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Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonists

In the Treatment of Type 2 Diabetes Mellitus and the Metabolic Syndrome

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Treatments in Endocrinology

Abstract

The metabolic syndrome consists of a combination of cardiovascular risk factors that include hyperglycemia with or without type 2 diabetes mellitus, visceral obesity, elevated blood pressure, and atherogenic dyslipidemia. These interrelated disorders and their associated lipotoxicity, oxidative stress, and inflammatory state predispose to a constellation of cardiovascular conditions leading to high risk of heart attack, stroke, renal failure, blindness, and lower extremity amputation. Visceral obesity, a prime risk factor for type 2 diabetes and a major component of the metabolic syndrome, potentiates atherogenesis, atherosclerosis, organ lipotoxicity, and oxidative tissue damage.

Peroxisome proliferator-activated receptors (PPARs) are relatively recently discovered nuclear transcription factors that are modulated by dietary fatty acids, including the essential polyunsaturated fatty acids, arachidonic acid and its metabolites, and are essential to the control of energy metabolism. Of the three PPAR isoforms (α, γ, and δ), synthetic pharmaceutical ligands that activate PPARα (the antidyslipidemic fibric acid derivatives [‘fibrates’]) and PPARγ (the antidiabetic thiazolidinediones) have been studied extensively. Recently developed dual PPARα/γ agonists may combine the therapeutic effects of these drugs, creating the expectation of greater efficacy, and perhaps other advantages in the treatment of type 2 diabetes and the metabolic syndrome. However, thiazolidinediones are hampered by adverse effects related to increased weight gain and fluid overload. It remains to be seen whether the dual PPARα/γ agonists currently under development have similar limitations. Nevertheless, existing clinical data imply that the combined effects of thiazolidinediones and fibrates are likely to be emulated by dual PPARα/γ agonists, providing superior efficacy to these classes for the treatment of type 2 diabetes, the metabolic syndrome, and their cardiovascular and other end-organ complications.

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  1. Kern Medical Center and University of California, 1830 Flower Street, Irvine, Bakersfield, California, 93305, USA

    Harrihar A. Pershadsingh

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Pershadsingh, H.A. Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonists. Mol Diag Ther 5, 89–99 (2006). https://doi.org/10.2165/00024677-200605020-00003

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