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

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: Alogliptin placebo
Drug: Alogliptin
Drug: Pioglitazone placebo
Drug: Pioglitazone

Registration Number: NCT00328627

Lead Sponsor: Takeda

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1554

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Alogliptin placebo	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Placebo	Pioglitazone placebo	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Placebo	Pioglitazone placebo	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Placebo	Pioglitazone placebo	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 15	Pioglitazone	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.
Placebo + Pioglitazone 30	Alogliptin placebo	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Placebo + Pioglitazone 45	Alogliptin placebo	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 45	Alogliptin	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 45	Pioglitazone	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Placebo	Alogliptin	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Placebo + Pioglitazone 15	Pioglitazone	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 15	Pioglitazone	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Placebo	Alogliptin	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 15	Alogliptin	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 15	Alogliptin	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 30	Alogliptin	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 30	Pioglitazone	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Placebo + Pioglitazone 30	Pioglitazone	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Placebo + Pioglitazone 45	Pioglitazone	Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 30	Pioglitazone	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 25 + Pioglitazone 30	Alogliptin	Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 45	Alogliptin	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.
Alogliptin 12.5 + Pioglitazone 45	Pioglitazone	Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 26 in Glycosylated Hemoglobin (HbA1c) (Grouped Analysis)	Baseline and Week 26	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).
Change From Baseline to Week 26 in HbA1c	Baseline and Week 26	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in HbA1c Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16 and 20.	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.
Change From Baseline to Week 4 in HbA1c	Baseline and Week 4	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.
Change From Baseline to Week 8 in HbA1c	Baseline and Week 8	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.
Change From Baseline to Week 12 in HbA1c	Baseline and Week 12	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.
Change From Baseline to Week 16 in HbA1c	Baseline and Week 16	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.
Change From Baseline to Week 20 in HbA1c	Baseline and Week 20	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.
Change From Baseline in Fasting Plasma Glucose Over Time (Grouped Analysis)	Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 1 in Fasting Plasma Glucose	Baseline and Week 1	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.
Change From Baseline to Week 2 in Fasting Plasma Glucose	Baseline and Week 2	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.
Change From Baseline to Week 4 in Fasting Plasma Glucose	Baseline and Week 4	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.
Change From Baseline to Week 8 in Fasting Plasma Glucose	Baseline and Week 8	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.
Change From Baseline to Week 12 in Fasting Plasma Glucose	Baseline and Week 12	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.
Change From Baseline to Week 16 in Fasting Plasma Glucose	Baseline and Week 16	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.
Change From Baseline to Week 20 in Fasting Plasma Glucose	Baseline and Week 20	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.
Change From Baseline to Week 26 in Fasting Plasma Glucose	Baseline and Week 26	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.
Percentage of Participants With Marked Hyperglycemia (Grouped Analysis)	From Week 1 to Week 26	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.
Percentage of Participants With Marked Hyperglycemia	From Week 1 to Week 26	Marked hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.10 mmol/L).
Percentage of Participants Meeting Rescue Criteria (Grouped Analysis)	From Week 1 to Week 26.	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: 1. After the Week 1 Visit but prior to the Week 4 Visit: a single fasting plasma glucose ≥300 mg/dL; 2. From the Week 4 Visit but prior to the Week 8 Visit: a single fasting plasma glucose ≥275 mg/dL; 3. From the Week 8 Visit but prior to the Week 12 Visit: a single fasting plasma glucose ≥250 mg/dL; 4. 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.
Percentage of Participants Meeting Rescue Criteria	From Week 1 to Week 26	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: 1. After the Week 1 Visit but prior to the Week 4 Visit: a single fasting plasma glucose ≥300 mg/dL; 2. From the Week 4 Visit but prior to the Week 8 Visit: a single fasting plasma glucose ≥275 mg/dL; 3. From the Week 8 Visit but prior to the Week 12 Visit: a single fasting plasma glucose ≥250 mg/dL; 4. 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.
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5% (Grouped Analysis)	Week 26	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.
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5%	Week 26	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 6.5%.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% (Grouped Analysis)	Week 26	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.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7%	Week 26	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7%.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% (Grouped Analysis)	Week 26	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.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5%	Week 26	Clinical response at Week 26 was assessed by the percentage of participants with HbA1c less than or equal to 7.5%.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% (Grouped Analysis)	Baseline and Week 26	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.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5%	Baseline and Week 26	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%.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1% (Grouped Analysis)	Baseline and Week 26	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.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1%	Baseline and Week 26	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%.
Change From Baseline to Week 8 in Total Cholesterol Levels	Baseline and Week 8	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.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% (Grouped Analysis)	Baseline and Week 26	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.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5%	Baseline and Week 26	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%.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% (Grouped Analysis)	Baseline and Week 26.	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.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2%	Baseline and Week 26	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%.
