WO2014137090A1

WO2014137090A1 - Formulation for prevention or treatment of diabetes

Info

Publication number: WO2014137090A1
Application number: PCT/KR2014/001455
Authority: WO
Inventors: Eun Ji Kim; Hye Jung Park; Sang Jun Youn; Hyo Ju PARK; Min Ju Hong; Hyo Ju Pyo; Yun Ah Jung; Hyun Wook Park; Yun Jung Kim; Geun Seog Song; Byoung Seok Moon; Kwi Man Kang
Original assignee: CJ Healthcare Corp
Current assignee: HK Inno N Corp
Priority date: 2013-03-06
Filing date: 2014-02-24
Publication date: 2014-09-12
Anticipated expiration: 2015-09-06
Also published as: KR101336499B1; BR112015018934A2; TW201434463A; PH12014500736A1; CN104027328A; JP2016509065A; EP2964211A4; EP2964211A1; HK1212587A1

Abstract

The present invention relates to a formulation of voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof which is provided for the reduction, in a substantially equivalent or increased amount compared to single administration of metformin, of HbAlc levels, fasting and postprandial blood glucose levels and postprandial blood glucose variation, or glycemic variability and also the reduction of the frequency of hypoglycemia, cardiovascular complications, and gastrointestinal complications in a patient with no prior experience of anti-diabetes medication or a patient in the early stage of type 2 diabetes showing a HbAlc (%) level of 7 to 11%, and ultimately, is able to effectively treat diabetes in patients in the early stage of type 2 diabetes and to minimize adverse effects, side-effects, and risk of complications.

Description

FORMULATION FOR PREVENTION OR TREATMENT OF DIABETES

The present invention relates to a pharmaceutical composition for a combination therapy comprising a therapeutically effective amount of voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof for preventing or treating the diabetes in a patient with type 2 diabetes which provides substantially equivalent or increased efficacy and substantially reduced side-effects compared to the administration of metformin alone,

wherein the administration of the said composition reduces glycosylated hemoglobin (HbAlc) levels, fasting and postprandial blood glucose levels and glycemic variability in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, in a substantially equivalent or increased amount, compared to the administration of metformin alone for first line therapy in treating diabetes,

wherein the administration of the said composition reduces the frequency of hypoglycemia, cardiovascular complications and gastrointestinal complications in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, compared to the administration of metformin alone,

wherein voglibose or a pharmaceutically acceptable salt thereof is present in an amount of 0.2 mg to 0.3 mg and metformin or pharmaceutically acceptable salt thereof is present in an amount of 250 mg to 1000 mg,

wherein the said pharmaceutical composition for a combination therapy is formulated as a single dosage form together with at least one pharmaceutically acceptable carrier,

wherein the said pharmaceutical composition is administered to a patient once to five times daily, at least the minimum amount required to regulate the blood glucose level.

Non-insulin-dependent diabetes, called Type 2 diabetes, is one of the most common metabolic disorders and its worldwide prevalence is estimated to be 5%. The total number of people with diabetes is expected to double within the next 10 years. The pathogenesis of type 2 diabetes is characterized by impaired insulin secretion and insulin resistance. Insulin resistance may cause over-secretion of insulin from the pancreatic beta cells, leading to hyperinsulinemia. Hyperinsulinemia exists before diagnosis of diabetes and functions as an independent risk factor for various other diseases. This can eventually lead to impaired beta-cell functions which cause a lack of insulin, resulting in diabetes characterized by impaired glucose tolerance after eating and impaired fasting glycemia. The long-term effects of diabetes cause various chronic complications including microvascular complications such as retinopathy, neuropathy, or renopathy, or macrovascular complications such as cardiovascular, cerebrovascular or peripheral vascular complications. These chronic complications reduce quality of life in diabetic patients and greatly increase risk of death. Therefore, management of type 2 diabetes is necessary to prevent chronic complications, that is, to retard the occurrence and progression of the chronic complications.

Diabetic patients having the risk of chronic complications associated with diabetes must attend strict diabetes management programs to keep their glycosylated hemoglobin (HbA1c) level at a normal level or as close to normal as possible until satisfactory metabolic control is achieved. The results of the Diabetes Control and Complication Trial and United Kingdom Prospective Diabetes Study (UKPDS) show that intensive blood glucose control reduces the risk of chronic complications associated with diabetes. In clinical practice, however, many patients with type 2 diabetes fail to maintain their blood glucose levels to be below the target range recommended by American Diabetes Association. In addition, the analysis results of UKPDS show that failure of single therapy of oral hypoglycemic agents increases over time. Thus, it is necessary to conduct combination therapy with other drugs for more effective blood glucose control.

Selection of appropriate drug combinations may differ depending on a subject’s conditions, but a combination of drugs with different mechanisms of action is preferred to bring about their synergistic effect. In this respect, combination of an alpha-glucosidase inhibitor and a biguanide-based drug is ideal in terms of simultaneously controlling two pathological mechanisms of type 2 diabetes: the elevation of blood sugar after eating and insulin resistance. However, although administration of the formulation of two or more active ingredients shows effective pharmacological action, there is a problem in that the active ingredients may exacerbate side-effects, cause adverse events, and increase the risk of complications compared to single administration.

The present inventors have made many efforts to develop a formulation for improved therapeutic treatment. As a result, they found that a composition for a combination therapy of voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof can be provided for the reduction, in a substantially equivalent or increased amount compared to single administration of metformin, of HbAlc levels, fasting and postprandial blood glucose levels and glycemic variability and also for the reduction of the frequency of hypoglycemia, cardiovascular complications, and gastrointestinal complications in a patient with no prior experience of anti-diabetes medication or in a patient in the early stage of type 2 diabetes showing the HbAlc(%) level of 7 to 11% and ultimately, the formulation is provided for treating diabetes in patients in the early stage of type 2 diabetes and reducing or minimizing adverse events, side-effects, and the risk of complications, thereby completing the present invention.

