Title:PPAR- γ Agonist in Treatment of Diabetes: Cardiovascular Safety Considerations
Volume: 10
Issue: 2
Author(s): Aamer Abbas, Jimena Blandon, Jennifer Rude, Ahmed Elfar and Debabrata Mukherjee
Affiliation:
Keywords:
Bladder cancer, bone loss, cardiovascular diseases, diabetes, edema, heart failure, insulin resistance, pioglitazone,
prediabetes, PPAR-γ agonist, rosiglitazone, thiazolidinedione
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.
