Study to Compare Pioglitazone and Rosiglitazone in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia

Pioglitazone Versus Rosiglitazone in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia

Efficacy comparison of Pioglitazone, once daily (QD), to Rosiglitazone in participants with Type 2 Diabetes

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Pioglitazone; Drug: Rosiglitazone

Detailed Description

At least two metabolic defects contribute to the development of type 2 diabetes mellitus: relative insulin insufficiency and insulin resistance. The majority of patients with type 2 diabetes mellitus demonstrate some degree of insulin resistance. Even in the absence of hyperglycemia (high blood sugar), insulin resistance is associated with a cluster of metabolic abnormalities that increase the risk for cardiovascular disease, including dyslipidemia (unhealthy blood fat), increased expression of inflammatory markers, activation of pro-coagulants (pro-clotting), hemodynamic changes, and endothelial dysfunction.

The dyslipidemia associated with insulin resistance and type 2 diabetes mellitus is characterized by elevated triglyceride levels and decreased high-density lipoprotein (good) cholesterol levels. Although low-density lipoprotein (bad) cholesterol levels may not be significantly elevated in patients with type 2 diabetes mellitus, an increase in the proportion of small, dense low-density lipoprotein cholesterol particles of increased atherogenicity (increased formation of lipid deposits in the arteries) is observed. When compared with individuals without type 2 diabetes mellitus, the risk of cardiovascular disease is 2- to 4-fold greater in patients with type 2 diabetes mellitus, and the dyslipidemia of diabetes is an important contributor to the increased risk in this population.

By targeting the insulin resistance underlying type 2 diabetes mellitus, the thiazolidinedione class of oral antihyperglycemic medications possesses both a glucose-lowering effect and the potential to alter lipid/lipoprotein metabolism. Two thiazolidinediones are currently available for the treatment of type 2 diabetes mellitus: pioglitazone hydrochloride (ACTOS, Takeda Pharmaceuticals North America, Inc, Lincolnshire, IL) and rosiglitazone maleate (Avandia, GlaxoSmithKline, Research Triangle Park, NC).

The purpose of this study is to evaluate the triglyceride-lowering effects of pioglitazone to rosiglitazone in patients with type 2 diabetes mellitus and dyslipidemia who are not receiving any other glucose- or lipid-lowering therapies at the same time as the study medications.

Individuals who participate in this study will provide written informed consent and will be required to commit to a screening visit and approximately 7 additional visits at the study center. Study participation is anticipated to be about 39 weeks (or approximately 8 months). Multiple procedures will occur at each visit which may include fasting, blood collection, physical examinations and electrocardiograms. Participants will be required to follow a diabetic diet, self-monitor their blood glucose and maintain a study diary for the duration of the study.

