Clinical trial NCT00331487: Study to Compare Pioglitazone and Rosiglitazone in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia
Official title: Pioglitazone Versus Rosiglitazone in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus
Lipoatrophic
Dyslipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2006-05-31
Enrollment: 719
Sex: ALL
Minimum age (years): 35
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in fasting triglyceride level
timeFrame: Final Visit
Secondary outcomes:
measure: Change in fasting low-density lipoprotein cholesterol.
timeFrame: Final Visit
measure: Change in fasting high-density lipoprotein cholesterol.
timeFrame: Final Visit
measure: Change in fasting total cholesterol.
timeFrame: Final Visit
measure: Change in fasting free fatty acids.
timeFrame: Final Visit
measure: Change in plasminogen activator inhibitor 1
timeFrame: Final Visit
measure: Change in high-sensitivity C-reactive protein
timeFrame: Final Visit
measure: Change in fasting C-peptide.
timeFrame: Final Visit
measure: Homeostasis model assessment-insulin resistance mode.
timeFrame: Final Visit
measure: Change in fasting insulin.
timeFrame: Final Visit
measure: Homeostasis model assessment-beta cell function.
timeFrame: Final Visit
measure: Change in glycosylated hemoglobin.
timeFrame: Final Visit
measure: Change in fasting plasma glucose.
timeFrame: Final Visit
measure: Low-density lipoprotein particle concentration.
timeFrame: Final Visit
measure: Low-density lipoprotein particle size.
timeFrame: Final Visit
measure: High-density lipoprotein particle size.
timeFrame: Final Visit
measure: Very low-density lipoprotein particle size.
timeFrame: Final Visit
measure: Apolipoprotein A-I.
timeFrame: Final Visit
measure: Apolipoprotein B
timeFrame: Final Visit
measure: Lipoprotein a
timeFrame: Final Visit
measure: Apolipoprotein C-III.
timeFrame: Final Visit
Other outcomes:
Locations:
city: Anniston
country: United States
state: Alabama
city: Birmingham
country: United States
state: Alabama
city: Tucson
country: United States
state: Arizona
city: Concord
country: United States
state: California
city: Fremont
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Palos Verdes Estates
country: United States
state: California
city: San Diego
country: United States
state: California
city: Santa Barbara
country: United States
state: California
city: Santa Rosa
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Englewood
country: United States
state: Colorado
city: Avon
country: United States
state: Connecticut
city: Hamden
country: United States
state: Connecticut
city: Longwood
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Fayetteville
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Idaho Falls
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: South Bend
country: United States
state: Indiana
city: New Orleans
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Frederick
country: United States
state: Maryland
city: Salisbury
country: United States
state: Massachusetts
city: South Yarmouth
country: United States
state: Massachusetts
city: Waltham
country: United States
state: Massachusetts
city: Minneapolis
country: United States
state: Minnesota
city: Chesterfield
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: East Setauket
country: United States
state: New York
city: Endwell
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Staten Island
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Greenville
country: United States
state: North Carolina
city: Morehead City
country: United States
state: North Carolina
city: Wilmington
country: United States
state: North Carolina
city: Columbus
country: United States
state: Ohio
city: Franklin
country: United States
state: Ohio
city: Tulsa
country: United States
state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Salem
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Pottstown
country: United States
state: Pennsylvania
city: Providence
country: United States
state: Rhode Island
city: Mount Pleasant
country: United States
state: South Carolina
city: Knoxville
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: Beaumont
country: United States
state: Texas
city: Conroe
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Lake Jackson
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Ogden
country: United States
state: Utah
city: Mechanicsville
country: United States
state: Virginia
city: Newport News
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Federal Way
country: United States
state: Washington
city: Wenatchee
country: United States
state: Washington
city: Milwaukee
country: United States
state: Wisconsin
Study officials:
affiliation: Takeda
name: Alfonso Perez, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.