Clinical trial NCT00424762: Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride
Official title: Effect of Rosiglitazone Versus Placebo on Cardiovascular Performance and Myocardial Triglyceride
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Mellitus, Type 2
Congestive Heart Failure
Cardiopulmonary exercise testing
intracellular cardiomyocyte triglycerides
thiazolidinedione
rosiglitazone
nuclear magnetic resonance
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: Abbott RDx Cardiometabolic
First posted: 2007-01-22
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Peak Oxygen Uptake (VO2)
timeFrame: 6 months
Secondary outcomes:
measure: Intra-myocardial Triglyceride Content Using in Vivo Magnetic Resonance Spectroscopy at 6 Months
timeFrame: 6 months
measure: Percentage of Patients Developing New or Worsening Peripheral Edema
timeFrame: 6 months
Other outcomes:
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: University of Texas Southwestern Medical Center
name: Darren K McGuire, MD, MHSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Southwestern Medical Center
name: Darren K McGuire, M.D., MHSc
role: STUDY_CHAIR
References:
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.
citation: 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 function. Eur Heart J. 2010 Sep;31(18):2262-70. doi: 10.1093/eurheartj/ehq228. Epub 2010 Jul 2.
citation: Jarvie JL, Pandey A, Ayers CR, McGavock JM, Senechal M, Berry JD, Patel KV, McGuire DK. Aerobic Fitness and Adherence to Guideline-Recommended Minimum Physical Activity Among Ambulatory Patients With Type 2 Diabetes Mellitus. Diabetes Care. 2019 Jul;42(7):1333-1339. doi: 10.2337/dc18-2634. Epub 2019 May 21.
citation: McGavock J, Szczepaniak LS, Ayers CR, Abdullah SM, See R, Gore MO, Drazner MH, de Lemos JA, McGuire DK. The effects of rosiglitazone on myocardial triglyceride content in patients with type 2 diabetes: a randomised, placebo-controlled trial. Diab Vasc Dis Res. 2012 Apr;9(2):131-7. doi: 10.1177/1479164111428628. Epub 2011 Nov 8.
citation: Narang N, Armstead SI, Stream A, Abdullah SM, See R, Snell PG, McGavock J, Ayers CR, Gore MO, Khera A, de Lemos JA, McGuire DK. Assessment of cardiac structure and function in patients without and with peripheral oedema during rosiglitazone treatment. Diab Vasc Dis Res. 2011 Apr;8(2):101-8. doi: 10.1177/1479164111403334.