An object of the present invention is to provide a composition for a combination therapy comprising voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof which is provided for the reduction, in substantially equivalent or increased amount compared to single administration of metformin, of HbAlc levels, fasting and postprandial blood glucose levels and glycemic variability and also the reduction of the frequency of hypoglycemia, cardiovascular complications, and gastrointestinal complications in a patient with no prior experience of anti-diabetes medication or a patient in the early stage of type 2 diabetes showing the HbAlc (%) level of 7 to 11% and ultimately, is able to effectively treat diabetes in patients in the early stage of type 2 diabetes and to minimize adverse events, side-effects, and the risk of complications.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diabetes which comprises i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof and minimizes hypoglycemia, gastrointestinal complications and cardiovascular complications.

Still another object of the present invention is to provide a pharmaceutical composition for the prevention or improvement of cardiovascular complications, comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a formulation for a combination therapy for the prevention or treatment of diabetes in a patient with type 2 diabetes, which comprises i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof and minimizes hypoglycemia, gastrointestinal complications and cardiovascular complications, in which the patient with type 2 diabetes has the glycosylated hemoglobin (HbAlc) of 7 to 11% and the patient has the glycosylated hemoglobin of 6 to 7% at 24 weeks after administration of the formulation.

Still another object of the present invention is to provide a formulation for a combination therapy comprising (i) voglibose of 0.2 mg, and (ii) metformin hydrochloride of 250 mg for the improvement of one or more gastrointestinal complications selected from the group consisting of diarrhea, nausea, upper abdominal pain, periodontitis, flatulence and abdominal distension of diabetic patients.

A composition for a combination therapy comprising voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof according to the present invention is provided for the reduction, in a substantially equivalent or increased amount compared to single administration of metformin, of HbAlc levels, fasting and postprandial blood glucose levels and glycemic variability and also the reduction of the frequency of hypoglycemia, cardiovascular complications, and gastrointestinal complications in a patient with no prior experience of anti-diabetes medication or a patient in the early stage of type 2 diabetes showing the HbAlc (%) level of 7 to 11%, and ultimately, is able to effectively treat diabetes in patients in the early stage of type 2 diabetes and to minimize adverse events, side-effects, and risk of complications.

FIG. 1 is a graph showing changes from baseline in HbA1c levels after 24 weeks according to one Experimental Example of the present invention;

FIG. 2 is a graph showing changes from baseline in FPG (mg/dL) levels after 4 weeks, 8 weeks, 12 weeks, 18 weeks, and 24 weeks according to one Experimental Example of the present invention;

FIG. 3 is a graph showing glycemic variability from baseline using self-monitored blood glucose levels after 8 weeks, 18 weeks, and 24 weeks according to one Experimental Example of the present invention; and

FIG. 4 is a graph showing the number of the subjects whose blood glucose levels were controlled in the target range according to one Experimental Example of the present invention.

The present invention provides a pharmaceutical composition for a combination therapy comprising a therapeutically effective amount of voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof for preventing or treating the diabetes in a patient with type 2 diabetes which provides substantially equivalent or increased efficacy and substantially reduced side-effects compared to the administration of metformin alone, wherein the administration of the said composition reduces glycosylated hemoglobin (HbAlc) levels, fasting and postprandial blood glucose levels and glycemic variability in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, in a substantially equivalent or increased amount, compared to the administration of metfrmin alone for first line therapy in treating diabetes, wherein the administration of the said composition reduces the frequency of hypoglycemia, cardiovascular complications and gastrointestinal complications in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, compared to the administration of metformin alone, wherein voglibose or a pharmaceutically acceptable salt thereof is present in an amount of 0.2 mg to 0.3 mg and metformin or pharmaceutically acceptable salt thereof is present in an amount of 250 mg to 1000 mg, wherein the said pharmaceutical composition for a combination therapy is formulated as a single dosage form together with at least one pharmaceutically acceptable carrier, wherein the said pharmaceutical composition is administered to a patient once to five times daily, at least the minimum amount required to regulate the blood glucose level.

Preferably, the glycosylated hemoglobin (HbAlc) level of the patient in the early stage of type 2 diabetes is 7 to 11%, and the fasting and postprandial glycosylated hemoglobin levels of the patient are 6 to 7% at 24 weeks after administration of the formulation, and M-value as the index of glycemic variability is 8.20±1.01.

The composition according to the present invention may be used for a combination therapy, and the composition may comprise a therapeutically effective amount of voglibose or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof, in combination.

As used herein, the term 'voglibose' means a compound having the structure of the following Chemical Formula 1 as a therapeutic agent used for improving postprandial hyperglycemia of diabetes.

[Chemical Formula 1]

The voglibose may be isolated from a natural source, or prepared by obtaining it from the natural source and then chemically modifying it, or chemically synthesized by a synthetic method known in the art. Alternatively, a commercially available product may be purchased and used.

Preferably, the voglibose or a pharmaceutically acceptable salt thereof is comprised in the composition of the present invention in an amount of 0.2 mg to 0.3 mg.

As used herein, the term 'metformin' means a compound having the structure of the following Chemical Formula 2 as a compound used for prevention or treatment of non-insulin dependent diabetes.

[Chemical Formula 2]

The metformin may be separated from a natural source, or prepared by obtaining it from the natural source and then chemically modifying it, or chemically synthesized by a synthetic method known in the art. Alternatively, a commercially available product may be purchased and used.

Preferably, the metformin or a pharmaceutically acceptable salt thereof may be preferably comprised in the composition of the present invention in an amount of 250 mg to 1000 mg, and more preferably, in an amount of 250 mg or 500 mg.

