Safety and Efficacy Study to Compare Vildagliptin to Pioglitazone as Adding on Metformin in Type 2 Diabetes

An Open-label, Randomized, Active-controlled Study to Compare the Effect of 16 Weeks Treatment With Vildagliptin to Pioglitazone as add-on Therapy to Metformin in Type 2 Diabetic Patients Inadequately Controlled With Metformin Monotherapy

The purpose of this study is to compare the effect of 16 weeks treatment with vildagliptin to pioglitazone as add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by hyperglycemia that result from pancreatic islet dysfunction. Presently available oral antihypoglycemic drug improves glycemic control over the short term, none has been shown to stop the progressive decline in beta cell function which contributes to the deterioration of glycemic control over time.

Pathophysiology of T2DM is known as tissue resistance for insulin and progressive beta cell failure. Which one attributes first is unclear, but non-obese T2DM patients often show normal fasting plasma glucose (FPG) but postprandial plasma glucose (PPG) level is high and reduced or lacking normal compensatory insulin secretion. In Korea, more than 80% of T2DM are non-obese type (BMI >= 27 ) and it was observed that basal insulin level and compensatory insulin secretion reaction were reduced in normal healthy population. Based on that, metformin is an established first line treatment for type 2 diabetes, acting primarily to enhance hepatic and peripheral insulin sensitivity. However, it has become increasingly apparent that many patients require a combination of agents to attain optimal glycemic control.

Better understanding of incretin effect on the pathophysiology of T2DM has recently led to development of new oral hypoglycemic agents. Vildagliptin is a potent and highly selective dipeptidyl peptidase (DPP)-IV inhibitor that improves islet function by increasing pancreatic alpha and beta cell responsiveness to glucose. Studies in patients with T2DM have shown that vildagliptin significantly reduced HbA1c and FPG level from baseline and did not induce weight gain and the incidence of hypoglycemia was low. In addition, studies in rodents support an effort of vildagliptin on beta cell remodeling.

The thiazolidinediones are effective in reducing HbA1C in obese T2DM patients and it is known that only thiazolidinedione can delay the beta cell failure . But recently, thiazolidinediones were found to be associated with a decrease in bone mineral density and to raise the risk of myocardial infarct and cardiovascular related mortality. Thus, there is a need for new classes of blood glucose lowering drug which has the potential to delay or prevent the progression of T2DM.

Inclusion Criteria:

1. Age in the range of 18 to 80 years
2. HbA1c 7 to 11%
3. FPG < 270 mg/dL (15 mmol/L);
4. Agreement to maintain prior diet & exercise
5. Written informed consent to participate in the study

Exclusion criteria:

1. Type 1 diabetes or Any kind of secondary diabetes

2. Pregnant or lactating women

3. Acute infections which may affect blood glucose control within 4 weeks prior to visit 1.

4. Significant diabetes complications e.g., symptomatic autonomic neuropathy or gastroparesis

5. Previous history of severe cardiovascular disease such as

   1. Torsades de Pointes, sustained and clinically relevant ventricular tachycardia, or ventricular fibrillation
   2. Percutaneous coronary intervention within the past 3 months

6. Any of the following within the past 6 months

   1. Myocardial infarction (MI) (if the visit 1 ECG reveals patterns consistent with an MI and the date of the event cannot be determined, then the patient can enter the study at the discretion of the investigator and the sponsor)
   2. Coronary artery bypass surgery
   3. Unstable angina
   4. Stroke

7. Congestive heart failure (NYHA class I to IV)

8. Liver disease such as cirrhosis or chronic active hepatitis

9. Known sensitivity to pioglitazone, rosiglitazone, or similar drugs

10. Chronic insulin treatment (> 4 weeks of treatment in the absence of an intercurrent illness) within the past 6 months

11. Chronic oral or parenteral corticosteroid treatment (> 7 consecutive days of treatment) within 8 weeks prior to visit 1

12. Any of the following laboratory abnormalities

    1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than 2.5 times the upper limit of the normal range at visit 1
    2. Direct bilirubin greater than 1.3 times the upper limit of the normal range at visit 1
    3. Serum creatinine levels > 2.5 mg/dL (220 μmol/L) at visit 1
    4. Clinically significant thyroid-stimulating hormone (TSH) outside normal range at visit 1