Glitazones and heart failure: critical appraisal for the clinician.

Abstract

Mr S. is a 46-year-old East-Indian male with typical manifestations of the cardiovascular dysmetabolic syndrome of insulin resistance (type II diabetes, obesity, dyslipidemia, hypertension, and elevated levels of high-sensitivity C-reactive protein). His medications include ramipril, simvastatin, enteric-coated aspirin, metformin, and glyburide. He has no symptoms of cardiac ischemia or congestive heart failure and has preserved left ventricular function. Over the past few months his glycemic control has been inadequate, and a decision to initiate an insulin sensitizer (glitazone) is made. Treatment is initiated with rosiglitazone 4 mg twice daily, with marked improvement in glycemic control and other components of the cardiovascular dysmetabolic syndrome. Approximately 6 months after initiation of therapy, your junior resident receives a phone call from Mr S, who is extremely anxious and distraught about the possibility of developing heart failure on glitazone therapy. The resident and the patient request your expert opinion about the effects of glitazones on cardiac function and associated hemodynamics. Insulin resistance has been increasingly recognized as a central metabolic disturbance predisposing a patient to hypertension, hyperlipidemia, premature atherosclerosis, left ventricular hypertrophy, and endothelial dysfunction.1 In addition to being a powerful risk marker for the development of cardiovascular disease, insulin resistance is also closely related to cardiac dysfunction and heart failure.2 Thiazolidinediones (TZD; glitazones) are peroxisome proliferator-activated receptor (PPAR) agonists that specifically augment insulin sensitivity and counter insulin resistance in patients with the cardiovascular dysmetabolic syndrome. Currently, there are 2 commercially available glitazones, rosiglitazone and pioglitazone. Troglitazone was withdrawn from the market because of hepatic side effects. The PPAR family is composed of 3 subtypes. TZDs bind with high affinity to the PPARγ isoform. The PPARγ isoform is found in the heart,3–6 endothelium, vascular smooth muscle (including atherosclerotic lesions and neointima formed after angioplasty), liver, skeletal muscle, monocytes/macrophages, and many other …