As used herein, the term 'pharmaceutically acceptable salt' is a substance that does not impair biological activities and physical properties of the active ingredient to be administered, and comprise acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid or the like, organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid or the like, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like. For example, the pharmaceutically acceptable carboxylic acid salts comprise metal salts or alkali earth metal salts formed by lithium, sodium, potassium, calcium, magnesium or the like, amino acid salts of lysine, arginine, guanidine or the like, organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine or the like.

Preferably, the metformin may be metformin hydrochloride.

As used herein, the term 'substantially equivalent or increased efficacy' means that HbAlc levels, fasting and postprandial blood glucose levels and glycemic variability are reduced, compared to individual treatment of active ingredients which are those comprised in the composition of the preset invention, for example, single administration of metformin, when a patient with no prior experience of anti-diabetes medication or a patient in the early stage of type 2 diabetes is treated.

Specifically, substantially equivalent or increased efficacy compared to single administration of metformin means that the HbAlc levels are reduced to 6 to 7%, the fasting blood glucose levels are reduced to 115 to 120 mg/dL, the postprandial blood glucose levels (blood glucose level after 2 hours) are reduced to 165 to 170 mg/dL, the average blood glucose levels by self-monitoring of blood glucose are reduced to 130 to 135 mg/dL, and glycemic variability (M-value) is reduced to 8.20±1.01 at 24 weeks after administration of the composition of the present invention.

The composition according to the present invention is characterized in that hypoglycemia and gastrointestinal complications are substantially reduced.

The sentence 'hypoglycemia and gastrointestinal complications are substantially reduced' means that frequency of hypoglycemia and gastrointestinal complications such as diarrhea, nausea, vomit, dyspepsia, constipation, periodontitis, flatulence, abdominal pain or abdominal distension caused by the use of anti-diabetic drugs is reduced, compared to patients administered with each of the active ingredients comprised in the composition of the present invention in isolation, for example, single administration of metformin. The terms of 'complication' and 'side effect' are interchangeable with each other in the present invention.

Hypoglycemia refers to a pathologic state produced by a lower blood glucose level than normal. Most frequently, it can be caused by oral hypoglycemic agents or insulin used in the treatment of diabetes. Excessive doses of oral hypoglycemic agents or insulin, or administration at inappropriate times may cause blood sugar imbalance, leading to hypoglycemia.

Combination therapy of anti-diabetic drugs can trigger a drastic drop of blood glucose due to a synergistic effect, compared to single therapy. Thus, frequency of hypoglycemia generally increases.

In this respect, because voglibose and metformin as active ingredients of the present invention have different mechanisms of action, it is expected that the risk of the hypoglycemia side effect is further increased due to blood glucose lowering effects thereof upon administration of the formulation.

Unexpectedly, the composition of the present invention has an effect of reducing the frequency of hypoglycemia side effect, compared to single administration of metformin.

In one specific Experimental Example, a formulation comprising voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, and glycemic variability and frequency of side effects were examined for 24 weeks as an efficacy and safety test. From the result, it was confirmed that the formulation of the present invention showed a lower M-value by 4.20 (glycemic variability index) than single administration of metformin, and thus the blood glucose levels could be maintained with a small deviation. Also, the frequency of side effects was further reduced. Accordingly, it can be seen that the composition of the present invention is able to effectively regulate the blood glucose levels of diabetes patients, and therefore, side effects such as hypoglycemia due to failure of blood sugar regulation can be minimized.

Meanwhile, voglibose is an alpha-glucosidase inhibitor. Alpha-glucosidase is an enzyme present in the brush border of the small intestine, and functions to break down the ingested carbohydrate into monosaccharide that can be easily absorbed by the intestine. Therefore, the alpha-glucosidase inhibitor voglibose inhibits degradation of polysaccharides in the small intestine to delay digestion and absorption of complex carbohydrates, thereby inhibiting postprandial hyperglycemia and reducing hyperinsulinemia. Normally, complex carbohydrates are mostly digested in the upper small intestine and do not reach the lower small intestine. Generally, less alpha-glucosidase activity is present in the ileum. When carbohydrate digestion in the upper small intestine is inhibited or blocked in the initial use of alpha-glucosidase inhibitor, undigested complex carbohydrates enter into the large intestine, which causes gastrointestinal complications such as abdominal distension by intestinal air, diarrhea or the like.

Meanwhile, metformin is a hypoglycemic agent that reduces hyperglycemia to the normal blood glucose level but does not reduce the blood glucose level in non-diabetic persons. Its blood glucose-lowering mechanism has not been completely revealed yet, but some studies reported that metformin increases insulin receptor activation to improve insulin receptor-tyrosine kinase activity and to stimulate glucose transport into adipocytes and skeletal muscles. The most common side effect of metformin administration is a digestive disorder, and is observed in approximately 30% of metformin-administrated patients. General side effects of metformin are loss of appetite, nausea, abdominal discomfort, diarrhea or the like.

As such, both voglibose, an alpha-glucosidase inhibitor, and metformin, cause gastrointestinal complications as major side effects. Thus, it can be expected that combination administration of these two drugs may cause more severe gastrointestinal complications. The previous studies also reported that combination administration of alpha-glucosidase inhibitor and metformin remarkably increased gastrointestinal complications (α-glycosidase inhibitors and their use in clinical practice, Arch Med Sci 2012; 8, 5:899-906).

Surprisingly, the present inventors found that the formulation of voglibose and metformin of the present invention reduces frequency of gastrointestinal complications, compared to single administration of metformin, in contrast with the above studies.

In one specific Experimental Example, a formulation of voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, respectively, and then frequency of gastrointestinal complications was examined for 24 weeks as the safety test. From the result, it was confirmed that dyspepsia, diarrhea and vomit were observed as the major gastrointestinal complications of the formulation of the present invention and metformin, and the formulation of the present invention showed significantly low frequency of gastrointestinal complications, compared to metformin.

Further, the formulation for a combination therapy comprising voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof according to the present invention is characterized in that it minimizes cardiovascular complications.

