Is saroglitazar approved for the treatment of metabolic-associated steatotic liver disease (MASLD)?

Is Saroglitazar Approved for Treatment of MASLD?

No, saroglitazar is not approved for the treatment of MASLD and is explicitly not recommended by current international guidelines due to lack of robust evidence from large Phase III trials demonstrating histological efficacy on steatohepatitis and liver fibrosis. 1, 2, 3

Guideline Position on Saroglitazar

The 2024 EASL-EASD-EASO clinical practice guidelines—the most authoritative and recent guidance on MASLD management—do not include saroglitazar in their treatment recommendations for MASLD/MASH. 1 These guidelines explicitly state that only therapies with demonstrated histological efficacy in large Phase III trials should be recommended as MASH-targeted treatments. 3

The guidelines prioritize resmetirom as the only currently recommended MASH-targeted pharmacotherapy for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2), based on large Phase III registrational trial data. 1, 3

What IS Recommended Instead

For MASH-Targeted Therapy:

• Resmetirom is the sole medication with a strong recommendation for non-cirrhotic MASH with fibrosis stage ≥2, demonstrating histological efficacy on both steatohepatitis and fibrosis with acceptable safety profile. 1, 3

For Metabolic Comorbidities (Safe in MASLD but not MASH-targeted):

• GLP-1 receptor agonists (semaglutide, liraglutide) or dual GIP/GLP-1 agonists (tirzepatide) should be used for their approved indications of type 2 diabetes and obesity, as they improve cardiometabolic outcomes and are safe in MASH including compensated cirrhosis. 1, 2 With substantial weight loss, hepatic histological benefit could be expected, though not extensively documented. 1

• SGLT2 inhibitors are safe in MASLD and should be used for type 2 diabetes, heart failure, and chronic kidney disease indications, though insufficient evidence exists for MASH-targeted therapy. 1, 2, 4

• Pioglitazone is safe in non-cirrhotic MASH but cannot be recommended as MASH-targeted therapy due to lack of robust Phase III trial evidence. 1

Why Saroglitazar Is Not Recommended

The exclusion of saroglitazar from guidelines is based on the absence of large-scale Phase III trials demonstrating histological improvement. 1, 3 While small observational studies and case series from India have shown improvements in liver stiffness, transaminases, and metabolic parameters 5, 6, 7, 8, these do not meet the evidentiary threshold required by international guideline bodies.

The available evidence for saroglitazar consists primarily of:

• Small retrospective case series (n=10) showing reduction in shear wave elastography values 5
• Observational studies (n=30-85) demonstrating improvements in FibroScan measurements and liver enzymes 6, 8
• Real-world electronic medical record data (n=553) showing metabolic improvements 7

These studies lack the histological endpoints, sample size, and methodological rigor of Phase III registrational trials required for guideline inclusion. 9

Clinical Algorithm for MASLD Pharmacotherapy

Step 1: Risk Stratification

• Calculate FIB-4 score; if indeterminate or high risk, proceed to liver stiffness measurement or ELF testing. 2
• Identify clinically significant fibrosis (≥F2) or advanced fibrosis. 1, 2

Step 2: MASH-Targeted Therapy (if locally approved)

• For non-cirrhotic MASH with fibrosis stage ≥2: Consider resmetirom. 1, 3
• For cirrhotic MASH: No MASH-targeted pharmacotherapy currently recommended. 1, 4

Step 3: Metabolic Comorbidity Management

• Type 2 diabetes with overweight/obesity: GLP-1 RAs or GIP/GLP-1 agonists as first-line. 2, 4
• Type 2 diabetes with cardiovascular/renal disease: SGLT2 inhibitors. 2, 4
• Consider combination therapy with pioglitazone plus GLP-1 RA for biopsy-proven MASH or high fibrosis risk. 2

Step 4: Lifestyle Modification (Foundation for All)

• Target 7-10% weight loss through Mediterranean diet and 150-300 minutes weekly moderate-intensity exercise. 2, 3

Critical Pitfalls to Avoid

• Do not use saroglitazar as a MASH-targeted therapy based on current guideline recommendations, even though it may be approved in some countries (like India) for diabetic dyslipidemia. 1, 3

• Do not delay treatment waiting for liver biopsy confirmation in patients with high-risk noninvasive test results who require diabetes management—initiate GLP-1 RAs or other appropriate agents. 2

• Do not discontinue GLP-1 RAs in patients who develop compensated cirrhosis, as they remain safe in this population. 2, 4

• Saroglitazar may only be considered in specific contexts where guideline-recommended therapies are unavailable, unaffordable, or contraindicated, but this represents off-guideline use based solely on observational data. 2 Patients should be counseled about the lack of robust evidence for liver-specific outcomes. 2