Efficacy and Safety of Alogliptin Combined With Pioglitazone in Treating Subjects With Type 2 Diabetes Mellitus.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of the Combination of SYR-322 (SYR110322) and Pioglitazone HCl (ACTOS®), in Subjects With Type 2 Diabetes

The purpose of this study is to evaluate the safety and efficacy of alogliptin, once daily (QD), taken in combination with pioglitazone in adults with type 2 diabetes mellitus.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Alogliptin placebo; Drug: Pioglitazone placebo; Drug: Alogliptin; Drug: Pioglitazone

Detailed Description

Over the past 30 years, the prevalence of diabetes has increased dramatically throughout the world due to population growth, aging, urbanization, increasing obesity, and physical inactivity. The total number of people with type 2 diabetes mellitus is projected to rise from 171 million in 2000 to 366 million in 2030. The incidence of type 2 diabetes mellitus in the United States alone is expected to increase from approximately 17 to 30.3 million by the year 2030. Type 2 diabetes mellitus is associated with a number of long-term microvascular and macrovascular complications associated with a reduced quality of life and increased morbidity and mortality. It is anticipated that the increasing incidence of type 2 diabetes mellitus will place an ever-increasing burden on families, increase national expenditures for health care services, and decrease worker productivity.

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 achieving 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 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.

Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity), the goal of this study is to evaluate the efficacy of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on metformin. Study participation is anticipated to be approximately 7 months.

• Study Type: Interventional
• Enrollment (Actual): 1554
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Multiple Cities, Australia
• Brazil
  • Multiple Cities, Brazil
• Bulgaria
  • Multiple Cities, Bulgaria
• Chile
  • Multiple Cities, Chile
• Croatia
  • Multiple Cities, Croatia
• Estonia
  • Multiple Cities, Estonia
• Guatemala
  • Multiple Cities, Guatemala
• India
  • Multiple Cities, India
• Israel
  • Multiple Cities, Israel
• Latvia
  • Multiple Cities, Latvia
• Mexico
  • Multiple Cities, Mexico
• New Zealand
  • Multiple Cities, New Zealand
• Peru
  • Multiple Cities, Peru
• Romania
  • Multiple Cities, Romania
• Russian Federation
  • Multiple Cities, Russian Federation
• Serbia
  • Multiple Cities, Serbia
• South Africa
  • Multiple Cities, South Africa
• Ukraine
  • Multiple Cities, Ukraine
• United States
  • Alabama
    • Birmingham, Alabama, United States
    • Columbiana, Alabama, United States
    • Huntsville, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
  • Arkansas
    • Little Rock, Arkansas, United States
    • Searcy, Arkansas, United States
    • Sherwood, Arkansas, United States
  • California
    • Burbank, California, United States
    • Foothill Ranch, California, United States
    • Irvine, California, United States
    • Sacramento, California, United States
    • San Diego, California, United States
    • Temecula, California, United States
    • Tustin, California, United States
  • Colorado
    • Colorado Springs, Colorado, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Hollywood, Florida, United States
    • Kissimmee, Florida, United States
    • Miami, Florida, United States
    • New Port Richey, Florida, United States
    • Pembroke Pines, Florida, United States
    • Pinellas Park, Florida, United States
    • Sarasota, Florida, United States
    • Vero Beach, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Roswell, Georgia, United States
    • Savannah, Georgia, United States
    • Warner Robins, Georgia, United States
  • Illinois
    • Chicago, Illinois, United States
    • Peoria, Illinois, United States
  • Indiana
    • Lafayette, Indiana, United States
    • South Bend, Indiana, United States
  • Iowa
    • Waterloo, Iowa, United States
  • Kentucky
    • Munfordville, Kentucky, United States
  • Louisiana
    • Baton Rouge, Louisiana, United States
    • Marrero, Louisiana, United States
  • Maryland
    • Elkridge, Maryland, United States
    • Prince Frederick, Maryland, United States
    • Towson, Maryland, United States
  • Massachusetts
    • Marlborough, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
    • Cadillac, Michigan, United States
    • Detroit, Michigan, United States
    • Livonia, Michigan, United States
  • Missouri
    • Kansas City, Missouri, United States
  • Nevada
    • North Las Vegas, Nevada, United States
  • New Jersey
    • Blackwood, New Jersey, United States
    • Trenton, New Jersey, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
    • Statesville, North Carolina, United States
  • Ohio
    • Gallipolis, Ohio, United States
    • Marion, Ohio, United States
  • Oklahoma
    • Clinton, Oklahoma, United States
    • Oklahoma City, Oklahoma, United States
    • Tulsa, Oklahoma, United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States
    • Altoona, Pennsylvania, United States
    • Philadelphia, Pennsylvania, United States
    • Pittsburgh, Pennsylvania, United States
  • Tennessee
    • Alcoa, Tennessee, United States
    • Milan, Tennessee, United States
    • Morristown, Tennessee, United States
  • Texas
    • Arlington, Texas, United States
    • Carrollton, Texas, United States
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • Houston, Texas, United States
    • San Antonio, Texas, United States
    • Temple, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Vermont
    • Burlington, Vermont, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women with a historical diagnosis of type 2 diabetes mellitus who were treated with metformin greater than or equal to 1500 mg alone but were experiencing inadequate glycemic control.
• A stable dose of metformin of greater than or equal to 1500 mg or maximum tolerated dose.
• No treatment with antidiabetic agents other than metformin within the 2 months prior to Screening.
• A body mass index greater than or equal to 23 kg/m^2 and less than or equal to 45 kg/m^2.
• Fasting C-peptide greater than or equal to 0.8 ng/mL.
• Regular use of other, non-excluded medications was allowed if a stable dose had been established for at least 4 weeks prior to Screening.
• Systolic blood pressure less than or equal to 160 mmHg and diastolic pressure less than or equal to 100 mmHg.
• Hemoglobin greater than or equal to 12 g/dL for men and greater than or equal to 10 g/dL for women.
• Alanine aminotransferase less than or equal to 2.5 times the upper limit of normal.
• Serum creatinine less than 1.5 mg/dL for men and less than 1.4 mg/dL for women.
• Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the subject was 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 prohibited the patient from completing the study.