In a long-term study, UKPDS (United Kingdom Prospective Diabetes Study), which was conducted on patients with type 2 diabetes in the United Kingdom for 20 years from 1976 to 1997, the patients were divided into a group treated with the conventional therapy and an intensive treatment group treated with strict blood glucose control. In the result, the intensive treatment group showed a 25% reduction in microvascular complications, and the calculation of the relative risk of complication occurrence showed significant reductions in vascular diseases; 16%, 21%, and 24% reductions in cardiac infarction, worsening of retinopathy, and cataract surgery, respectively.

Diabetes means a state in which the insulin action and the blood glucose levels are not properly controlled, and is characterized by high glycemic variability, compared to non-diabetic patients. Therefore, in typical methods of diabetes management, control of blood glucose greatly affects acute and chronic complications of diabetes. In particular, the diabetic complications caused by failure of blood glucose control damage small and large blood vessels in the body, resulting in impairment of blood circulation of the retina, kidney, arms and legs and various other diseases. Any abnormalities in the large blood vessels may cause heart attack, angina, myocardial infarction, heart failure, diabetic dementia or the like, and any abnormalities in the small blood vessels may cause impairments in the retina, kidney, nerve or the like, leading to disease such as chronic renal failure, retinopathy, loss of eyesight or the like.

The glycemic variability is quantification of the amplitude of glycemic excursion, and MAGE (Mean Amplitude of Glycemic Excursion) refers to differences between the highest and lowest levels of blood glucose for one day.

The composition of the present invention effectively reduces the amplitude of glycemic excursion so as to minimize cardiovascular complications which may occur as a diabetic complication or side effect.

Preferably, when the composition of the present invention is administered to a patient in the early stage of type 2 diabetes having HbAlc (%) level of 7 to 11%, the patient may have the HbAlc (%) level of 6 to 7% and the M-value (glycemic variability index) of 8.20±1.01 after 24 weeks.

In one specific Experimental Example, as the efficacy test, a formulation comprising voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, and the HbAlc (%) level and M-value as a glycemic variability index were examined for 24 weeks.

In the result after 24 weeks, the group treated with the formulation of the present invention showed the HbAlc levels of -1.62±0.07%, compared to the baseline, and the group treated with the single formulation of metformin showed the HbAlc levels of -1.31±0.07%, compared to the baseline.

Meanwhile, the M-value was calculated from the following Equation.

M-value = Σ{[10^*log(blood glucose/100]3}/n+{Max(blood glucose)-Min(blood glucose)}/20

24 weeks after administration of the composition of the present invention, the average blood glucose level was 133.08±2.32 mg/dL, which was approximately -9.48 mg/dL reduction, compared to 142.56±2.35 mg/dL of the single administration of metformin. The M-value after administration of the formulation of the present invention was 8.20±1.01, which is approximately -4.20 reduction, compared to 12.40±1.03 of the single administration of metformin. Accordingly, it was confirmed that the formulation according to the present invention effectively controls the blood glucose without a significant variability so as to minimize side-effects of cardiovascular diseases.

Furthermore, one's highest blood glucose levels, that is, blood glucose levels within 2 hours of eating, are a more important risk factor of cardiovascular complications than the amplitude of glycemic excursion.

The patients in the early stage of type 2 diabetes and with appropriate blood glucose control and the patients with gestational diabetes show more prominent elevation of postprandial blood glucose than fasting blood glucose. In general, abrupt elevation of postprandial blood glucose increases reactive oxygen species, oxidized low density lipoprotein (LDL), nitrotyrosine or the like, but defense mechanisms against them become weak. Thus, oxidative stress remarkably increases. In turn, functionality of blood endothelial cells is reduced. Consequently, deterioration of blood endothelial cell function occurs and the risk of cardiovascular complications increases. Recently, many studies have reported that postprandial hyperglycemia is strongly associated with the incidence of cardiovascular diseases and mortality attributed thereto and microvascular complications.

The composition of the present invention is able to effectively inhibit elevation of postprandial blood glucose (PPG, post plasma glucose).

In one specific Experimental Example, as the efficacy test, a formulation comprising voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, respectively, and 2-hour postprandial blood glucose level was examined for 24 weeks. From the result, it was confirmed that the formulation of the present invention significantly inhibited blood glucose elevation, compared to single administration of metformin.

Further, the composition for a combination therapy comprising voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof according to the present invention provides an effect of reducing the substantially equivalent or increased body weight and an effect of increasing body weight substantially reduced, compared to single administration of metformin.

Obesity is a major cause of diabetes, because the adipose tissue in obese people is insulin resistant, resulting in uncontrolled blood glucose. For this reason, patients with obesity are the highest percentage of patients with diabetes. In US, it was reported that 60% or more of diabetic patients, that is, 6 out of 10, are obese. In Korea, 40%~50% of diabetic patients are also obese.

Diabetic patients have rapid weight loss in the early stages, but gradually gain weight with blood glucose control. In particular, most anti-diabetic agents including insulin increase body weight. The exact cause has not been revealed but insulin regulation is suggested as one of the causes. Specifically, if anti-diabetic agents do not provide insulin at the exact time of insulin-deficiency, insulin can be abused, and therefore, excessive insulin stimulates lipogenesis and inhibits lipolysis, resulting in obesity.

Meanwhile, body weight control is also important in patients who are already diabetic, because body weight control of diabetic patients prevents diabetes complications. In particular, vascular complications can be prevented. Thus, it is important to control the body weight of the patients in the early stage of diabetes.

As described above, obesity and diabetes are closely associated in a vicious circle. Clinically, losing as little as 5~10% of body weight improves the blood glucose level of obese patients with diabetes and also reduces accompanying diseases. In general, a 5~10% weight loss is a practical weight loss goal of diabetic patients. However, if the diabetic patients are treated with drugs or insulin, 5~10% weight loss is difficult to achieve because of weight gain due to the above described effect of insulin regulation.

