medicaments and not injurious to the subject.
  • the term “medicament” refers to a substance that can affect the physiological functions and cell metabolic activities of a subject's body organs, thereby producing beneficial biological effects on the subject (including prevention, treatment or diagnosis of diseases) .
  • “medicament” may refer only to an active pharmaceutical ingredient (drug substance) , but also encompasses a pharmaceutical composition (including a dosage form thereof) .
  • the term “pharmaceutical composition” refers to a substance suitable for administration to a subject for a specific medical purpose.
  • dosage form refers to a specific form of a pharmaceutical composition formulated according to certain dosage requirements that can be used by individuals directly in order to meet the needs of preventing, treating or diagnosing diseases.
  • unit dosage form refers to a physically discrete unit suitable for use in a subject in need thereof and is individually packaged as known in the art.
  • Each unit dosage form contains a predetermined amount of active pharmaceutical ingredient sufficient to produce the desired prophylactic and/or therapeutic effect, optionally together with one or more pharmaceutically acceptable carriers.
  • unit dosage forms include, but are not limited to, individually packaged tablets or capsules.
  • the term “dose” refers to a single quantity of a substance administered to a subject in need thereof to achieve a desired effect therein.
  • the dose is expressed in milligrams (mg) .
  • the dose is expressed in milligrams (mg) per day/7 days/14 days/28 days.
  • the dose is expressed in milligrams (mg) per kilogram (kg) of body weight of the subject.
  • the dose is expressed in milligrams (mg) per kilogram (kg) of body weight of the subject per day/7 days/14 days/28 days.
  • the dose may vary depending upon factors such as stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent are well within the skill of a person skilled in the relevant art.
  • each pharmaceutical agent When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • the optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions When trade names are used herein, applicants intend to independently include the trade name product formulation, the generic drug, and the active pharmaceutical ingredient (s) of the trade name product.
  • Pharmaceutical Compositions are used herein, applicants intend to independently include the trade name product formulation, the generic drug, and the active pharmaceutical ingredient (s) of the trade name product.
  • compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins, 1999) .
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the carriers can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self-micro emulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop.
  • the compound may also be formulated for inhalation. In certain embodiments, a compound may be simply
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • Pharmaceutical acceptable carriers are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)) .
  • Exemplary pharmaceutically acceptable carriers include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent (s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • At least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained or controlled release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the amount of pharmaceutical agent contained within a sustained or controlled release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses are provided.
  • Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • the following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
  • Ferrets, dogs, and house musk shrews are commonly used in preclinical pharmaceutical studies to investigate emesis as they all possess a functional emetic reflex.
  • the ferret is considered the gold standard for the pharmacological evaluation of emetic or anti-emetic drugs due to the high sensitivity of its vomiting reflex (S. Goineau, V. Castagne, Comparison of three preclinical models for nausea and vomiting assessment, J Pharmacol Toxicol Methods, 82 (2016) 45-53) .
  • the tree shrew (Tupaia belangeri) , another small mammal closely related to primates and house musk shrews, as a promising alternative.
  • the tree shrew is increasingly recognized as a valuable model for human diseases. Since it also exhibits a vomiting reflex, allowing for direct observation of vomiting. Therefore, it was selected as one of our experimental animal models.
  • dogs are notably sensitive to the gag reflex induced by various drugs, making them suitable for vomiting experiments.
  • Example 1 Induced Emesis Model - Danuglipron
  • FIG. 1 shows that latency to the first vomiting induced by danuglipron in the three animal species.
  • the results of vomiting incidence are summarized in Table 1 and FIG. 2. These results demonstrated that danuglipron successfully induced vomiting in all three of the animal models with the latency to the first vomiting being less than 3 hours. Furthermore, the incidence of vomiting is dose-dependent, with higher doses resulting in an increased rate of emesis.
  • the corresponding human equivalent dose can be estimated based on body surface area (BSA) , with conversion factors derived from FDA guidelines and relevant literature (FDA, Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U. S. Food and Drug Administration, July 2005; Xia W, Huang ZJ, Feng YW, Tang AZ, Liu L. Body surface area-based equivalent dose calculation in tree shrew. Science progress. 2021 May; 104 (2) : 00368504211016935. ) .
  • the calculation results of danuglipron are summarized in the table below.
  • BSA body surface area
  • danuglipron (denotated as “Literature” in Table 1) showed that subjects had a very high probability of vomiting after taking a single dose of 120 mg. Specifically, at a dose of 120 mg administered twice daily (BID) , the incidence of vomiting reached 77.8%. The average baseline body weight of the subjects was 101.6 kg, corresponding to a dose of approximately 2.4 mg/kg. Therefore, the extrapolated dose of danuglipron required to achieve a 100%incidence of vomiting is estimated to be 4.8 mg/kg. (A.R. Saxena, D.N. Gorman, R.M. Esquejo, A. Bergman, K. Chidsey, C. Buckeridge, D.A. Griffith, A.M.
  • the vomitus was photographed, collected and analyzed, revealing that it contained the majority of the dosed GLP-1R agonist.
  • Physiological monitoring indicated no significant rise in body temperature, and both breathing and heart rate remained normal.