Exclusion Criteria:

• Urine albumin/creatinine ratio greater than 113 mg/mmol at Screening.
• A history of cancer, other than squamous cell or basal cell carcinoma of the skin, that had not been in full remission for at least 5 years prior to Screening.
• A history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
• A history of treated diabetic gastroparesis.
• New York Heart Association Class III or 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.
• History of infection with hepatitis B, hepatitis C or human immunodeficiency virus.
• History of a psychiatric disorder that could have affected 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.
• A history of alcohol or substance abuse within 2 years prior to Screening.
• Receipt of any investigational drug within 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within 3 months prior to Screening.
• Previous participation in an investigational study of alogliptin.
• Hypersensitive to pioglitazone, alogliptin, or other excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin placebo; Alogliptin placebo-matching tablets.; Drug: Pioglitazone placebo; Pioglitazone placebo-matching tablets.
Experimental: Alogliptin 12.5 + Placebo; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.	Drug: Pioglitazone placebo; Pioglitazone placebo-matching tablets.; Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322
Experimental: Alogliptin 25 + Placebo; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.	Drug: Pioglitazone placebo; Pioglitazone placebo-matching tablets.; Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322
Active Comparator: Placebo + Pioglitazone 15; Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 12.5 + Pioglitazone 15; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 25 + Pioglitazone 15; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Active Comparator: Placebo + Pioglitazone 30; Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin placebo; Alogliptin placebo-matching tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 12.5 + Pioglitazone 30; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 25 + Pioglitazone 30; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Active Comparator: Placebo + Pioglitazone 45; Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin placebo; Alogliptin placebo-matching tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 12.5 + Pioglitazone 45; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®
Experimental: Alogliptin 25 + Pioglitazone 45; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 26 in Glycosylated Hemoglobin (HbA1c) (Grouped Analysis)	The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The primary analysis compared the groupings (combinations of individual treatment groups) of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone (Pioglitazone Alone).	Baseline and Week 26
Change From Baseline to Week 26 in HbA1c	The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).	Baseline and Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c Over Time (Grouped Analysis)	The change from Baseline to Weeks 4, 8, 12, 16 and 20 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an analysis of covariance (ANCOVA) model with treatment and geographic region as class variables, and baseline metformin dose and HbA1c as continuous covariates.	Baseline and Weeks 4, 8, 12, 16 and 20.
Change From Baseline to Week 4 in HbA1c	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at week 4. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HbA1c as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in HbA1c	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at week 8. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HbA1c as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in HbA1c	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at week 12. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HbA1c as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in HbA1c	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at week 16. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HbA1c as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in HbA1c	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at week 20. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HbA1c as continuous covariates.	Baseline and Week 20
Change From Baseline in Fasting Plasma Glucose Over Time (Grouped Analysis)	The change from Baseline in fasting plasma glucose was assessed at weeks 1, 2, 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 1 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 1
Change From Baseline to Week 2 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 2
Change From Baseline to Week 4 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Fasting Plasma Glucose	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline fasting plasma glucose as covariates.	Baseline and Week 26
Percentage of Participants With Marked Hyperglycemia (Grouped Analysis)	Marked hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.10 mmol/L). This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	From Week 1 to Week 26
Percentage of Participants With Marked Hyperglycemia	Marked hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.10 mmol/L).	From Week 1 to Week 26
Percentage of Participants Meeting Rescue Criteria (Grouped Analysis)	Rescue was defined as meeting 1 of the following criteria, confirmed by a 2nd sample drawn within 5 days of the first and analyzed by the central laboratory: After the Week 1 Visit but prior to the Week 4 Visit: a single fasting plasma glucose ≥300 mg/dL;; From the Week 4 Visit but prior to the Week 8 Visit: a single fasting plasma glucose ≥275 mg/dL;; From the Week 8 Visit but prior to the Week 12 Visit: a single fasting plasma glucose ≥250 mg/dL;; From the Week 12 Visit through the End-of-Treatment Visit: HbA1c ≥8.5% and ≤0.5% reduction in HbA1c as compared with Baseline HbA1c.	From Week 1 to Week 26.
