PPAR- γ Agonist in Treatment of Diabetes: Cardiovascular Safety Considerations

Abstract

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.

PPAR-γ agonist attenuates inflammation in aortic aneurysm patients

“…Following side effects are widely known to cause by administration; Water retention, weight gain, peripheral edema and congestive heart failure [26]. In addition to these circulatory side effects, possible risk of bladder cancer is recently reported [27,28].…”

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

“…The functional interaction between PGC-1α and PPAR-α can stimulate lipid oxidation and decrease TG accumulation (32), while PPAR-γ may govern whole-body insulin sensitivity and lipid metabolism (33). In this study, the mRNA content of PPAR-α, CD36, and PPAR-γ was reduced in liver while only PPAR-α mRNA level was attenuated in the muscle of CG-IUGR rats, implicating a possible impairment of fatty acid oxidation at a different extent in the liver and muscle of GC-IUGR rats.…”

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

“…During a followup of 5 years, TZDs decreased the risk of new-onset AF by 31% after adjustment for age, underlying diseases and baseline medications. Although growing evidence suggests TZDs use prevents the development and recurrence of AF in diabetic patients, the cardiovascular safety considerations on rosiglitazone recently prompted the European Medicines Agency (EMA) to suspended this drug from the European market and patients taking rosiglitazone were advised to discuss alternative options with their physicians [39]. Since November 18, 2011 the FDA does not allow rosiglitazone to be sold without a prescription from certified doctors.…”