Efficacy and Safety of Pioglitazone and Azilsartan in Treating Subjects With Type 2 Diabetes Mellitus

A Phase II, Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study of the Efficacy, Safety, and Tolerability of Pioglitazone HCl (ACTOS™) in Combination With TAK-536 in Subjects With Type II Diabetes

The purpose of this study is to determine the efficacy of pioglitazone, once daily (QD), combined with azilsartan in the treatment of subjects with Type 2 Diabetes Mellitus.

Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes has a genetic predisposition, but lifestyle, body constitution and age play important roles in determining its time of onset and severity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral-tissue cells to circulating insulin (i.e., insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (i.e., insulin deficiency due to beta cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 15.7 million people have diabetes, with type 2 diabetes occurring in approximately 90-95% of cases.

Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. The oral therapeutic agents used in the treatment of type 2 diabetes can be separated into the following four categories based on their mechanisms of action: insulin secretagogues, inhibitors of hepatic glucose output, inhibitors of complex carbohydrate breakdown in the intestine and insulin sensitizers.

Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis) with no direct impact on insulin secretion. Thus thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors -gamma receptors is in adipose tissue. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd.

Research suggests that Angiotensin II receptor blockers are involved in endothelial and cardiovascular function, and in insulin sensitization and obesity. TAK-536 (azilsartan) is an angiotensin II receptor antagonist with affinity for and selective antagonistic activity at the angiotensin II type 1 receptor.

This study was designed to evaluate the efficacy, safety, and tolerability of pioglitazone in combination with azilsartan in subjects with type 2 diabetes.

Study participation is anticipated to be approximately 6 months.

Inclusion Criteria:

• Had type 2 diabetes, with a hemoglobin value of greater than or equal to 8.0% or less than 10.0% at Screening.
• Females of childbearing potential who were sexually active agreed to use adequate contraception, and were neither pregnant nor lactating from Screening throughout the duration of the study.
• Received antihypertensive therapy and must have been on a stable dose for a minimum of 8 weeks prior to Screening.
• Had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory unless the results were deemed not clinically significant for inclusion into this study by the investigator or sponsor.
• Had been on stable diet and exercise program and oral anti-glycemic therapy including sulfonylurea or metformin for 8 weeks prior to Screening.

Exclusion Criteria:

• Had a hemoglobin value less than 8.0% or greater than 10.0% at Screening.

• Was taking an angiotensin II receptor blocker.

• Had uncontrolled hypertension defined as systolic blood pressure greater than 160 mm Hg and diastolic blood pressure greater than 100 mm Hg. - Had a systolic blood pressure less than or equal to 110 mm Hg and/or diastolic blood pressure less than or equal to 60 mm Hg.

• Was taking or was expected to take the following medications:

  • antidiabetic agents (other than sulfonylurea or metformin)
  • tricyclic antidepressants
  • monoamine oxidase inhibitors
  • phenothiazines
  • diet medications
  • amphetamines or their derivatives
  • lithium
  • common cold medications with chronic use
  • nonsteroidal anti-inflammatory drugs with chronic use (including aspirin greater than 325 mg/day or cyclooxygenase 2 inhibitors).

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

• Had a history of myocardial infarction.

• Had clinically significant cardiac conduction defects (eg, second or third degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation or flutter).

• Had secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).

• Had a history of collagen vascular disorder (eg, systemic lupus erythematosus, scleroderma) within the last 5 years.

• Had a body mass index greater than 39 kg/m2.

• Had significant, moderate-to-severe renal dysfunction (creatinine greater than 2.4 mg/dL). If receiving metformin, a creatinine greater than 1.5 mg/dL for male subjects or greater than 1.4 mg/dL for female subjects led to exclusion.

• Had a history of drug abuse or a history of alcohol abuse within the past 2 years.

• Had a previous history of cancer, other than basal cell carcinoma, that had not been in remission for at least 5 years prior to the first dose of study drug.

• Had type 2 diabetes with clinically important retinopathy or peripheral or autonomic neuropathy.

• Had an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.

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

• Had any other serious disease or condition at Screening (or randomization) that might have compromised subject safety, affected life expectancy, or made it difficult to successfully manage and follow the subject according to the protocol.

• Was hypersensitive to angiotensin II receptor blockers.

• Was hypersensitive to thiazolidinediones.