Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator
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Hypertension commonly occurs as part of a genetically complex disorder of carbohydrate and lipid metabolism known as the metabolic syndrome. Most current antihypertensive drugs appear ineffective against the metabolic syndrome, which is a strong predictor of cardiovascular disease and death in affected patients. Angiotensin II can influence the activity of certain genes and cellular and biochemical pathways that may contribute to the pathogenesis of the metabolic syndrome. However, as a class, angiotensin II receptor blockers (ARBs) have proven only minimally to modestly effective in ameliorating the disturbances in carbohydrate and lipid metabolism that characterise the metabolic syndrome. Recent preclinical studies indicate that the ARB telmisartan acts as a selective peroxisome proliferators-activated receptor-gamma (PPARγ) modulator when tested at concentrations that might be achievable with oral doses recommended for treatment of hypertension; this property does not appear to be shared by other ARBs. PPARγ is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and is an attractive therapeutic target for the prevention and control of insulin resistance, type 2 diabetes and atherosclerosis. In cellular transactivation assays, telmisartan functioned as a partial agonist of PPARγ and achieved 25–30% of maximal receptor activation attained with conventional PPARγ ligands. Preclinical and clinical studies indicate that administration of telmisartan can improve carbohydrate and lipid metabolism without causing the side effects that accompany full PPARγ activators. If the preliminary data are supported by the results of ongoing large-scale clinical studies, telmisartan could have a central role in the prevention and treatment of metabolic syndrome, diabetes and atherosclerosis.