Therefore, anti-diabetic agents to prevent weight gain as well as to control blood glucose, and furthermore to reduce body weight, can be key therapeutic agents capable of breaking the vicious circle of diabetes and obesity.

The composition of the present invention has the effects of effectively suppressing body weight gain and furthermore reducing body weight.

In one specific Experimental Example, a formulation comprising voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, respectively and changes in body weight were examined for 24 weeks. As a result, after 24 weeks, the formulation of the present invention showed the body weight loss of -1.63±2.25 kg, and the single formulation of metformin showed the body weight loss of -0.86±2.52 kg, compared to the baseline, indicating the formulation of the present invention is effective for body weight loss.

The composition of the present invention can be used for the patients in the early stage of type 2 diabetes whose blood glucose is not sufficiently controlled by diet and exercise, and in particular, it can be used in anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes.

Preferably, the patients in the early stage of type 2 diabetes may have HbAlc(%) levels of 7 to 11%.

Further, the composition of the present invention is characterized in that it is able to minimize the risk of gastrointestinal complications and cardiovascular complications, and its overall adverse reactions related to drug treatment are less than the conventional anti-diabetic agents.

In one specific Experimental Example, as a safety test, a formulation comprising voglibose (0.2 mg) and metformin (250 mg or 500 mg) and a control group metformin (500 mg) were administered, and the frequency of adverse events, adverse drug reactions, and serious adverse events were examined for 24 weeks. From the result, it was confirmed that the formulation of the present invention significantly reduced the frequency, compared to single administration of metformin.

Preferably, the composition of the present invention may comprise voglibose or a pharmaceutically acceptable salt thereof in an amount of 0.2 to 0.3 mg and metformin or a pharmaceutically acceptable salt thereof in an amount of 250 to 1000 mg, and more preferably, voglibose or a pharmaceutically acceptable salt thereof in an amount of 0.2 mg and metformin or a pharmaceutically acceptable salt thereof in an amount of 250 mg or 500 mg.

Further, the formulation of the present invention may be formulated by further using typical additives such as a pharmaceutically acceptable diluent, binder, disintegrating agent, lubricant, pH adjuster, anti-foaming agent, solubility enhancer or the like within the range of not deteriorating the effects of the present invention.

Further, the composition of the present invention may be prepared into various formulations, for example, tablets such as uncoated tablet, film-coated tablet, single layer tablet, double layer tablet, multi-layer tablet, or core tablets, powder, granules, capsules or the like.

Preferably, the composition may be formulated into a single dosage form, together with at least one pharmaceutically acceptable carrier.

Preferably, the composition may be administered once to five times a day, and more preferably, three times a day between meals on an empty stomach up to the minimum effective daily dosage needed for proper blood glucose regulation.

The composition of the present invention thus prepared can be effectively used for the prevention and treatment of diabetes or diabetes complications as a hypoglycemic agent for minimizing hypoglycemia, gastrointestinal complications and cardiovascular complications in the patients in the early stage of type 2 diabetes.

Further, the present invention provides a pharmaceutical composition comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof for the prevention or treatment of diabetes, in which hypoglycemia, gastrointestinal complications and cardiovascular complications are minimized.

The voglibose, metformin, pharmaceutically acceptable salts thereof, hypoglycemia, gastrointestinal complications, and cardiovascular complications are the same as described above.

Preferably, the pharmaceutical composition has an effect of reducing body weight or suppressing body weight gain. The effect of reducing body weight or suppressing body weight gain is the same as described above.

Further, the present invention provides a pharmaceutical composition comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof for the prevention or improvement of cardiovascular complications.

The voglibose, metformin, and pharmaceutically acceptable salt are the same as described above.

Preferably, the cardiovascular complications refer to those caused by type 2 diabetes, and specifically, refer to complications caused by blood vessel damages in the body and impairment of blood circulation due to failure in blood glucose control. For example, the cardiovascular complications may be diseases such as heart attack, angina, myocardial infarction, heart failure, diabetic dementia, chronic renal failure, retinopathy, loss of eyesight or the like.

Further, the present invention provides a formulation comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof for the prevention or treatment of diabetes in a patient with type 2 diabetes, which is characterized in that hypoglycemia, gastrointestinal complications and cardiovascular complications are minimized, and in which the glycosylated hemoglobin (HbAlc) level of the patient with type 2 diabetes is 7 to 11%, the glycosylated hemoglobin level of the patient is 6 to 7% at 24 weeks after administration of the formulation.

The voglibose, metformin, pharmaceutically acceptable salt, hypoglycemia, gastrointestinal complications, cardiovascular complications are the same as described above.

Preferably, the glycemic variability index M-value of the patient at 24 weeks after administration of the formulation is 8.20±1.01. The glycemic variability index M-value is the same as described above.

Further, the present invention provides a formulation comprising (i) voglibose of 0.2 mg and (ii) metformin hydrochloride of 250 mg for the improvement of one or more gastrointestinal complications selected from the group consisting of diarrhea, nausea, upper abdominal pain, periodontitis, flatulence, and abdominal distension of diabetic patients.

The voglibose, metformin, and gastrointestinal complications are the same as described above.

Preferably, the formulation can further improve cardiovascular complications. The cardiovascular complications are the same as described above.

Preferably, the formulation can further improve hypoglycemia side effect. The hypoglycemia side effect is the same as described above.

Further, the present invention provides a method for alleviating hypoglycemia, gastrointestinal complications and cardiovascular complications, comprising the step of administering the composition or the formulation to a subject in need thereof.

The composition or the formulation, hypoglycemia, gastrointestinal complications and cardiovascular complications are the same as described above.

Further, the present invention provides a method for preventing or treating diabetes, comprising the step of administering the composition or the formulation to a subject in need thereof, in which hypoglycemia, gastrointestinal complications and cardiovascular complications are minimized.