• Study Type: Interventional
• Enrollment (Actual): 719
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
    • Birmingham, Alabama, United States, 35234
  • Arizona
    • Tucson, Arizona, United States, 85710
  • California
    • Concord, California, United States, 94520
    • Fremont, California, United States, 94538
    • Los Angeles, California, United States, 90095
    • Palos Verdes Estates, California, United States, 90274
    • San Diego, California, United States, 92120
    • Santa Barbara, California, United States, 93105
    • Santa Rosa, California, United States, 95405
  • Colorado
    • Aurora, Colorado, United States, 80010
    • Englewood, Colorado, United States, 80110
  • Connecticut
    • Avon, Connecticut, United States, 06001
    • Hamden, Connecticut, United States, 06518
  • Florida
    • Longwood, Florida, United States, 32750
    • Miami, Florida, United States, 33136
    • Miami, Florida, United States, 33133
  • Georgia
    • Atlanta, Georgia, United States, 30342
    • Fayetteville, Georgia, United States, 30214
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
  • Illinois
    • Chicago, Illinois, United States, 60610
  • Indiana
    • Indianapolis, Indiana, United States, 46202
    • South Bend, Indiana, United States, 46601
  • Louisiana
    • New Orleans, Louisiana, United States, 70127
  • Maryland
    • Baltimore, Maryland, United States, 21204
    • Frederick, Maryland, United States, 21702
  • Massachusetts
    • Salisbury, Massachusetts, United States, 01952
    • South Yarmouth, Massachusetts, United States, 02664
    • Waltham, Massachusetts, United States, 02453
  • Minnesota
    • Minneapolis, Minnesota, United States, 55416
  • Missouri
    • Chesterfield, Missouri, United States, 63017
  • Nebraska
    • Omaha, Nebraska, United States
  • New York
    • East Setauket, New York, United States, 11733
    • Endwell, New York, United States, 13760
    • New York, New York, United States, 10025
    • Rochester, New York, United States, 14607
    • Staten Island, New York, United States, 10305
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
    • Durham, North Carolina, United States, 27713
    • Greenville, North Carolina, United States, 27834
    • Morehead City, North Carolina, United States, 28557
    • Wilmington, North Carolina, United States, 28412
  • Ohio
    • Columbus, Ohio, United States, 43210
    • Franklin, Ohio, United States, 45005
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
  • Oregon
    • Portland, Oregon, United States, 97201
    • Salem, Oregon, United States, 97302
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19124
    • Pottstown, Pennsylvania, United States, 19464
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
  • South Carolina
    • Mount Pleasant, South Carolina, United States, 29464
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
    • Memphis, Tennessee, United States, 38119
  • Texas
    • Beaumont, Texas, United States, 77701
    • Conroe, Texas, United States, 77384
    • Dallas, Texas, United States, 75390
    • Houston, Texas, United States, 77024
    • Lake Jackson, Texas, United States, 77566
    • San Antonio, Texas, United States, 78229
  • Utah
    • Ogden, Utah, United States, 84403
  • Virginia
    • Mechanicsville, Virginia, United States, 23111
    • Newport News, Virginia, United States, 23606
    • Virginia Beach, Virginia, United States, 23455
  • Washington
    • Federal Way, Washington, United States, 98003
    • Wenatchee, Washington, United States, 98801
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53209

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Type 2 diabetes mellitus according to the World Health Organization criteria and have diabetes-associated dyslipidemia (fasting triglycerides level between greater than or equal to 150 mg per dL and less than or equal to 600 mg per dL, and a fasting direct low-density lipoprotein cholesterol less than or equal to 130 mg per dL).
• Fasting serum C-peptide greater than or equal to1 ng per
• Glycosylated hemoglobin greater than or equal to 7% and less than or equal to 11% if naive to oral antihyperglycemic medications, or greater than or equal to 9.5% if previously treated with oral antihyperglycemic monotherapy

Exclusion Criteria

• Investigator site personnel and their immediate families. Immediate family defined as a spouse, parent, child or sibling, whether biological or legally adopted.
• Treatment with a drug within 30 days of Visit 1 that had not received regulatory approval.

• Treatment within 60 days of Visit 1 with any of the following:

  • insulin
  • systemic glucocorticoid therapy (excluding topical and inhaled preparations)
  • combination glycemic therapy (two or more oral anti-diabetes medications)
  • any lipid-lowering agent (including nicotinic acid, fibrates, bile acid resin binders, statins, d thyroxine or neomycin)
  • any weight loss agent (prescription or over the counter)
• Pregnant, breast feeding, or intending to become pregnant during the study.
• Serum creatinine greater than or equal to 176.8 μmol per L or greater than or equal to 2 plus per dipstick.
• Proteinuria at Visit 1.
• Alanine transaminase or aspartate transaminase greater than or equal to 1.5 times the upper limit of normal at Visit 1 or had significant clinical signs or symptoms of liver disease.
• History of signs or symptoms of liver disease, such as jaundice or alanine transaminase greater than or equal to 1.5 times the upper limit of normal, while treated with any thiazolidinedione
• Hemoglobin less than 10.5 g per dL for females and less than11.5 g per dL for males at Visit 1.
• Clinically or biochemically based on thyroid stimulating hormone at Visit 1 hypothyroid or hyperthyroid.
• History of myocardial infarction, acute cardiovascular event, or heart surgery within 6 months of Visit 1.
• Functional New York Heart Association Cardiac Class III or IV disease.
• Receiving renal dialysis or has had received a renal transplant.
• Undergoing therapy for a malignancy other than basal cell or squamous cell skin cancer.
• Clinical signs or symptoms of drug or alcohol abuse.
• History of HIV infection.
• Allergy to any glitazone drug.
• Medical history or the presence of any clinically significant or unstable medical condition that made the patient unlikely to complete the study.
• Any condition or situations that precluded adherence and completion of the protocol or a precluding ability to voluntarily give informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone QD	Drug: Pioglitazone; Pioglitazone 30 mg capsules, orally, once daily and placebo-matching capsules, orally, once daily for up to 12 weeks; increasing to pioglitazone 45 mg, capsules, orally, once daily and placebo-matching capsules, orally, once daily for up to 12 weeks; Other Names: Actos; AD4833
Active Comparator: Rosiglitazone QD	Drug: Rosiglitazone; Rosiglitazone 4 mg capsules, orally, once daily and placebo-matching capsules, orally, once daily for up to 12 weeks; increasing to rosiglitazone 4 mg, capsules, orally, twice daily for up to 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in fasting triglyceride level	Final Visit