Percentage of Participants Meeting Rescue Criteria	Rescue was defined as meeting 1 of the following criteria, confirmed by a 2nd sample drawn within 5 days of the first and analyzed by the central laboratory: After the Week 1 Visit but prior to the Week 4 Visit: a single fasting plasma glucose ≥300 mg/dL;; From the Week 4 Visit but prior to the Week 8 Visit: a single fasting plasma glucose ≥275 mg/dL;; From the Week 8 Visit but prior to the Week 12 Visit: a single fasting plasma glucose ≥250 mg/dL;; From the Week 12 Visit through the End-of-Treatment Visit: HbA1c ≥8.5% and ≤0.5% reduction in HbA1c as compared with Baseline HbA1c.	From Week 1 to Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 6.5%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5%	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 6.5%.	Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 7%	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7%.	Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7.5%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Week 26
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5%	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7.5%.	Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5%	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5%.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1%	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1%.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5%	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5%.	Baseline and Week 26
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% (Grouped Analysis)	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0%. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone.	Baseline and Week 26.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2%	Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2%.	Baseline and Week 26
Change From Baseline in Fasting Proinsulin Over Time (Grouped Analysis)	Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and proinsulin as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Fasting Proinsulin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin as continuous covariates.	Baseline and Week 26
Change From Baseline in Insulin Over Time (Grouped Analysis)	The change from Baseline in fasting insulin was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Insulin Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline insulin as continuous covariates.	Baseline and Week 26
Change From Baseline in Proinsulin/Insulin Ratio Over Time (Grouped Analysis)	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL) at weeks 4, 8, 12, 16, 20 and 26 relative to the Baseline value. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Proinsulin/Insulin Ratio	The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL). Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as continuous covariates.	Baseline and Week 26
Change From Baseline in C-peptide Over Time (Grouped Analysis)	C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in C-peptide Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline C-peptide as continuous covariates.	Baseline and Week 26
Change From Baseline in Total Cholesterol Over Time (Grouped Analysis)	Change from Baseline in total cholesterol was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Total Cholesterol Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as continuous covariates.	Baseline and Week 26
Change From Baseline in Low-Density Lipoprotein Cholesterol Over Time (Grouped Analysis)	Change from Baseline in low-density lipoprotein cholesterol (LDL-C) was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Low-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as continuous covariates.	Baseline and Week 26
Change From Baseline in High-Density Lipoprotein Cholesterol Over Time (Grouped Analysis)	Change from Baseline in high-density lipoprotein cholesterol (HDL-C) was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in High-Density Lipoprotein Cholesterol	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as continuous covariates.	Baseline and Week 26
Change From Baseline in Triglycerides Over Time (Grouped Analysis)	Change from Baseline in triglycerides was assessed at Weeks 4, 8, 12, 16, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Weeks 4, 8, 12, 16, 20 and 26.
Change From Baseline to Week 4 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 4
Change From Baseline to Week 8 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 16 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 16
Change From Baseline to Week 20 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Triglyceride Levels	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline triglycerides as continuous covariates.	Baseline and Week 26
Change From Baseline in Free Fatty Acids Over Time (Grouped Analysis)	Change from Baseline in free fatty acids (FFA) was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline free fatty acid as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in Free Fatty Acids	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline free fatty acid as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Free Fatty Acids	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline free fatty acid as continuous covariates.	Baseline and Week 26
Change From Baseline in Plasminogen Activator Inhibitor-1 Over Time (Grouped Analysis)	Change from Baseline in plasminogen activator inhibitor-1 (PAI-1) was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in Plasminogen Activator Inhibitor-1	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Plasminogen Activator Inhibitor-1	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as continuous covariates.	Baseline and Week 26
Change From Baseline in High-sensitivity C-Reactive Protein Over Time (Grouped Analysis)	Change from Baseline in high-sensitivity C-Reactive Protein (hsCRP) was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline hsCRP as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in High-sensitivity C-Reactive Protein	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline hsCRP as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in High-sensitivity C-Reactive Protein	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline hsCRP as continuous covariates.	Baseline and Week 26
