An insight into the role of telmisartan as PPAR-γ/α dual activator in the management of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease. It is rapidly emerging as the frequent cause for liver transplantation with the risk of disease recurrence, even after transplantation. Clinical evidence showed an abnormally altered expression of different peroxisome proliferator-activated receptor (PPAR) isotypes (PPAR-α/γ/δ) in NAFLD with an involvement in the induction of insulin resistance, hepatic steatosis, reactive oxygen species (ROS) formation, and hepatic inflammation. Recently, several dual PPAR-γ/α agonists were developed to simultaneously achieve the insulin-sensitizing effect of PPAR-γ as well as lipid catabolizing effect of PPAR-α. PPAR-α activation could counterbalance the steatogenic and adipogenic effects of PPAR-γ. But most of the drugs were ended in the initial level itself due to harmful adverse effects. In the present review, we discuss the possible mechanism of telmisartan, a typical angiotensin receptor blocker with excellent safety and pharmacokinetic profile, as a PPAR-γ/α dual agonist in the treatment of NAFLD.

Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models.

Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01-3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.