Rosiglitazone to Treat Patients With Heart Failure and Glucose Intolerance or Type II Diabetes

The current medical management for heart failure invariably employs a 'one treatment fits all' approach. The failure to appreciate specific genotypic/phenotypic features in heart failure subjects is postulated to be a reason recent heart failure studies evaluating the efficacy of tumor necrosis factor alpha antagonists and endothelin receptor blockers showed no overall benefit. This experience suggests that the future improvement in the medical management of patients with heart failure may require pre-prescription genotyping/phenotyping to tailor drug therapy to the underlying mechanistic processes orchestrating the development and progression of heart failure.

In this regard, the insulin-resistance syndrome has been recognized as a significant associated factor with the development of cardiac hypertrophy and heart failure. A novel class of agents has been developed that increase insulin sensitivity via the activation of the transcription factor-peroxisomal proliferators activated receptor gamma (PPAR gamma). These drugs, known as the thiazolidinediones are currently licensed for the treatment of type II diabetes mellitus. Interestingly, at the preclinical level, PPAR gamma appears to play a regulatory role in attenuating the development of cardiac hypertrophy and thiazolidinedione therapy has been shown to attenuate the development of contractile dysfunction in mice following myocardial infarction.

The hypothesis intrinsic to this proposal is that insulin resistance is commonly associated with the development/progression of heart failure and that improving insulin sensitivity will be of clinical benefit in this select group of patients with heart failure. The primary objective of this study is to establish the safety and efficacy of thiazolidinedione therapy in insulin-resistant heart failure subjects. The study is designed as a phase II, randomized, double-blind, placebo-controlled dose escalation study. The primary outcomes will be the safety of administration, and the evaluation of the modulation in contractile function in heart failure subjects treated with thiazolidnediones. Moreover, changes in functional capacity and the determination of the biochemical and genomic modification of heart failure and insulin-resistance will be measured in response to thiazolidnedione therapy in heart failure subjects.

• INCLUSION CRITERIA:

Adult normal volunteers, age matched (55-75 years of age)

Adult patients greater than 21 years of age who meet the following criteria:

• Heart Failure due to ischemic heart disease or of idiopathic etiology
• Depressed LV systolic function, EF less than or equal to 0.45 by Radionuclide Angiography (MUGA)
• New York Heart Association Functional Class II or III
• Patient stable on current heart failure therapy
• Evidence of insulin resistance or type II diabetes on insulin-sensitivity screening
• No predicted cardiac revascularization therapy requirements

Exclusion criteria

Pregnant or lactating

History of admission for acute heart failure exacerbation within last one month

Acute myocardial infarction within the last three months

Cardiac resynchronization pacemaker placement within the last three months

Genetic defect known to have induced heart failure

Serum creatinine greater than 2.5 mg/dL.

Liver transaminase levels greater than 2.5 x upper limit of normal

Requirement for insulin therapy to control blood glucose

Current use of thiazolidinedione for diabetic control or history of discontinuation of thiazolidinedione therapy following development of side effects

Uncontrolled blood glucose levels or the use of insulin therapy to control diabetes

Immune compromise including chronic HIV, HBV, and HCV infection

Chronic systemic inflammatory disease such as SLE, rheumatoid arthritis, collagen vascular disease

Participation in unrelated research involving investigational pharmacological agent 30 days before planned dosing

Current alcohol or drug abuse

Inability to provide informed consent