Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus
Condition: Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Alogliptin; Pioglitazone; Metformin; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Alogliptin tablets.; Pioglitazone tablets.; Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.; Matching placebo tablets.
Other intervention name(s): SYR-322; ACTOS®
Intervention MeSH terms: Metformin; Pioglitazone; Alogliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus, Lipoatrophic; Dyslipidemia; Hyperglycemia; Drug Therapy