Change From Baseline in Fasting Proinsulin Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Fasting Proinsulin	Baseline and Week 4	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.
Change From Baseline to Week 8 in Fasting Proinsulin	Baseline and Week 8	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.
Change From Baseline to Week 12 in Fasting Proinsulin	Baseline and Week 12	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.
Change From Baseline to Week 16 in Fasting Proinsulin	Baseline and Week 16	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.
Change From Baseline to Week 20 in Fasting Proinsulin	Baseline and Week 20	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.
Change From Baseline to Week 26 in Fasting Proinsulin	Baseline and Week 26	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.
Change From Baseline in Insulin Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Insulin Levels	Baseline and Week 4	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.
Change From Baseline to Week 8 in Insulin Levels	Baseline and Week 8	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.
Change From Baseline to Week 12 in Insulin Levels	Baseline and Week 12	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.
Change From Baseline to Week 16 in Insulin Levels	Baseline and Week 16	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.
Change From Baseline to Week 20 in Insulin Levels	Baseline and Week 20	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.
Change From Baseline to Week 26 in Insulin Levels	Baseline and Week 26	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.
Change From Baseline in Proinsulin/Insulin Ratio Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Proinsulin/Insulin Ratio	Baseline and Week 4	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.
Change From Baseline to Week 8 in Proinsulin/Insulin Ratio	Baseline and Week 8	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.
Change From Baseline to Week 12 in Proinsulin/Insulin Ratio	Baseline and Week 12	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.
Change From Baseline to Week 16 in Proinsulin/Insulin Ratio	Baseline and Week 16	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.
Change From Baseline to Week 20 in Proinsulin/Insulin Ratio	Baseline and Week 20	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.
Change From Baseline to Week 26 in Proinsulin/Insulin Ratio	Baseline and Week 26	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.
Change From Baseline in C-peptide Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in C-peptide Levels	Baseline and Week 4	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.
Change From Baseline to Week 8 in C-peptide Levels	Baseline and Week 8	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.
Change From Baseline to Week 12 in C-peptide Levels	Baseline and Week 12	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.
Change From Baseline to Week 16 in C-peptide Levels	Baseline and Week 16	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.
Change From Baseline to Week 20 in C-peptide Levels	Baseline and Week 20	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.
Change From Baseline to Week 26 in C-peptide Levels	Baseline and Week 26	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.
Change From Baseline in Total Cholesterol Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Total Cholesterol Levels	Baseline and Week 4	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.
Change From Baseline to Week 12 in Total Cholesterol Levels	Baseline and Week 12	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.
Change From Baseline to Week 16 in Total Cholesterol Levels	Baseline and Week 16	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.
Change From Baseline to Week 20 in Total Cholesterol Levels	Baseline and Week 20	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.
Change From Baseline to Week 26 in Total Cholesterol Levels	Baseline and Week 26	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.
Change From Baseline in Low-Density Lipoprotein Cholesterol Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Low-Density Lipoprotein Cholesterol	Baseline and Week 4	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.
Change From Baseline to Week 8 in Low-Density Lipoprotein Cholesterol	Baseline and Week 8	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.
Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol	Baseline and Week 12	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.
Change From Baseline to Week 16 in Low-Density Lipoprotein Cholesterol	Baseline and Week 16	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.
Change From Baseline to Week 20 in Low-Density Lipoprotein Cholesterol	Baseline and Week 20	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.
Change From Baseline to Week 26 in Low-Density Lipoprotein Cholesterol	Baseline and Week 26	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.
Change From Baseline in High-Density Lipoprotein Cholesterol Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in High-Density Lipoprotein Cholesterol	Baseline and Week 4	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.
Change From Baseline to Week 8 in High-Density Lipoprotein Cholesterol	Baseline and Week 8	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.
Change From Baseline to Week 12 in High-Density Lipoprotein Cholesterol	Baseline and Week 12	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.
Change From Baseline to Week 16 in High-Density Lipoprotein Cholesterol	Baseline and Week 16	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.
Change From Baseline to Week 20 in High-Density Lipoprotein Cholesterol	Baseline and Week 20	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.
Change From Baseline to Week 26 in High-Density Lipoprotein Cholesterol	Baseline and Week 26	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.
Change From Baseline in Triglycerides Over Time (Grouped Analysis)	Baseline and Weeks 4, 8, 12, 16, 20 and 26.	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.
Change From Baseline to Week 4 in Triglyceride Levels	Baseline and Week 4	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.
Change From Baseline to Week 8 in Triglyceride Levels	Baseline and Week 8	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.
Change From Baseline to Week 12 in Triglyceride Levels	Baseline and Week 12	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.
Change From Baseline to Week 16 in Triglyceride Levels	Baseline and Week 16	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.
Change From Baseline to Week 20 in Triglyceride Levels	Baseline and Week 20	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.
Change From Baseline to Week 26 in Triglyceride Levels	Baseline and Week 26	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.
Change From Baseline in Free Fatty Acids Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in Free Fatty Acids	Baseline and Week 12	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.
