What is the role of Saroglitazar in the management of Metabolic Associated Fatty Liver Disease (MAFLD) in diabetic patients?

Saroglitazar in MAFLD Management for Diabetic Patients

Current Guideline Position

Saroglitazar is not recommended by major international guidelines (EASL-EASD-EASO 2024) as a MAFLD/MASLD-targeted therapy, as it lacks large Phase III trials demonstrating histological improvement in liver fibrosis or steatohepatitis. 1

The most recent 2024 EASL-EASD-EASO guidelines do not include saroglitazar among recommended pharmacological options for MASLD/MASH treatment in diabetic patients. 1 Instead, these guidelines prioritize:

• GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) as preferred agents for diabetic patients with MASLD, given their proven benefits on cardiometabolic outcomes and potential hepatic histological benefits with substantial weight loss 1, 2
• SGLT2 inhibitors (empagliflozin, dapagliflozin) are safe in MASLD and should be used for their approved indications (diabetes, heart failure, chronic kidney disease), though insufficient evidence exists for MASH-targeted therapy 1
• Pioglitazone cannot be recommended as MASH-targeted therapy despite some benefits, due to lack of Phase III trial evidence on fibrosis 1

Real-World Evidence for Saroglitazar

Despite absence from international guidelines, real-world studies from India demonstrate saroglitazar's effects on MAFLD-related parameters:

Hepatic Benefits

• Liver stiffness reduction: One observational study (n=30) showed significant improvement in FibroScan elastography measurements at 6 months in T2DM patients with NAFLD 3
• Transaminase improvement: Multiple real-world studies demonstrated ALT reductions of 2.62-7.95 IU/L and AST improvements 3, 4, 5
• Fatty liver improvement: Studies reported improvements in fatty liver assessed by FibroScan in NAFLD patients with diabetic dyslipidemia 4

Metabolic Benefits

• Glycemic control: HbA1c reductions of 0.7-1.6% across studies 4, 5
• Lipid parameters: Triglyceride reductions of 45-62%, with improvements in total cholesterol, LDL-C, and non-HDL-C 4, 5
• Weight neutral: Unlike pioglitazone, saroglitazar does not cause weight gain 6, 7, 4

Safety Profile

• No significant adverse events reported in real-world studies involving 5,824+ patients over 12-58 weeks 4, 5
• No renal impairment observed 5

Critical Limitations

The evidence for saroglitazar in MAFLD consists entirely of observational studies and lacks:

• Large randomized controlled trials with liver biopsy endpoints 3
• Long-term data on liver-related outcomes (cirrhosis, hepatocellular carcinoma, liver-related mortality) 3
• Validation outside of Indian populations 4, 5
• Comparison to guideline-recommended therapies (GLP-1 RAs, SGLT2 inhibitors) in head-to-head trials

Clinical Algorithm for Diabetic Patients with MAFLD

First-Line Approach

1. Lifestyle modification: Weight loss (7-10%), Mediterranean diet, 150-300 minutes moderate-intensity exercise weekly 1
2. Risk stratification: Calculate FIB-4 score; if >1.3, proceed to liver stiffness measurement to identify clinically significant fibrosis (≥F2) 1, 2

Pharmacological Management Priority

For diabetic patients with MAFLD:

• Preferred: GLP-1 receptor agonists (semaglutide, liraglutide) or dual GIP/GLP-1 agonists (tirzepatide) for patients with overweight/obesity, especially those with high-risk fibrosis 1, 2
• Alternative: SGLT2 inhibitors for cardiovascular/renal protection 1
• Continue metformin if already prescribed (safe in compensated cirrhosis, may improve transplant-free survival) 1

Saroglitazar Consideration

Saroglitazar may be considered in the Indian context when:

• Guideline-recommended therapies (GLP-1 RAs, SGLT2 inhibitors) are unavailable, unaffordable, or contraindicated
• Diabetic dyslipidemia (high triglycerides) is the predominant metabolic abnormality requiring treatment 6, 7, 4
• Patient has demonstrated intolerance to fibrates or pioglitazone 7

However, recognize that:

• This represents off-guideline use based on observational data only 3, 4, 5
• Patients should be counseled about the lack of robust evidence for liver-specific outcomes
• Transition to guideline-recommended therapies should occur when feasible

Common Pitfalls to Avoid

• Do not use saroglitazar as first-line MAFLD therapy when GLP-1 RAs or SGLT2 inhibitors are available and appropriate 1
• Do not assume lipid/glycemic improvements translate to histological liver benefits without biopsy or validated non-invasive test confirmation 3
• Do not delay proven therapies (lifestyle modification, GLP-1 RAs) while pursuing saroglitazar treatment 1, 2
• Do not use in decompensated cirrhosis (Child-Pugh C) without safety data 2

Monitoring Approach if Saroglitazar Used

• Baseline and periodic liver function tests (AST, ALT) 3, 5
• FibroScan or FIB-4 score at 6-12 months to assess fibrosis progression 3
• HbA1c and lipid panel every 3 months 4, 5
• Reassess need for transition to guideline-recommended therapies at each visit