Saroglitazar as a Metabolic Modulator: A Critical Narrative Review of PPAR-Driven Therapeutic Actions

Abstract

Saroglitazar is an orally active dual peroxisome proliferator-activated receptor alpha/gamma agonist developed to couple triglyceride-rich lipoprotein lowering with insulin-sensitising activity while limiting the adverse effects historically associated with broad glitazar pharmacology. Its clinical evidence base now spans diabetic dyslipidaemia, hypertriglyceridaemia, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease, yet the strength of support differs substantially across these domains. This critical narrative review evaluates saroglitazar as a metabolic modulator rather than as a single-indication lipid-lowering drug. Literature was selected through live searches of major open scholarly databases and regional biomedical indexes, with bibliographic and Digital Object Identifier verification and critical appraisal of study design, endpoint validity, duration, comparator choice, sponsorship and external validity. Mechanistically, saroglitazar engages both PPAR alpha and PPAR gamma, but the frequently stated predominance of PPAR alpha is assay-dependent and should not be reduced to a universal potency ratio. Clinically, the most consistent evidence supports marked lowering of triglycerides and related atherogenic lipoprotein measures. Glycaemic improvements are reproducible but generally modest relative to the lipid effect, while a small clamp study provides direct evidence of improved insulin sensitivity. In steatotic liver disease, randomised trials, observational cohorts and a large 2026 phase 4 interim analysis show improvements in aminotransferases, liver fat and several non-invasive markers; nevertheless, recent randomised studies have not consistently demonstrated superiority over lifestyle intervention for liver stiffness or fibrosis-related endpoints. Safety has been broadly reassuring over short-to-intermediate follow-up, but a small creatinine increase has appeared in meta-analysis and long-term cardiovascular, renal and histological outcome data remain insufficient. Saroglitazar is therefore best interpreted as a clinically active PPAR-driven metabolic modulator with established surrogate metabolic efficacy and promising hepatic effects, but with disease-modifying and hard-outcome benefits still requiring dedicated confirmation.