Efficacy and Safety of Pioglitazone and Metformin Combination Therapy in Treating Type 2 Diabetes Mellitus.

A Phase 3b, Double-Blind, Randomized Study to Determine the Efficacy and Safety of Pioglitazone HCl and Metformin HCl Fixed-Dose Combination Therapy Compared to Pioglitazone HCl Monotherapy and to Metformin HCl Monotherapy in the Treatment of Subjects With Type 2 Diabetes

The purpose of this study is to determine the efficacy of pioglitazone, twice daily (BID), combined with metformin versus pioglitazone taken alone and metformin taken alone in treating Type 2 Diabetes Mellitus.

Pioglitazone hydrochloride (ACTOS®) is a member of a class of oral antidiabetic agents known as thiazolidinediones, which act by reducing insulin resistance. Insulin resistance is a key feature of dysmetabolic syndrome and has been suggested to be the common pathophysiologic basis of both atherosclerosis and type 2 diabetes. Pioglitazone binds to peroxisome proliferator-activated receptors, an effect that is associated with altered transcription of genes capable of influencing carbohydrate and lipid metabolism.

Metformin hydrochloride is an oral antihyperglycemic drug not chemically or pharmacologically related to thiazolidinediones. Metformin is a biguanide, which has been shown to be effective in improving glycemic control in diabetic patients. Metformin inhibits hepatic glucose production, most likely through an inhibition of gluconeogenesis, and its use is associated with an improvement in tissue sensitivity to insulin. In accordance with published algorithms for the use of combination therapy for the treatment of type 2 diabetes, physicians have traditionally combined metformin with other antidiabetic agents.

This study will determine the effect of a fixed-dose combination of metformin with pioglitazone, compared to metformin monotherapy and pioglitazone monotherapy.

Study participation is anticipated to be approximately 6.5 months.

Inclusion Criteria

• Has type 2 diabetes.
• Has received no treatment with antidiabetic medication in the 12 weeks prior to Screening, other than short-term use defined as less than or equal to 15 days.
• A glycosylated hemoglobin greater than or equal to 7.5% and less than or equal to 10.0% at Screening.
• Body mass index less than or equal to 45 kg/m2.
• Has received counseling on lifestyle modification for type 2 diabetes, including diet and exercise.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
• Stable condition as determined by a physician.

Exclusion Criteria

• Type 1 diabetes.

• Unstable angina or heart failure of any etiology with New York Heart Association functional class III or IV.

• History of myocardial infarction, cerebrovascular accident, percutaneous coronary intervention, coronary artery bypass graft, or transient ischemic attack in the 6 months prior to Screening.

• Male participant has a serum creatinine level greater than or equal to 1.5 mg per dL or female subject has a serum creatinine level greater than or equal to 1.4 mg per dL.

• Has a triglyceride level greater than 500 mg per dL.

• Male participant has a hemoglobin level less than 10.5 g per dL or female subject has a hemoglobin level less than 10.0 g per dL.

• Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.

• History of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day) within 2 years prior to Screening.

• Has been discontinued from a thiazolidinedione or metformin therapy due to lack of efficacy or clinical or laboratory signs of intolerance.

• Previous history of cancer, other than basal cell or stage 1 squamous cell carcinoma, that has not been in remission for at least 5 years prior to the first dose of study medication.

• History of acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.

• Any disease or condition at Screening or Randomization that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol.

• Currently participating in another investigational study or has participated in an investigational study within 30 days prior to randomization.

• Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • Antidiabetic medications other than study medication
  • Chronically used oral or parenteral glucocorticoids
  • Niacin greater than 200 mg per day, including niacin-containing products such as Advicor
  • Chronically used steroid-joint injections