Change From Baseline in Adiponectin Over Time (Grouped Analysis)	Change from Baseline in adiponectin was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline adiponectin as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in Adiponectin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline adiponectin as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Adiponectin	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline adiponectin as continuous covariates.	Baseline and Week 26
Change From Baseline in Body Weight Over Time (Grouped Analysis)	Change from Baseline in body weight was assessed at Weeks 8, 12, 20 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline weight as continuous covariates.	Baseline and Weeks 8, 12, 20 and 26.
Change From Baseline to Week 8 in Body Weight	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline weight as continuous covariates.	Baseline and Week 8
Change From Baseline to Week 12 in Body Weight	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline weight as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 20 in Body Weight	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline weight as continuous covariates.	Baseline and Week 20
Change From Baseline to Week 26 in Body Weight	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline weight as continuous covariates.	Baseline and Week 26
Change From Baseline in Calculated Homeostatic Model Assessment Insulin Resistance (HOMA IR) (Grouped Analysis)	HOMA IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (µIU/mL) * fasting plasma glucose (mmol/L) / 22.5. A higher number indicates a greater insulin resistance. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least Squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and HOMA-IR as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in Calculated HOMA Insulin Resistance	The Homeostasis Model Assessment of insulin resistance (HOMA IR) measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (µIU/mL) * fasting plasma glucose (mmol/L) / 22.5. A higher number indicates a greater degree of insulin resistance. Least Squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and HOMA-IR as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Calculated HOMA Insulin Resistance	The Homeostasis Model Assessment of insulin resistance (HOMA IR) measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (µIU/mL) * fasting plasma glucose (mmol/L) / 22.5. A higher number indicates a greater degree of insulin resistance. Least Squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and HOMA-IR as continuous covariates.	Baseline and Week 26
Change From Baseline in Homeostatic Model Assessment Beta Cell Function (Grouped Analysis)	The homeostatic model assessment estimates steady state beta cell function as a percentage of a normal reference population (%B). HOMA %B = 20 * insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Calculated HOMA Beta-cell Function	The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA %B = 20 * insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Calculated HOMA Beta-cell Function	The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA %B = 20 * insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as continuous covariates.	Baseline and Week 26
Change From Baseline in Apolipoprotein A1 Over Time (Grouped Analysis)	Change from Baseline in Apolipoprotein A1 was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in Apolipoprotein A1	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Apolipoprotein A1	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as continuous covariates.	Baseline and Week 26
Change From Baseline in Apolipoprotein A2 Over Time (Grouped Analysis)	Change from Baseline in Apolipoprotein A2 was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Apolipoprotein A2	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Apolipoprotein A2	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as continuous covariates.	Baseline and Week 26
Change From Baseline in Apolipoprotein B Over Time (Grouped Analysis)	Change from Baseline in Apolipoprotein B was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Apolipoprotein B	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Apolipoprotein B	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as continuous covariates.	Baseline and Week 26
Change From Baseline in Apolipoprotein C-III Over Time (Grouped Analysis)	Change from Baseline in apolipoprotein C-III was assessed at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Apolipoprotein C-III	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Apolipoprotein C-III	Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as continuous covariates.	Baseline and Week 26
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Over Time (Grouped Analysis)	Nuclear Magnetic Resonance (NMR) lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR total triglycerides as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in NMR Lipid Fractionation Total Triglycerides	NMR lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Week 12. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR total triglycerides as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in NMR Lipid Fractionation Total Triglycerides	NMR lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Week 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR total triglycerides as continuous covariates.	Baseline and Week 26
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Over Time (Grouped Analysis)	The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron particles as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in VLDL / Chylomicron Particles	The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron particles as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in VLDL / Chylomicron Particles	The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron particles as continuous covariates.	Baseline and Week 26
