Is there robust evidence for the use of saraglitazar in the management of Metabolic Associated Steatohepatitis Liver Disease (MASLD)?

Saroglitazar for MASLD: Limited Evidence, Not Recommended by Major Guidelines

Saroglitazar is not mentioned or recommended in the most recent 2024 EASL-EASD-EASO clinical practice guidelines for MASLD management, and therefore cannot be recommended as a MASH-targeted therapy based on current high-quality guideline evidence. 1

Current Guideline-Recommended Pharmacotherapy

The 2024 joint European guidelines establish a clear hierarchy for MASLD pharmacological treatment:

• Resmetirom is the only MASH-targeted therapy with a strong recommendation for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2), based on large phase III trial data demonstrating histological efficacy on steatohepatitis and fibrosis with acceptable safety 1

• No MASH-targeted pharmacotherapy can currently be recommended for cirrhotic stage disease 1

• Vitamin E cannot be recommended as MASH-targeted therapy despite prior use, due to lack of robust demonstration of histological efficacy in large phase III trials and potential long-term risks 1

• GLP-1 receptor agonists (semaglutide, tirzepatide) cannot currently be recommended as MASH-targeted therapies in the absence of formal demonstration of histological improvement in large phase III trials, though they should be used for their approved indications (type 2 diabetes, obesity) as they improve cardiometabolic outcomes 1

• Pioglitazone cannot be recommended as MASH-targeted therapy given lack of robust demonstration of histological efficacy in large phase III trials 1

Why Saroglitazar Is Not Included

The comprehensive 2024 guidelines explicitly state there is insufficient evidence to support using any other glucose-lowering drug class as MASH-targeted therapies beyond those specifically discussed 1. Saroglitazar, a dual PPAR-α/γ agonist, falls into this category of agents lacking the robust phase III trial evidence required for guideline recommendation.

Available Evidence on Saroglitazar

While not guideline-endorsed, emerging research suggests potential benefits:

• A 2024 prospective randomized trial (SVIN trial) in 175 NAFLD patients showed that combination therapy of saroglitazar plus vitamin E significantly reduced liver stiffness measurement (LSM), controlled attenuation parameter (CAP), and improved biochemical, glycemic, and lipid parameters over 24 weeks 2

• Real-world evidence from 553 Indian patients demonstrated improvements in glycemic control (HbA1c reduction -0.71%), lipid profile (triglycerides -55.41 mg/dL), and liver enzymes (ALT -7.95 IU/L) with favorable safety 3

• However, these studies are limited by small sample sizes, short duration, lack of histological endpoints, and absence of large phase III registrational trials 4, 2

Critical Limitations

The evidence gap is substantial:

• No large phase III trials with histological endpoints (steatohepatitis resolution, fibrosis improvement) have been completed 4
• Limited regulatory approval outside India 4
• Lack of long-term safety and efficacy data on liver-related clinical outcomes 4
• The 2024 guidelines emphasize that histological surrogates must translate into clinical benefit, which has not been demonstrated for saroglitazar 1

Clinical Approach

For patients with MASLD requiring pharmacotherapy:

1. First-line: Lifestyle modification (weight loss >5-10%, Mediterranean diet, physical activity >150 min/week) remains cornerstone therapy 1

2. Metabolic comorbidity management: Use GLP-1 RAs, SGLT2 inhibitors, or other agents for their approved indications (diabetes, obesity, heart failure, chronic kidney disease) as they are safe in MASLD and improve cardiometabolic outcomes 1

3. MASH-targeted therapy: If locally approved, consider resmetirom for non-cirrhotic MASH with significant fibrosis (stage ≥2) 1

4. Saroglitazar: Cannot be recommended based on current guideline evidence; if considering use, it should only be in the context of clinical trials or in regions where approved, with clear understanding of the limited evidence base 4

Common pitfall: Prescribing agents like saroglitazar or vitamin E based on small studies or surrogate markers (liver enzymes, imaging) without robust phase III histological data demonstrating steatohepatitis resolution or fibrosis improvement, which are the validated endpoints required by regulatory agencies 1.