The composition or the formulation, hypoglycemia, gastrointestinal complications, cardiovascular complications, and diabetes are the same as described above.

Further, the present invention provides the use for the alleviation or improvement of hypoglycemia, gastrointestinal complications and cardiovascular complications in the preparation of the composition or the formulation for a combination therapy comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof.

Further, the present invention provides the use for the prevention or treatment of diabetes for minimizing hypoglycemia, gastrointestinal complications and cardiovascular complications in the preparation of the composition or the combined comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

Example 1: Preparation of combined pharmaceutical formulation (1)

300 g of metformin hydrochloride and 36 g of hydroxypropylcellulose were uniformly mixed, and then passed through a 20 mesh sieve. The resultant was placed in a fluid-bed granulator, and preheated at 60°C for 10 minutes. 6 g of hydroxypropylcellulose was dissolved in 120 ㎖ of water to prepare a binding solution. The binding solution thus prepared was sprayed at a rate of 7 ㎖ per minute to prepare primary granules, which were passed through the 20 mesh sieve. 0.18 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 ㎖ of water with stirring, and then this solution was sprayed onto the above prepared granules to prepare secondary granules. The secondary granules were passed through the 20 mesh sieve, and completed by drying.

Example 2: Preparation of formulation of metformin and voglibose (2)

300 g of metformin hydrochloride and 36 g of hydroxypropylcellulose were uniformly mixed, and then passed through a 20 mesh sieve. The resultant was placed in a fluid-bed granulator, and preheated at 60°C for 10 minutes. 6 g of hydroxypropylcellulose was dissolved in 120 ㎖ of water to prepare a binding solution. The binding solution thus prepared was sprayed at a rate of 7 ㎖ per minute to prepare primary granules, which were passed through the 20 mesh sieve. 0.12 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 ㎖ of water with stirring, and then this solution was sprayed onto the above prepared granules to prepare secondary granules. The secondary granules were passed through the 20 mesh sieve, and completed by drying.

Example 3: Preparation of formulation of metformin and voglibose (3)

300 g of metformin hydrochloride and 36 g of hydroxypropylcellulose were uniformly mixed, and then passed through a 20 mesh sieve. The resultant was placed in a fluid-bed granulator, and preheated at 60°C for 10 minutes. 6 g of hydroxypropylcellulose was dissolved in 120 ㎖ of water to prepare a binding solution. The binding solution thus prepared was sprayed at a rate of 7 ㎖ per minute to prepare primary granules, which were passed through the 20 mesh sieve. 0.36 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 ㎖ of water with stirring, and then this solution was sprayed onto the above prepared granules to prepare secondary granules. The secondary granules were passed through the 20 mesh sieve, and completed by drying.

Example 4: Preparation of formulation of metformin and voglibose (4)

300 g of metformin hydrochloride and 36 g of hydroxypropylcellulose were uniformly mixed, and then passed through a 20 mesh sieve. The resultant was placed in a fluid-bed granulator, and preheated at 60°C for 10 minutes. 6 g of hydroxypropylcellulose was dissolved in 120 ㎖ of water to prepare a binding solution. The binding solution thus prepared was sprayed at a rate of 7 ㎖ per minute to prepare primary granules, which were passed through the 20 mesh sieve. 0.24 g of voglibose and 6 g of hydroxypropylcellulose were dissolved in 120 ㎖ of water with stirring, and then this solution was sprayed onto the above prepared granules to prepare secondary granules. The secondary granules were passed through the 20 mesh sieve, and completed by drying.

Example 5: Preparation of formulation of metformin and voglibose (5)

The granules prepared in Example 1 were mixed with 3 g of magnesium stearate as a lubricant for a proper time, and then 585.3±30 mg thereof was press-molded to prepare oval tablets. Each tablet contained 500 mg of metformin hydrochloride and 0.3 mg of voglibose in average.

Example 6: Preparation of formulation of metformin and voglibose (6)

The granules prepared in Example 2 were mixed with 3 g of magnesium stearate as a lubricant for a proper time, and then 585.3±30 mg thereof was press-molded to prepare oval tablets. Each tablet contained 500 mg of metformin hydrochloride and 0.2 mg of voglibose in average.

Example 7: Preparation of formulation of metformin and voglibose (7)

The granules prepared in Example 3 were mixed with 3 g of magnesium stearate as a lubricant for a proper time, and then 292.8±15 mg thereof was press-molded to prepare oval tablets. Each tablet contained 250 mg of metformin hydrochloride and 0.3 mg of voglibose in average.

Example 8: Preparation of formulation of metformin and voglibose (8)

The granules prepared in Example 1 were mixed with 3 g of magnesium stearate as a lubricant for a proper time, and then 292.8±15 mg thereof was press-molded to prepare oval tablets. Each tablet contained 250 mg of metformin hydrochloride and 0.2 mg of voglibose in average.

Experimental Example: Phase 3 clinical trial

<Test method>

CJ-30001 containing 0.2 mg of voglibose/500 mg of metformin hydrochloride and CJ-30002 containing 0.2 mg of voglibose/250 mg of metformin hydrochloride prepared in the same manner as in Example 6 or 8 were orally administered for 24 weeks to patients with type 2 diabetes whose blood glucose levels were not properly controlled, in order to evaluate whether their blood glucose-lowering effects were superior to those of metformin administration alone.

1. Selection of subjects

This clinical trial was subjected to patients with type 2 diabetes who signed a voluntary consent form before test involvement, and satisfied the selection criteria and were not disqualified by the exclusion criteria. The selection criteria and the exclusion criteria are as follows.

[Selection criteria]

1) Patients with type 2 diabetes whose blood glucose levels were not adequately controlled.

2) Adult males and females aged 20 to 70 who voluntarily agreed to participate in this clinical trial.

