Effect of a Dual PPAR α/γ agonist on Insulin Sensitivity in Patients of Type 2 Diabetes with Hypertriglyceridemia- Randomized double-blind placebo-controlled trial

Saroglitazar is a dual PPAR-alpha/gamma agonist approved for the treatment of diabetic dyslipidemia. In addition to reduction in atherogenic lipids, it may also contribute to improvement in insulin sensitivity through PPAR-alpha/gamma agonism, which remains unexplored. We conducted a randomized, double-blind, placebocontrolled trial in treatment-naive T2DM individuals with serum triglyceride >150 mg/dL. Participants were randomized to receive either saroglitazar 4 mg or placebo (1:1) daily for 4 months (n = 30). Insulin sensitivity (Sl(clamp)) was studied using hyperinsulinemic-euglycemic clamp at baseline and at 4 months. We observed a significant reduction in TG (p = 0.001), HbA1c (p = 0.019) and fasting plasma glucose (p = 0.019) and significant increase in HDL-C levels (p < 0.01) with saroglitazar compared to placebo. Further, patients on saroglitazar had a greater improvement in Sl(clamp) (p = 0.026) with the effect persisting despite adjusting for baseline weight, TG, HDL-C and HbA1c (p = 0.002). This was accompanied with significant increase in HOMA-beta (p = 0.01) in the saroglitazar group and change in HOMA-beta showed a trend towards significance with Sl(clamp )(r= 0.503, p = 0.056). However, change in Sl(clamp) did not significantly correlate with reduction in HbA1c and TG. We conclude that saroglitazar effectively reduces hypertriglyceridemia and improves insulin sensitivity along with beta-cell function by reduction in gluco-lipotoxicity and possibly directly through PPAR-gamma agonism in patients ofT2DM with hypertriglyceridemia.