Abstract
Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR- agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.
Highlights
Drugs affecting peroxisome proliferator-activated receptors (PPARs) are of intense interest for regulating disorders of glucose and fatty acid metabolism [1].As an end-stage manifestation of insulin resistance and glucose intolerance, diabetes confers a 2-to-8-fold higher risk of coronary heart disease (CHD), stroke, and mortality [2].Impaired glucose tolerance contributes to the development of atherogenic dyslipidemia, which is characterized by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, small dense low-density lipoprotein (LDL) cholesterol, and elevated LDL particle number
Agonists of PPAR-α and PPAR-γ have been evaluated for the long-term prevention of cardiovascular events
In the Veterans Affairs HDL Intervention Trial (VAHIT), a >20% reduction in CHD and stroke occurred despite no effect on LDL and only a 6% increase in HDL
Summary
Drugs affecting peroxisome proliferator-activated receptors (PPARs) are of intense interest for regulating disorders of glucose and fatty acid metabolism [1].As an end-stage manifestation of insulin resistance and glucose intolerance, diabetes confers a 2-to-8-fold higher risk of coronary heart disease (CHD), stroke, and mortality [2].Impaired glucose tolerance contributes to the development of atherogenic dyslipidemia, which is characterized by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, small dense low-density lipoprotein (LDL) cholesterol, and elevated LDL particle number. Fibrates are low-affinity PPAR-α agonists which lower triglycerides by increasing lipolysis and β-oxidation of fatty acids [4]. Pharmacologic activation of PPAR-γ lowers triglyceride levels by promoting fatty acid storage [5]. Thiazolidinediones (TZDs), or glitazones, are primarily PPAR-γ agonists that promote fatty acid oxidation and insulin sensitivity in liver and muscle [1]. These beneficial effects appear to be mediated, at least in part, through inhibition of the release of signaling molecules from adipose tissue that promote insulin resistance, including inflammatory factors such as tumor necrosis factor-α (TNF-α) and resistin, and stimulating the release of adiponectin. PPAR Research cardiovascular risk reduction benefit from these agents? Several recently completed large trials addressing this question have had mixed results
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