Change From Baseline to Week 26 in Free Fatty Acids	Baseline and Week 26	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.
Change From Baseline in Plasminogen Activator Inhibitor-1 Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in Plasminogen Activator Inhibitor-1	Baseline and Week 12	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.
Change From Baseline to Week 26 in Plasminogen Activator Inhibitor-1	Baseline and Week 26	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.
Change From Baseline in High-sensitivity C-Reactive Protein Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in High-sensitivity C-Reactive Protein	Baseline and Week 12	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.
Change From Baseline to Week 26 in High-sensitivity C-Reactive Protein	Baseline and Week 26	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.
Change From Baseline to Week 12 in IDL Particles	Baseline and Week 12	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.
Change From Baseline in Adiponectin Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in Adiponectin	Baseline and Week 12	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.
Change From Baseline to Week 26 in Adiponectin	Baseline and Week 26	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.
Change From Baseline in Body Weight Over Time (Grouped Analysis)	Baseline and Weeks 8, 12, 20 and 26.	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.
Change From Baseline to Week 8 in Body Weight	Baseline and Week 8	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.
Change From Baseline to Week 12 in Body Weight	Baseline and Week 12	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.
Change From Baseline to Week 20 in Body Weight	Baseline and Week 20	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.
Change From Baseline to Week 26 in Body Weight	Baseline and Week 26	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.
Change From Baseline to Week 12 in Apolipoprotein B	Baseline and Week 12	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.
Change From Baseline in Calculated Homeostatic Model Assessment Insulin Resistance (HOMA IR) (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in Calculated HOMA Insulin Resistance	Baseline and Week 12	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.
Change From Baseline to Week 26 in Calculated HOMA Insulin Resistance	Baseline and Week 26	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.
Change From Baseline in Homeostatic Model Assessment Beta Cell Function (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Calculated HOMA Beta-cell Function	Baseline and Week 12	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.
Change From Baseline to Week 26 in Calculated HOMA Beta-cell Function	Baseline and Week 26	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.
Change From Baseline in Apolipoprotein A1 Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in Apolipoprotein A1	Baseline and Week 12	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.
Change From Baseline to Week 26 in Apolipoprotein A1	Baseline and Week 26	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.
Change From Baseline in Apolipoprotein A2 Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Apolipoprotein A2	Baseline and Week 12	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.
Change From Baseline to Week 26 in Apolipoprotein A2	Baseline and Week 26	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.
Change From Baseline in Apolipoprotein B Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 26 in Apolipoprotein B	Baseline and Week 26	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.
Change From Baseline in Apolipoprotein C-III Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Apolipoprotein C-III	Baseline and Week 12	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.
Change From Baseline to Week 26 in Apolipoprotein C-III	Baseline and Week 26	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.
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in NMR Lipid Fractionation Total Triglycerides	Baseline and Week 12	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.
Change From Baseline to Week 26 in NMR Lipid Fractionation Total Triglycerides	Baseline and Week 26	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.
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in VLDL / Chylomicron Particles	Baseline and Week 12	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.
Change From Baseline to Week 26 in VLDL / Chylomicron Particles	Baseline and Week 26	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.
Change From Baseline in VLDL / Chylomicron Triglycerides Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in VLDL / Chylomicron Triglycerides	Baseline and Week 12	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.
Change From Baseline to Week 26 in VLDL / Chylomicron Triglycerides	Baseline and Week 26	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.
Change From Baseline in VLDL Particles Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in VLDL Particles	Baseline and Week 12	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.
Change From Baseline to Week 26 in VLDL Particles	Baseline and Week 26	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
Change From Baseline in Mean VLDL Particle Size Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Mean VLDL Particle Size	Baseline and Week 12	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.
Change From Baseline to Week 26 in Mean VLDL Particle Size	Baseline and Week 26	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.
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 26 in IDL Particles	Baseline and Week 26	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.
Change From Baseline in Low Density Lipoprotein (LDL) Particles Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in LDL Particles	Baseline and Week 12	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.
Change From Baseline to Week 26 in LDL Particles	Baseline and Week 26	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.
Change From Baseline in Mean LDL Particle Size Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Mean LDL Particle Size	Baseline and Week 12	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.
Change From Baseline to Week 26 in Mean LDL Particle Size	Baseline and Week 26	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.
Change From Baseline in High Density Lipoprotein (HDL) Particles Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26.	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.
Change From Baseline to Week 12 in HDL Particles	Baseline and Week 12	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.
Change From Baseline to Week 26 in HDL Particles	Baseline and Week 26	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.
Change From Baseline in Mean HDL Particle Size Over Time (Grouped Analysis)	Baseline and Weeks 12 and 26	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.
Change From Baseline to Week 12 in Mean HDL Particle Size	Baseline and Week 12	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.
Change From Baseline to Week 26 in Mean HDL Particle Size	Baseline and Week 26	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.