  • the animals exhibited decreased activity, poor mental state, reduced appetite, and temporary weight loss. By the second day, these conditions had returned to normal.
  • mice Thirty C57BL/6 mice (15 males, 15 females, each with an age of about 6-8 weeks) were used for the experiment. The mice were divided into three groups, with 10 mice in each group.
  • the mitochondrial uncoupler was dissolved in sterile water to a predetermined concentration and adjusted to pH 7.
  • the vehicle or mitochondrial uncoupler was orally administered. Rectal temperature was measured at 0h, 0.5h, 1h, and 3h after administration, and physiological states, including respiration, heart rate, and activity, were continuously observed and recorded until end of experiment.
  • the lethal dose of the uncoupler cannot be directly determined in humans, it must be estimated based on the median lethal dose (LD 50 ) or the total lethal dose (LD 100 ) observed in animal models.
  • the corresponding human equivalent dose can be estimated based on body surface area (BSA) , with conversion factors derived from FDA guidelines (FDA, Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U. S. Food and Drug Administration, July 2005) . The calculated results are summarized below.
  • ferrets Twenty-four ferrets (12 males and 12 females, each weighing about 1-1.5kg, each with an age of about 4-6 months) were used to evaluate the protective effect of combining mitochondrial uncouplers with GLP-1R agonists against mitochondrial uncouplers overdose. The ferrets were divided into four groups with six in each group. The experiment was conducted in a crossover design, with at least seven days between each administration
  • the vomitus was photographed, collected and analyzed, revealing that it contained the majority of the administered mitochondrial uncouplers.
  • the ferrets vomited 2-20 times until their stomachs were empty.
  • Physiological status monitoring indicated no significant rise in body temperature, and both breathing and heart rate remained normal.
  • No symptoms associated with systemic side effects of mitochondrial uncouplers were observed.
  • the ferrets exhibited decreased activity, poor mental state, drowsiness, reduced appetite, and temporary weight loss. By the second day, these conditions had returned to normal.
  • Fifty adult tree shrews (25 males and 25 females, each weighing about 120-140g) were used to evaluate the protective effect of combining mitochondrial uncouplers with GLP-1R agonist against mitochondrial uncouplers overdose.
  • the tree shrews were housed individually in plastic cages under a 12-hour: 12-hour light/dark cycle in a temperature-and humidity-controlled environment. They were fed ad libitum with standard food and had ad libitum access to tap water.
  • the tree shrews were divided into five groups with ten in each group.
  • the experiment was conducted in a crossover design, with at least seven days between each administration.
  • the combinations of mitochondrial uncoupler and GLP-1R agonist were dissolved in solvent, and the types, dosage and ratios of the combination shown in Table 6 and Table 7. No fasting was required.
  • the vehicle or combination solution was administered orally once. After administration, the emesis events were observed and recorded for 3 hours, and the physiological states were continuously monitored until the end of the experiment.
  • Example 5.1 Parameters Recorded and Evaluated
  • the vomitus was photographed, collected and analyzed, revealing that it contained the majority of the administered mitochondrial uncouplers.
  • Physiological status monitoring indicated no significant rise in body temperature, and both breathing and heart rate remained normal.
  • No symptoms associated with systemic side effects of mitochondrial uncouplers were observed.
  • the tree shrews exhibited decreased activity, poor mental state, reduced appetite, salivation and temporary weight loss. By the second day, these conditions had returned to normal.
  • the vomitus was photographed, collected and analyzed, revealing that it contained the majority of the administered mitochondrial uncouplers.
  • the beagle dogs vomited 1-20 times until their stomachs were empty.
  • Physiological status monitoring showed no significant rise in body temperature, and both breathing and heart rate remained normal.
  • No symptoms associated with systemic side effects of mitochondrial uncouplers were observed.
  • the beagle dogs exhibited decreased activity, poor mental state, reduced appetite and temporary weight loss. By the second day, these conditions had returned to normal.
  • Table 8 Experimental Conditions and Results for Combination of Mitochondrial Uncouplers with GLP-1R Agonists - Beagle Dog Model
  • Table 9 Experimental Conditions and Results for Combination of Mitochondrial Uncouplers with GLP-1R Agonists - Beagle Dog Model
  • Example 7 Effects of the Combination of Mitochondrial Uncouplers with GLP-1R Agonists on Body Weight and Body Composition (Fat and Lean mass) - DIO Mice Model
  • mice were fed a 60%high-fat diet for 12 weeks. When the average weight of the mice reached 50 g, the experiment began, and the high-fat diet was maintained throughout the experiments.
  • the mice were divided into four treatment groups: vehicle (60%HFD) , mitochondrial uncoupler, GLP-1R agonist, and a combination of mitochondrial uncoupler and GLP-1R agonist, with 8 mice in each group.
  • the mitochondrial uncoupler and GLP-1R agonist were dissolved in solvent, and the treatment was administered via gavage once a day until the end of the experiment.
  • the types and dosage of the compounds are shown in Table 10. Body weight was monitored daily, and body composition was assessed by Body Composition Analyzer at days 0, and 14.
  • mice expressing humanized GLP-1R were fed a 60%high-fat diet for 12 weeks to establish diet-induced obesity (DIO) model. When the average weight of the mice reached 50 g, the experiment began. The high-fat diet was maintained throughout the experiments. Mice were divided into four treatment groups: vehicle (60%HFD) , mitochondrial uncoupler, small molecule GLP-1R agonist, and a combination of mitochondrial uncoupler with small molecule GLP-1R agonist, with 8 mice in each group. The mitochondrial uncoupler and small molecule GLP-1R agonist were dissolved in solvent, treatment was administered via gavage once a day until the end of the experiment (14 days) . The types and dosage of the compounds are shown in Table 11. Body weight was monitored daily, and body composition was assessed by Body Composition Analyzer at days 0, and 14.