[Exclusion criteria]

1) Patients with type 1 diabetes

2) Patients with HbA1c of less than 7% and more than 11% and FPG of more than 270 mg/dL

3) Patients under insulin treatment

2. Administration, dosage and period

CJ-30001 (formulation of 0.2 mg of voglibose and 500 mg of metformin hydrochloride) and CJ-30002 (formulation of 0.2 mg of voglibose and 250 mg of metformin hydrochloride) were used as test drugs. CJ-30002 was orally administered at an initial dose three times a day before meals. If the insufficient blood glucose-controlling effect was observed, the dose was increased with administration of CJ-30001 three times a day.

Commercially available Glucophage^® tablet (500 mg of metformin hydrochloride) was orally administered as a control drug at an initial dose of 1000 mg three times a day before meals. If the insufficient blood glucose-controlling effect was observed, the dose was increased to 1500 mg three times a day.

The total administration period was 24 weeks (168 days).

3. Efficacy evaluation

[Primary efficacy variable]

Changes in HbA1c from baseline to 24 weeks: with respect to the difference in the HbA1c-lowering effect between CJ-30001/CJ-30002 administration and metformin administration, changes in HbA1c 24 weeks after administration of test drug and control drug were analyzed using ANCOVA with baseline measure as covariate.

[Secondary efficacy variable]

1) Changes in FPG from baseline to 4 weeks, 8 weeks, 12 weeks, 18 weeks, and 24 weeks: the difference between administration groups was analyzed using the GLM procedure with FPG as the response variable.

2) The number of the subjects whose HbA1c after 24 weeks was controlled to below 6.5% and to below 7%, respectively, the number of the subjects whose FPG after 24 weeks was controlled to be less than 126 mg/dL, and the number of the subjects whose 2h PPG after 24 weeks was controlled to be less than 200 mg/dL: the numbers were compared using Chi-square test or Fisher's exact test.

3) Glycemic variability from baseline using self-monitored blood glucose after 8 weeks, 18 weeks, and 24 weeks: changes in glucose and M-value at 24 weeks after administration of test drug and control drug were analyzed using ANCOVA with baseline as covariate.

4. Safety evaluation

Adverse events and adverse drug reactions were summarized to present frequency and 95% confidence interval. Further, the differences before and after administration between the two administration groups were compared and analyzed by unpaired t-test or Wilcoxon's rank sum test.

<Test result>

1. Result of primary efficacy evaluation

The result of change in HbA1c from baseline to 24 weeks is shown in FIG. 1.

As shown in FIG. 1, changes from baseline in HbA1c after 24 weeks for 172 subjects (LS Mean±SE) were -1.62±0.07% in CJ-30001/CJ-30002 group and -1.31±0.07% in metformin group. The difference in the changes between two groups was 0.31±0.10%, and CJ-30001/CJ-30002 group showed significantly higher change, compared to metformin group.

Therefore, it was demonstrated that CJ-30001/CJ-30002 showed superior HbA1c-lowering effect at 24 weeks after oral administration compared to metformin.

2. Result of secondary efficacy evaluation

The results onthe number of the subjects whose were controlled with respect to FPG (mg/dL), glycemic variability and target blood glucose levels are shown in FIGs. 2 to 4.

FIG. 2 shows changes in FPG (mg/dL) from baseline to 4 weeks, 8 weeks, 12 weeks, 18 weeks, and 24 weeks. As shown in FIG. 2, CJ-30001/CJ-30002 group showed significantly larger FPG reduction, compared to metformin group.

FIG. 3 shows changes in glycemic variability using self-monitored blood glucose levels from baseline to 8 weeks, 18 weeks, and 24 weeks. As shown in FIG. 3, there was a significant difference in glycemic variability between CJ-30001/CJ-30002 and metformin groups.

Further, FIG. 4 demonstrates the number of subjects whose blood glucose levels were controlled within the target range. As shown in FIG. 4, there were significant differences in the numbers of subjects whose HbA1c, FPG or 2h-PPG levels were controlled to below the target level(HbA1c less than 6.5% or 7%, FPG less than 126 mg/dL, and 2h-PPG less than 200 mg/dL) in CJ-30001/CJ-30002 group after 24 weeks, compared to metformin group. Additionally, CJ-30001/CJ-30002 group had a larger number of the subjects whose blood glucose levels reached the target range.

3. Result of safety evaluation

The number of adverse events, adverse drug reactions, serious adverse events, gastrointestinal adverse events, adverse events in the low dose-treated group, and the change in body weight are shown in Tables 1 to 4.

Table 1

Adverse events, adverse drug reactions and serious adverse events

	CJ-30001/CJ-30002N=94			MetforminN=92
	n	(%)	[Frequency]	n	(%)	[Frequency]
Adverse events	62	(65.96)	[154]	58	(63.04)	[189]
Adverse drug reactions	27	(28.72)	[42]	24	(26.09)	[63]
Serious adverse events	2	(2.13)	[2]	5	(5.43)	[7]
Serious adversedrug reactions	0	(0.00)	[0]	0	(0.00)	[0]

Table 2

Gastrointestinal adverse events

Preferred Term	CJ-30001/CJ-30002N=94			MetforminN=92
	n	(%)	Frequency	n	(%)	Frequency
Dyspepsia	18	(19.15)	[25]	8	(8.70)	[13]
Diarrhea	14	(14.89)	[17]	19	(20.65)	[37]
Nausea	9	(9.57)	[9]	7	(7.61)	[14]
Constipation	5	(5.32)	[5]	3	(3.26)	[4]
Upper abdominal pain	3	(3.19)	[3]	5	(5.43)	[6]
Reflux oesophagitis	1	(1.06)	[1]	0	(0.00)	[0]
Periodontitis	1	(1.06)	[1]	2	(2.17)	[2]
Haemorrhagic erosive gastritis	1	(1.06)	[1]	0	(0.00)	[0]
Gingivitis	1	(1.06)	[1]	1	(1.09)	[1]
Flatulence	1	(1.06)	[1]	0	(0.00)	[0]

