Safety Comparison of Pioglitazone and Glyburide in Type 2 Diabetes Subjects With Mild to Moderate Congestive Heart Failure
The purpose of this study is to compare the safety of Pioglitazone, once daily (QD), to Glyburide in Type 2 Diabetes Subjects with Mild to Moderate Congestive Heart Failure
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Randomized, Double-Blind, Comparator-Controlled Study of Pioglitazone HCl vs Glyburide in the Treatment of Subjects With Type 2 (Non-Insulin Dependent) Diabetes Mellitus and Mild to Moderate Congestive Heart Failure|
- Progression of Congestive Heart Failure. [ Time Frame: At First Event. ] [ Designated as safety issue: Yes ]
- Change from baseline in Glycosylated Hemoglobin. [ Time Frame: Weeks 12, 20 and Final Visit. ] [ Designated as safety issue: No ]
- Change from baseline in Fasting Plasma Glucose. [ Time Frame: At All Visits. ] [ Designated as safety issue: No ]
- Change from baseline in Triglycerides. [ Time Frame: Weeks 8, 16 and Final Visit. ] [ Designated as safety issue: No ]
- Change from baseline in cholesterol (total cholesterol, high-density lipoprotein and low-density lipoprotein). [ Time Frame: Weeks 8, 16 and Final Visit. ] [ Designated as safety issue: No ]
- Change from baseline in 6 Minute Walking test distance [ Time Frame: At Final Visit ] [ Designated as safety issue: No ]
- Physician & Subject Congestive Heart Failure Global Assessment Score [ Time Frame: At Final Visit ] [ Designated as safety issue: No ]
- Change in New York Heart Association classification [ Time Frame: At All Visits. ] [ Designated as safety issue: No ]
- Minnesota Living with Heart Failure Questionnaire total score. [ Time Frame: At Final Visit. ] [ Designated as safety issue: No ]
- Changes in blood pressure and heart rate. [ Time Frame: At All Visits. ] [ Designated as safety issue: Yes ]
- All cause mortality. [ Time Frame: At First Event. ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2000|
|Study Completion Date:||October 2003|
|Primary Completion Date:||October 2003 (Final data collection date for primary outcome measure)|
|Experimental: Pioglitazone QD||
Pioglitazone 30 mg (titrated to 45mg with tolerance), tablets, orally once daily and glyburide placebo-matching tablets, orally, once daily for up to 24 weeks.
|Active Comparator: Glyburide QD||
Pioglitazone placebo-matching tablets, orally, once daily and glyburide 10 mg (titrated to 15mg with tolerance), capsules, orally, once daily for up to 24 weeks.
Approximately 16 million people in the United States have been diagnosed with type 2 diabetes, a prevalence rate of approximately 6%, and the numbers are expected to increase with the increasing age of the general population. The risk factors associated with development of type 2 diabetes, such as age, obesity, and diet and exercise habits, also contribute to the development of cardiovascular disease. Additionally, patients with diabetes are at an increased risk for development of microvascular and macrovascular disease.
With regard to congestive heart failure, the risk of congestive heart failure is increased in subjects with diabetes in the absence of coronary artery disease; in subjects with diabetes and established coronary artery disease there is a higher overall risk and greater risk for more severe congestive heart failure. There is evidence that increasing insulin sensitivity and reducing hyperinsulinemia may reduce cardiovascular risks by reducing blood pressure, improving endothelial function, and through cardiac remodeling and function.
Pioglitazone is a thiazolidinedione for the treatment of type 2 diabetes, and is an agonist of the peroxisome proliferator-activated receptor. Pioglitazone received marketing approval in the United States in 1999. As part of the approval process, Takeda fulfilled a postmarketing study evaluating the effects of pioglitazone in the treatment of type 2 diabetes in subjects with congestive heart failure in a6-month clinical study.
An independent Data Safety Monitoring Board used to monitor the overall safety pattern of the study and to conduct unblinded reviews of data found a difference in the composite endpoint of time to first event that approached nominal statistical significance in favor of glyburide. As a result, the committee recommended that Takeda terminate the trial. Consistent with regulatory agency requirements, Takeda is submitting an abbreviated report that focuses on the safety data derived from the terminated study.