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Abstract

L'invention concerne des compositions contre le surdosage et leurs utilisations. Plus particulièrement, l'invention concerne des compositions pharmaceutiques contre le surdosage comprenant un découpleur mitochondrial et un agoniste du GLP-1R et leurs utilisations, ainsi que des procédés de prévention de surdosage du découpleur. De telles compositions pharmaceutiques peuvent être utiles pour traiter des maladies, telles que, entre autres, la SHNA, le surpoids, l'obésité, les complications médicales associées au surpoids ou à l'obésité, le diabète de type 2 (T2D), ainsi que la maladie d'Alzheimer et les démences associées.
PCT/CN2025/113562 2024-08-09 2025-08-08 Compositions contre le surdosage et leurs utilisations Pending WO2026032421A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125781A2 (fr) * 2005-05-23 2006-11-30 Novo Nordisk A/S Nouveaux anilides salicyliques substitues par haloalcoxy
WO2012068274A1 (fr) * 2010-11-16 2012-05-24 University Of Medicine And Dentistry Of New Jersey Traitement du diabète de type ii et de maladies associées au diabète par le biais de découplants mitochondriaux chimiques sûrs
WO2020257283A1 (fr) * 2019-06-18 2020-12-24 Mitopower Llc Composés nicotinyl riboside et leurs utilisations
WO2025196507A1 (fr) * 2024-03-18 2025-09-25 Mitotech S.A. Traitement et prévention de l'obésité à l'aide d'une combinaison de découpleurs mitochondriaux et d'agonistes du récepteur du peptide-1 de type glucagon

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125781A2 (fr) * 2005-05-23 2006-11-30 Novo Nordisk A/S Nouveaux anilides salicyliques substitues par haloalcoxy
WO2012068274A1 (fr) * 2010-11-16 2012-05-24 University Of Medicine And Dentistry Of New Jersey Traitement du diabète de type ii et de maladies associées au diabète par le biais de découplants mitochondriaux chimiques sûrs
WO2020257283A1 (fr) * 2019-06-18 2020-12-24 Mitopower Llc Composés nicotinyl riboside et leurs utilisations
WO2025196507A1 (fr) * 2024-03-18 2025-09-25 Mitotech S.A. Traitement et prévention de l'obésité à l'aide d'une combinaison de découpleurs mitochondriaux et d'agonistes du récepteur du peptide-1 de type glucagon

Non-Patent Citations (1)

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Title
CHEN SING-YOUNG, TELFSER AIDEN J., OLZOMER ELLEN M., VANCUYLENBERG CALUM S., ZHOU MINGYAN, BERETTA MARTINA, LI CATHERINE, ALEXOPOU: "Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice", CLINICAL SCIENCE., BIOCHEMICAL SOCIETY AND THE MEDICAL RESEARCH SOCIETY, LONDON,, GB, vol. 138, no. 4, 21 February 2024 (2024-02-21), GB , pages 173 - 187, XP093397556, ISSN: 0143-5221, DOI: 10.1042/cs20231016 *

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