Table 3

Adverse events in low dose-treated group

	CJ-30002N=94				Metformin 1000mgN=92
	N	n	(%)	Frequency	N	n	(%)	Frequency
4-week	94	26	(27.66)	[39]	92	34	(36.96)	[69]
8-week	31	14	(45.16)	[27]	27	10	(37.04)	[23]
12-week	22	10	(45.45)	[23]	19	9	(47.37)	[19]
18-week	19	9	(47.37)	[22]	17	9	(52.94)	[23]
24-week	18	12	(66.67)	[37]	16	10	(62.50)	[31]

^†Number of patients treated at each week

^‡Number of patients with AEs while receiving treatment with CJ-30002

Table 4

Change in body weight

Weight(kg)	CJ-30001/CJ-30002N=88	MetforminN=84	LS Mean Difference(95% CI)	p-value
Baseline Mean	66.71	67.82
24-week Mean/ LS Mean	65.08	67.87
24-week Mean/ LS Mean	65.62	66.38
Difference of LS Mean	-1.63	-0.86	-0.76(-1.48 to -0.04)	0.0387

^†between-group difference

^‡ANCOVA adjusted baseline

As shown in Tables 1 to 2, the frequencies of adverse events in the CJ-30001/CJ-30002 group and metformin group were 154 and 189 cases, respectively, with no statistically significant difference between the two groups. Most of the mild adverse events that occurred in both groups were gastrointestinal adverse events. The most frequent drug related gastrointestinal adverse events were dyspepsia (25 cases) in CJ-30001/CJ-30002 group and diarrhea (37 cases) in metformin group.

As shown in Table 3, when the frequencies of the adverse events in the low dose-treated groups were compared, the number of adverse events that occurred at 4 weeks after drug administration was remarkably low in CJ-30002 (39 cases) compared to metformin group (69 cases).

Further as shown in FIG. 4, changes in body weight from baseline to 24 weeks were -1.63±2.25 kg in CJ-30001/CJ-30002 group and -0.86±2.52 kg in metformin group, with statistically significant difference between the two groups.

Claims

A pharmaceutical composition for a combination therapy comprising a therapeutically effective amount of voglibose or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof for preventing or treating the diabetes in a patient with type 2 diabetes which provides substantially equivalent or increased efficacy and substantially reduced side-effects compared to the administration of metformin alone,

wherein the administration of the said composition reduces glycosylated hemoglobin (HbAlc) levels, fasting and postprandial blood glucose levels and glycemic variability in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, in a substantially equivalent or increased amount, compared to the administration of metformin alone for first line therapy in treating diabetes,

wherein the administration of the said composition reduces the frequency of hypoglycemia, cardiovascular complications and gastrointestinal complications in an anti-diabetes drug naive patient or in a patient with early stage of type 2 diabetes, compared to the administration of metformin alone,

wherein voglibose or a pharmaceutically acceptable salt thereof is present in an amount of 0.2 mg to 0.3 mg and metformin or pharmaceutically acceptable salt thereof is present in an amount of 250 mg to 1000 mg,

wherein the said pharmaceutical composition for a combination therapy is formulated as a single dosage form together with at least one pharmaceutically acceptable carrier,

wherein the said pharmaceutical composition is administered to a patient once to five times daily, at least the minimum amount required to regulate the blood glucose level.
A pharmaceutical composition for the prevention or treatment of diabetes comprising i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof, wherein hypoglycemia, gastrointestinal complications and cardiovascular complications are reduced compared to the administration of metformin alone.
The pharmaceutical composition according to claim 2, wherein the content of voglibose or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.2 mg to 0.3 mg, and the content of metformin or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 250 mg to 1000 mg.
The pharmaceutical composition according to claim 2, wherein the cardiovascular complications are caused by type 2 diabetes.
The composition according to claim 1 or 2, wherein the gastrointestinal complications are any one or more of diarrhea, dyspepsia, nausea, constipation, periodontitis, flatulence, upper abdominal pain and abdominal distension.
The composition according to any one of claims 1, 2, and 4, wherein the cardiovascular complications are any one or more of angina, heart failure, myocardial infarction and retinopathy.
A formulation for a combination therapy for the prevention or treatment of diabetes in a patient with type 2 diabetes, which comprises i) voglibose or a pharmaceutically acceptable salt thereof and ii) metformin or a pharmaceutically acceptable salt thereof and reduces hypoglycemia, gastrointestinal complications and cardiovascular complications compared to the administration of metformin alone, wherein the patient with type 2 diabetes has a glycosylated hemoglobin (HbAlc) of 7 to 11% and the patient has a glycosylated hemoglobin of 6 to 7% 24 weeks after administration of the said formulation.
A formulation for a combination therapy for the improvement of one or more gastrointestinal complications selected from the group consisting of diarrhea, nausea, upper abdominal pain, periodontitis, flatulence and abdominal distension of diabetic patients, comprising (i) voglibose of 0.2 mg, and (ii) metformin hydrochloride of 250 mg.
The formulation according to claim 8, wherein the formulation further improves cardiovascular complications.
The formulation according to claim 8, wherein the formulation further improves hypoglycemia side effects.
The formulation according to claim 7, wherein the gastrointestinal complications are any one or more of diarrhea, dyspepsia, nausea, constipation, periodontitis, flatulence, upper abdominal pain and abdominal distension.
The formulation according to claim 7 or 9, wherein the cardiovascular complications are any one or more of angina, heart failure, myocardial infarction and retinopathy.
A method for preventing or treating diabetes, comprising the step of administering the composition of any one of claims 1 to 6 and the formulation of any one of claims 7 to 12 to a subject in need thereof, wherein hypoglycemia, gastrointestinal complications and cardiovascular complications are reduced compared to the administration of metformin alone.