A Multicenter, Prospective, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared with Placebo in Type 2 Diabetes Mellitus Patients Having Hypertriglyceridemia Not Controlled with Atorvastatin Therapy (PRESS VI)

Abstract

Background: Dyslipidemia due to diabetes is characterized by hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol (HDL-C) and elevated or normal levels of low-density lipoprotein cholesterol (LDL-C) in type 2 diabetes mellitus (T2DM). The objectives of this Phase III study were to evaluate the safety, tolerability, and efficacy of saroglitazar (ZYH1) 2-mg and 4-mg tablets (LipaglynÔ; Zydus Cadila, Ahmedabad, India) compared with placebo in patients with diabetic dyslipidemia who are not controlled with atorvastatin 10 mg therapy. Subjects and Methods: This was a 16-week prospective, multicenter, randomized, double-blind, placebo controlled, three-arm Phase III study in subjects with hypertriglyceridemia (>200 and <500 mg/dL) with T2DM not controlled with atorvastatin 10 mg. The study consisted of a run-in period of 4 weeks of life-style modification followed by 12 weeks of treatment with saroglitazar (2-mg or 4-mg) or placebo tablets. The primary end point was the change in plasma triglyceride level compared with baseline and the placebo arm at the end of Week 12. The secondary exploratory end points were change in lipid profile and fasting plasma glucose at Week 12. In total, 302 subjects were randomized to receive one of the treatments, saroglitazar 2 mg (n = 101) or saroglitazar 4 mg (n = 99), or matching placebo (n = 102). Patients who received study medication and had undergone at least one post baseline efficacy evaluation were included in the efficacy analysis. Results: At Week 12, saroglitazar 2-mg and 4-mg tablets significantly reduced mean plasma triglyceride levels by -45.5 -3.03% and -46.7 -3.02% (mean -SE), respectively, and the difference was significant (P < 0.001) compared with placebo. Saroglitazar 2 mg demonstrated significant decrease in levels of non-HDL-C, very LDL-C, total cholesterol, and fasting plasma glucose. Additionally, saroglitazar 4 mg also significantly reduced LDL-C and apolipoprotein B levels. Saroglitazar was found to be safe and well tolerated by patients. Conclusions: Saroglitazar appeared to be an effective and safe therapeutic option for improving hypertriglyceridemia in patients with T2DM.

Fenofibrate Reverses Palmitate Induced Impairment in Glucose Uptake in Skeletal Muscle Cells by Preventing Cytosolic Ceramide Accumulation

“…The remarkable improvement in mitochondrial FAO and insulin-mediated glucose uptake in myotubes by fenofibrate observed in our study is not replicated to a similar extent in clinical practice, possibly because of a much lower dose are used in human subjects due to safety concerns. A more potent and a safer PPARα agonist, like saroglitazar, may be the answer to palmitate induced lipotoxicity and insulin resistance in skeletal muscles in human subject with type2 diabetes in future [51,52].…”

Saroglitazar, a novel cardiometabolic agent for diabetic dyslipidemia - A Review

“…Both the saroglitazar arms (saroglitazar 2 mg/day + atorvastatin and saroglitazar 4 mg/day + atorvastatin) showed significant reduction in triglycerides (-45.5 ± 3.03% and -46.7±3.02% respectively in 2 mg and 4 mg arms) as compared with the third control arm (placebo + atorvastatin). 23 There was a significant decrease in levels of non-HDL-C, very LDL-C, total cholesterol and FPG in saroglitazar 2 mg arm while an additional decrease in LDL-C and apolipoprotein B levels was also observed in saroglitazar 4 mg arm. A reduction in HbA1 c level was also observed in both the saroglitazar arms but it was considered non-significant statistically.…”

Adverse drug reactions monitoring of newer oral hypoglycemic drugs in a tertiary care hospital of North India: a prospective study

“…29 In another multicenter study to evaluate the efficacy and safety of different doses of saroglitazar versus placebo (PRESS VI), gastritis was reported to be most common adverse effect. 30 These studies did not provide any possible explanation of association of gastritis or fatigue with saroglitazar use but reported that the ADRs due to saroglitazar were mild to moderate in intensity. Our findings are similar to these studies.…”

“…There has been a 46.7% decrease in trigltcerides, 32.5% decrease in non-HDL-C, 0.3% absolute reduction in glycosylated hemoglobin (HbA1c). 13,14 With increasing cases of lifestyle disorders along with diabetic dyslipidemia, saroglitazar is bound to help several patients suffering from it. Simultaneous agonistic activity on PPAR-α and PPAR-γ is a novel treatment option for diabetic dyslipidemia and other such discoveries in this area shall benefit many.…”