Change From Baseline in VLDL / Chylomicron Triglycerides Over Time (Grouped Analysis)	The change from Baseline in levels of VLDL/chylomicron triglycerides was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron triglycerides as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in VLDL / Chylomicron Triglycerides	The change from Baseline in VLDL/chylomicron triglyceride levels was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron triglycerides as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in VLDL / Chylomicron Triglycerides	The change from Baseline in VLDL/chylomicron triglyceride levels was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL/chylomicron triglycerides as continuous covariates.	Baseline and Week 26
Change From Baseline in VLDL Particles Over Time (Grouped Analysis)	The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL particles as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in VLDL Particles	The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL particles as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in VLDL Particles	The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR VLDL particles as continuous covariates	Baseline and Week 26
Change From Baseline in Mean VLDL Particle Size Over Time (Grouped Analysis)	The change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean VLDL particle size as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Mean VLDL Particle Size	The change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean VLDL particle size as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Mean VLDL Particle Size	The change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean VLDL particle size as continuous covariates.	Baseline and Week 26
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Over Time (Grouped Analysis)	The change from Baseline in levels of IDL particles was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR IDL particles as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in IDL Particles	The change from Baseline in levels of IDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR IDL particles as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in IDL Particles	The change from Baseline in levels of IDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR IDL particles as continuous covariates.	Baseline and Week 26
Change From Baseline in Low Density Lipoprotein (LDL) Particles Over Time (Grouped Analysis)	The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR LDL particles as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in LDL Particles	The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR LDL particles as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in LDL Particles	The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR LDL particles as continuous covariates.	Baseline and Week 26
Change From Baseline in Mean LDL Particle Size Over Time (Grouped Analysis)	The change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean LDL particle size as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Mean LDL Particle Size	The change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean LDL particle size as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Mean LDL Particle Size	The change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean LDL particle size as continuous covariates.	Baseline and Week 26
Change From Baseline in High Density Lipoprotein (HDL) Particles Over Time (Grouped Analysis)	The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR HDL particles as continuous covariates.	Baseline and Weeks 12 and 26.
Change From Baseline to Week 12 in HDL Particles	The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR HDL particles as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in HDL Particles	The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR lipid fractionation. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline NMR HDL particles as continuous covariates.	Baseline and Week 26
Change From Baseline in Mean HDL Particle Size Over Time (Grouped Analysis)	The change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. This analysis compared the groupings of participants who received the combination of pioglitazone with each dose of alogliptin with the grouping of participants who received pioglitazone alone. Least squares means are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean HDL particle size as continuous covariates.	Baseline and Weeks 12 and 26
Change From Baseline to Week 12 in Mean HDL Particle Size	The change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation. Least squares means are from are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean HDL particle size as continuous covariates.	Baseline and Week 12
Change From Baseline to Week 26 in Mean HDL Particle Size	The change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation. Least squares means are from are from an ANCOVA model with treatment and geographic region as class variables, and baseline metformin dose and baseline mean HDL particle size as continuous covariates.	Baseline and Week 26

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012 May;97(5):1615-22. doi: 10.1210/jc.2011-2243. Epub 2012 Mar 14.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: May 19, 2006
• First Submitted That Met QC Criteria: May 19, 2006
• First Posted (Estimate): May 22, 2006

Study Record Updates

• Last Update Posted (Estimate): April 4, 2013
• Last Update Submitted That Met QC Criteria: February 19, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Drug Therapy; Hyperglycemia; Diabetes Mellitus, Type 2; Glucose Intolerance; Diabetes Mellitus, Non Insulin Dependent
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Pioglitazone; Alogliptin
• Other Study ID Numbers: 01-05-TL-322OPI-001; 2006-000694-30 (EudraCT Number); U1111-1113-8587 (Registry Identifier: WHO)