Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00424762
• Other study ID #: GSK 102610
• Status: Completed
• Phase: Phase 4
• First received: January 18, 2007
• Last updated: April 2, 2012
• Start date: February 2005
• Est. completion date: April 2007

Study information

• Verified date: April 2012
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if rosiglitazone treatment improves integrated cardiovascular performance in patients at risk for congestive heart failure. A second aim of this study is to determine if treatment with rosiglitazone decreases intracellular (ectopic) triglyceride (TG) deposition in cardiomyocytes using nuclear magnetic resonance (NMR) techniques, and how changes in intra-myocardial lipid content relate to changes in cardiac structure and function.

Description:

Cardiovascular disease (CVD), including congestive heart failure (CHF), accounts for over 75% of deaths among patients with diabetes. Thus, it is imperative to rigorously evaluate existing and emerging hypoglycemic therapies with regard to their cardiovascular consequences. The thiazolidinedione (TZD) class of drugs, alone or in combination with other oral hypoglycemic medications or with insulin, has emerged as a safe and effective treatment of hyperglycemia in type 2 diabetes. Both in vitro and in vivo studies have revealed favorable pleiotropic effects of TZD on myocyte and ventricular structure and function. However, approximately 10% of patients taking TZDs develop peripheral edema and some patients have developed heart failure decompensation on the drug. These observations have led to a Food and Drug Administration (FDA) warning regarding the use of TZDs in patients with or at high risk of developing congestive heart failure (CHF). The exact effects of TZDs on integrated cardiovascular performance remain unclear. The primary hypothesis of this study is that TZD treatment improves integrated cardiovascular performance in patients at risk for CHF by improving both central (i.e. cardiac output) and peripheral (i.e. vascular resistance) function.

Recently, we have developed a sensitive, reproducible noninvasive assay to measure intra-cardiomyocyte fat, which varies widely in amount between individuals. The relationship between the amount of cardiomyocyte triglyceride accumulation and LV mass and function remains unclear. TZDs have been previously shown to be associated with decreases in the TG content of the liver and muscle. The secondary hypothesis being tested in this study is that TZD treatment improves cardiac function by decreasing intra-cardiac myocyte triglyceride content.

Comparisons:

• Peak oxygen uptake (VO2) during cardiopulmonary exercise testing in individuals randomized to rosiglitazone, compared to those on placebo.

• Amount of intra-myocardial triglycerides using NMR techniques in in individuals randomized to rosiglitazone, compared to those on placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: April 2007
• Est. primary completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• type 2 diabetes mellitus (prior clinical diagnosis and current use of hypoglycemic medical therapy or by new diagnosis according to ADA criteria) with at least one of the following:

• prior diagnosis of cardiovascular disease (CAD, MI, revascularization, CVA/TIA, carotid or peripheral arterial disease)

• at least one additional CVD risk factor (smoking, hypertension, hypercholesterolemia, albuminuria, family history of premature CAD, or documented hsCRP>3)

Exclusion Criteria:

• treatment with a TZD within prior 6 months

• documented intolerance to TZD

• history or evidence of CHF

• AST/ALT>3X upper limits of normal

• creatinine >2.5

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• rosiglitazone
6 months of treatment of blinded study drug
• placebo
blinded treatment with matching placebo

Locations

Country	Name	City	State
United States	University of Texas Southwestern Medical Center	Dallas	Texas

Sponsors (3)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	Biosite, GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (2)

McGuire DK, Abdullah SM, See R, Snell PG, McGavock J, Szczepaniak LS, Ayers CR, Drazner MH, Khera A, de Lemos JA. Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and funct — View Citation

McGuire DK, See R, Abdullah SM, Snell PG, McGavock JM, Ayers CR, Szczepaniak LS. The effect of rosiglitazone on integrated cardiovascular performance, cardiac structure, function and myocardial triglyceride: trial design and rationale. Diab Vasc Dis Res. 2009 Jan;6(1):43-50. doi: 10.3132/dvdr.2009.009. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak Oxygen Uptake (VO2)	measurement of peak oxygen uptake (VO2peak) during treadmill exercise, in units of milliliters of oxygen per kilogram of fat-free mass per minute	6 months	Yes
Secondary	Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months	proton magnetic resonance spectroscopy determination of intra-myocardial triglyceride content at baseline and after 6 months, with triglyceride quantified analyzing fat and water signals assuming monoexponential signal decay and expressed as a percentage of fat-to-water (%)	6 months	Yes
Secondary	Percentage of Patients Developing New or Worsening Peripheral Edema	clinical evaluation of peripheral edema by physical exam at each study visit by a cardiologist using standard clinical severity scale 0-4, with new/worsening edema defined as any edema in patients with none at baseline, OR increase in severity by 2 or more points in patients with edema at baseline	6 months	Yes