Saroglitazar

Saroglitazar is used for: Diabetic dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD) and lipodystrophy

Oral Tablet Diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus not controlled by statin therapy. The recommended dose is one tablet of 4 mg once a day.

Hypersensitivity to saroglitazar or any of the excipients used in the formulation.

Although clinical studies with saroglitazar have not demonstrated any potential for myopathies or derangement of liver and/or renal function, saroglitazar treatment should be initiated with caution in patients with abnormal liver or renal function, or history of myopathies. Saroglitazar has not been studied in patients with established New York Heart Association (NYHA) Class III or IV heart failure. Saroglitazar should be initiated with caution in patients with type 2 diabetes having cardiac disease with episodic congestive heart failure and such patients should be monitored for signs and symptoms of congestive heart failure. Although during the clinical studies, no significant weight gain and edema was reported with saroglitazar, patients who experience rapid increase in weight should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.

Pregnancy Pregnancy: Category C The safety of saroglitazar in pregnant women has not been established as there is no adequate and well-controlled study carried out in pregnant women. Women who become pregnant during saroglitazartreatment should contact their physicians. Saroglitazar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, effects of saroglitazar on the embryo-fetal development were assessed in pregnant rats given repeated oral doses of 5, 25 and 125mg/kg/day. No maternal or fetal toxicity was noticed at 5 mg/kg, which is about 12-fold higher on body surface area basis than the maximum recommended human dose (MRHD) of LipaglynTM 4 mg. Saroglitazar was found to be non-teratogenic up to the highest dose of 125 mg/kg day in rats. In pregnant rabbits given repeated oral doses of 10, 50 and 200 mg/kg/day of saroglitazar, no maternal toxicity was noticed up to 10 mg/kg and no fetal toxicity up to 50 mg/kg. Saroglitazar was found to be non-teratogenic up to the highest dose of 200 mg/kg/day in rabbits. Nursing mothers Nursing mothers should not use saroglitazar because it is not known whether saroglitazar is excreted into the breast milk.

In vitro studies using recombinant human cytochrome P-450 (CYP) isozymes indicate that saroglitazar does not significantly inhibit CYP1A2, 2C9, 2C19, 2D6 and 3A4 at concentrations of 10 μM. Similarly, saroglitazar did not show any potential for CYP3A4 enzyme induction when tested up to 100 μM concentration in luciferase-based reporter assay in transiently transfected HepG2 cells. Although no clinical drug-drug interaction studies have been conducted with saroglitazar so far, because the tested concentrations (10 μM and 100 μM) are several times higher than the mean Cmax of saroglitazar, it can be inferred that saroglitazar would not cause clinically significant drug-drug interactions related to the above-evaluated CYPs.

Side effects of Saroglitazar : The most common adverse events (AEs >2%) reported were gastritis, asthenia and pyrexia. Most of the AEs were mild to moderate in nature and did not result in discontinuation of the study

Saroglitazar is a potent and predominantly Peroxisome Proliferator-Activated Receptor (PPAR)-alpha agonist with moderate PPAR-gamma agonistic activity. PPARs are nuclear lipid-activated transcription factors that regulate the expression of various genes involved in the control of lipid and lipoprotein metabolism, glucose homeostasis and inflammatory processes. The pharmacological effects of saroglitazar were extensively evaluated in various preclinical models. Saroglitazar showed both anti-dyslipidemic and anti-diabetic effects mainly mediated via activation of PPARα and PPARγ respectively. PPARα activation by saroglitazar increases the hepatic oxidation of fatty acids (FA) and reduces the synthesis and secretion of TG. This in turn increases diversion of FA from peripheral tissues (e.g. skeletal muscle and fat tissue) to the liver, and thereby decreasing both FA synthesis and delivery of TG to peripheral tissues. Saroglitazar also causes increased lipolysis and elimination of TG-rich particles from plasma by activating lipoprotein lipase (LPL) and reducing production of apolipoprotein C-III (an inhibitor of LPL activity). Consistent with the above mechanism, saroglitazar was also found to reduce plasma LDL cholesterol. PPARα activation by saroglitazar also induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol. Although saroglitazar is predominantly a PPARα agonist, it also causes activation of PPARγ and regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport and utilization. Saroglitazar increases the expression of numerous PPARγ-responsive genes involved in carbohydrate and lipid metabolism, including adiponectin, adipocyte fatty-acidbinding protein (aP2), LPL, fatty acid transport protein (FATP) and fatty acid translocase (CD36). By increasing the expression of these genes, saroglitazar decreases the post prandial rise of plasma free fatty acids, improves post-absorptive insulin-mediated suppression of hepatic glucose output, reduces the metabolic burden on liver & muscle and promotes glucose utilization. Robust antidiabetic and insulin sensitizing effects of saroglitazar were observed in preclinical models, in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues.