• Change from Baseline in Glycosylated Hemoglobin [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
  

• Change from Baseline in Glycosylated Hemoglobin [ Time Frame: Weeks 4, 8, 12, 16, and 20 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Fasting Plasma Glucose [ Time Frame: Weeks 1, 2, 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Marked Hyperglycemia (fasting plasma glucose greater than or equal to 200 mg/dL). [ Time Frame: Weeks 1, 2, 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Rescue. [ Time Frame: Weeks 1, 2, 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Fasting Proinsulin [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Insulin. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Proinsulin/Insulin ratio [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in C-peptide. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin less than or equal to 6.5%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin less than or equal to 7.0%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin less than or equal to 7.5%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of glycosylated hemoglobin decrease from Baseline greater than or equal to 0.5%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 1.0%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 1.5%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 2.0%. [ Time Frame: Week 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Total Cholesterol. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Low-Density Lipoprotein. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in High-Density Lipoprotein. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Triglycerides. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Nuclear Magnetic Resonance Lipid Fractionation [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Free Fatty Acids [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Plasminogen Activator Inhibitor-1. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in high-sensitivity C-Reactive Protein. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Adiponectin. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Body Weight. [ Time Frame: Weeks 8, 12, 20, and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Calculated Homeostatic Model Assessment Insulin Resistance [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Homeostatic Model Assessment Beta Cell Function. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Apolipoprotein A1. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Apolipoprotein A2. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Apolipoprotein B. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  
• Change from Baseline in Apolipoprotein C-III. [ Time Frame: Weeks 12 and 26 or Final Visit. ] [ Designated as safety issue: No ]
  

There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% is type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected, placing an ever-increasing burden on families and the health care system.

Current pharmacologic interventions for type 2 diabetes mellitus include a diverse range of antidiabetic medications with different mechanisms of action including insulin and insulin analogues, sulfonylureas, metformin, meglitinides, thiazolidinediones, inhibitors of alpha- glucosidase, analogs of glucagon-like peptide-1, and synthetic analogues of human amylin. Despite the variety of medications, many have clinically important or potentially life-threatening side effects, restricted use in many subpopulations, concerns with long-term tolerability, and challenges related to compliance due to side effects and route of administration. All of these reasons contribute to the difficulties patients have reaching the target glycosylated hemoglobin level less than 7%.

SYR-322 (alogliptin) is a selective, orally available inhibitor of the dipeptidyl peptidase-4 enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 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 beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus.

Pioglitazone (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan) that is approved for the treatment of type 2 diabetes mellitus. Pioglitazone is a potent and highly selective peroxisome proliferator-activated receptor-gamma agonist that decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

As the rate of newly diagnosed cases of type 2 diabetes mellitus continues to grow, so does the need for products that will provide better glycemic control and improved safety and tolerability. SYR-322 and pioglitazone have complementary actions. SYR-322 inhibits the degradation of glucagon-like peptide-1 by inhibiting the enzyme dipeptidyl peptidase IV, thus augmenting glucose-dependent insulin secretion while pioglitazone is a peripheral and hepatic insulin sensitizer. Given the complementary mechanisms of action of SYR-322 (stimulates insulin secretion) and pioglitazone (enhances insulin sensitivity), the addition of combination therapy in treatment naïve type 2 diabetes patients may potentially allow the patients to reach and maintain their glycosylated hemoglobin goal more effectively.

The aim of this study is to evaluate the effectiveness of the combination of SYR-322 with pioglitazone in subjects who are inadequately controlled on diet and exercise alone. Study participation is anticipated to be approximately 8.5 months.