Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus

The purpose of the study is to compare the effect of adding alogliptin, once daily (QD), to the ongoing treatment regimen of pioglitazone HCl and metformin in patients with inadequate glycemic control.

Despite the introduction of new classes of medications for glycemic control, just over half of adults with type 2 diabetes mellitus (T2DM) achieve a glycosylated hemoglobin level less than 7.0%, the American Diabetes Association recommended glycosylated hemoglobin goal. The rising incidence of type 2 diabetes mellitus along with limitations of the currently available treatments suggest the need for new therapies for glycemic control along with the increased requirement for combination therapy in type 2 diabetes mellitus.

Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal through an incompletely understood mechanism but one associated with binding of the drug to nuclear receptors known as peroxisome proliferator-activated receptors-gamma. Peroxisome proliferator-activated receptors-gamma 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. 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. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan). Pioglitazone depends on the presence of insulin for its mechanism of action. Worldwide clinical investigation has shown that, as an adjunct to diet and exercise, pioglitazone improves glycemic control when used as monotherapy, and in combination with commonly used antidiabetic medications (ie, sulfonylureas, metformin, or insulin).

SYR-322 (alogliptin) is a selective, orally available inhibitor of dipeptidyl peptidase IV currently in development by Takeda Global Research \& Development Center, Inc. as a treatment for type 2 diabetes mellitus. Dipeptidyl peptidase IV is the primary enzyme involved in the in vivo degradation of at least 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet β-cells to stimulate glucose-dependent insulin secretion and regulate β-cell proliferation and cytoprotection. Glucagon-like peptide-1 also inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes.

Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity) and the absence of overlapping safety risks, the introduction of this combination therapy in patients with T2DM could potentially show enhanced glycemic control and allow patients to reach and maintain their HbA1c goal more effectively.

This study is designed to determine if the addition of alogliptin to a combination of pioglitazone with metformin can be effective at achieving glycemic control without increasing safety risks versus the titration of pioglitazone to 45 mg with metformin in patients with type 2 diabetes mellitus who are experiencing inadequate glycemic control on a current regimen of metformin.

Eligibility Criteria:
Inclusion Criteria:

* Has a historical diagnosis of type 2 diabetes mellitus.
* Meets one of the following:

  * Has been inadequately controlled (HbA1c between 7% and 10%, inclusive) on a stable dose of greater than or equal to 1500 mg (or maximum tolerated dose) of metformin and 30 mg of pioglitazone
  * Has been inadequately controlled (as defined by an HbA1c ≥7.5%) on a combination therapy including metformin and another oral antidiabetic agent (ie, sulfonylureas, rosiglitazone maleate, or pioglitazone 15 mg, etc). Subjects on a combination therapy that included a DPP-4 inhibitor were excluded.
* No treatment with antidiabetic agents other than metformin and pioglitazone.
* Body mass index greater than or equal to 23 kg/m\^2 and less than or equal to 45 kg/m\^2.
* Fasting plasma C-peptide concentration greater than or equal to 0.8 ng/mL.
* Systolic blood pressure less than 160 mmHg and diastolic pressure less than 100 mmHg.
* Hemoglobin greater than or equal to 12 g/dL for males and greater than or equal to 10 g/dL for females.
* Alanine aminotransferase less than or equal to 2.5 x upper limit of normal.
* Serum creatinine less than 1.5 mg/dL for males and less than 1.4 mg/dL for females.
* Thyroid-stimulating hormone level less than or equal to the upper limit of normal range and the patient is clinically euthyroid.
* 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.
* Able and willing to monitor their own blood glucose concentrations with a home glucose monitor.
* No major illness or debility that in the investigator's opinion prohibits the patient from completing the study.

Exclusion Criteria:

* Urine albumin/creatinine ratio of greater than 1000 μg/mg.
* History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening.
* History of bladder cancer.
* History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
* Patients with unexplained microscopic hematuria of greater than +1, confirmed by repeat testing.
* History of treated diabetic gastroparesis.
* History of gastric bypass surgery.
* New York Heart Association Class I-IV heart failure regardless of therapy.
* History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening.
* History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin.
* History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
* History of a psychiatric disorder that will affect the patient's ability to participate in the study.
* History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
* History of alcohol abuse or substance abuse within the 2 years prior to Screening.
* Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening.
* Prior treatment in an investigational study of alogliptin.
* Hypersensitive to pioglitazone HCl, metformin, alogliptin or other excipients.
* The patient has donated more than 400 mL of blood within the 90 days prior to Screening and Pre-Screening, if applicable.