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in fasting low-density lipoprotein cholesterol.	Final Visit
Change in fasting high-density lipoprotein cholesterol.	Final Visit
Change in fasting total cholesterol.	Final Visit
Change in fasting free fatty acids.	Final Visit
Change in plasminogen activator inhibitor 1	Final Visit
Change in high-sensitivity C-reactive protein	Final Visit
Change in fasting C-peptide.	Final Visit
Homeostasis model assessment-insulin resistance mode.	Final Visit
Change in fasting insulin.	Final Visit
Homeostasis model assessment-beta cell function.	Final Visit
Change in glycosylated hemoglobin.	Final Visit
Change in fasting plasma glucose.	Final Visit
Low-density lipoprotein particle concentration.	Final Visit
Low-density lipoprotein particle size.	Final Visit
High-density lipoprotein particle size.	Final Visit
Very low-density lipoprotein particle size.	Final Visit
Apolipoprotein A-I.	Final Visit
Apolipoprotein B	Final Visit
Lipoprotein a	Final Visit
Apolipoprotein C-III.	Final Visit

Collaborators and Investigators

• Sponsor: Takeda
• Collaborators: Eli Lilly and Company
• Investigators: Study Director: Alfonso Perez, MD, Takeda

Publications and helpful links

General Publications

• Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ; GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005 Jul;28(7):1547-54. doi: 10.2337/diacare.28.7.1547.
• Tilden DP, Mariz S, O'Bryan-Tear G, Bottomley J, Diamantopoulos A. A lifetime modelled economic evaluation comparing pioglitazone and rosiglitazone for the treatment of type 2 diabetes mellitus in the UK. Pharmacoeconomics. 2007;25(1):39-54. doi: 10.2165/00019053-200725010-00005. Erratum In: Pharmacoeconomics. 2007;25(3):237.
• Deeg MA, Buse JB, Goldberg RB, Kendall DM, Zagar AJ, Jacober SJ, Khan MA, Perez AT, Tan MH; GLAI Study Investigators. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2007 Oct;30(10):2458-64. doi: 10.2337/dc06-1903. Epub 2007 Jun 26.

Study record dates

Study Major Dates

• Study Start: September 1, 2000
• Primary Completion (Actual): March 1, 2004
• Study Completion (Actual): March 1, 2004

Study Registration Dates

• First Submitted: May 30, 2006
• First Submitted That Met QC Criteria: May 30, 2006
• First Posted (Estimate): May 31, 2006

Study Record Updates

• Last Update Posted (Estimate): February 28, 2012
• Last Update Submitted That Met QC Criteria: February 27, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Drug Therapy; Dyslipidemia; Type II Diabetes; Diabetes Mellitus; Glucose Metabolism Disorder; Dysmetabolic Syndrome; Lipoatrophic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Lipid Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dyslipidemias; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone; Rosiglitazone
• Other Study ID Numbers: H6E-US-GLAI; U1111-1115-9039 (Registry Identifier: WHO)