Is saroglitazar appropriate for an overweight adult with non‑alcoholic fatty liver disease (NAFLD) or metabolic‑associated fatty liver disease (MAFLD) and metabolic risk factors (dyslipidaemia, type‑2 diabetes) who has not achieved adequate control with lifestyle measures, and what dosing and monitoring are recommended?

Saroglitazar in Fatty Liver Disease

Saroglitazar is not recommended as a first-line or standard therapy for NAFLD/MAFLD according to current international guidelines, despite showing promise in research studies. Major hepatology and diabetes societies do not include saroglitazar in their treatment algorithms, instead prioritizing GLP-1 receptor agonists, pioglitazone, and resmetirom (where approved) for patients with metabolic dysfunction-associated steatotic liver disease. 1

Guideline-Recommended Pharmacotherapy

For Non-Cirrhotic NAFLD/MAFLD with Type 2 Diabetes:

• GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, tirzepatide) are the preferred first-line agents for patients with type 2 diabetes and NAFLD, as they improve both glycemic control and cardiovascular outcomes 1
• Pioglitazone is recommended for patients with biopsy-proven NASH or high-risk fibrosis (≥F2), though it is not classified as a MASH-targeted therapy in the most recent guidelines 1
• SGLT2 inhibitors (empagliflozin, dapagliflozin) are safe to use for their diabetes indication but lack robust evidence as NASH-targeted therapies 1

For Non-Cirrhotic NAFLD/MAFLD with Significant Fibrosis (≥F2):

• Resmetirom (if locally approved) is the only medication with strong recommendation as MASH-targeted therapy, demonstrating histological efficacy on steatohepatitis and fibrosis in Phase III trials 1

For Dyslipidemia Management:

• Statins should be used according to cardiovascular risk guidelines; they are safe in compensated cirrhosis and reduce cardiovascular events 1

Saroglitazar: Research Evidence vs. Guideline Absence

Why Saroglitazar Is Not in Guidelines:

The 2024 EASL-EASD-EASO and 2024 ADA guidelines make no mention of saroglitazar despite its approval in India for diabetic dyslipidemia. 1 This absence reflects:

• Lack of large Phase III registrational trials demonstrating histological endpoints (NASH resolution, fibrosis regression)
• Limited geographic availability (primarily India)
• Insufficient long-term safety and liver-related outcome data

Research Evidence Supporting Saroglitazar:

Despite guideline omission, multiple observational studies and meta-analyses show:

• Significant ALT reduction (mean difference 26.01 U/L) and AST reduction (mean difference 19.68 U/L) at 24 weeks 2
• Liver stiffness improvement (mean difference 2.22 kPa reduction) measured by FibroScan 2, 3
• Metabolic benefits: HbA1c reduction (0.59%), triglyceride reduction (105.49 mg/dL), and total cholesterol reduction (19.20 mg/dL) 2
• Safety profile: Well-tolerated with rare adverse events (pruritus in <2% requiring discontinuation) 4, 3

Mechanism of Action:

Saroglitazar functions as a dual PPAR-α/γ agonist, reducing hepatic lipid accumulation through enhanced fatty acid β-oxidation, improved insulin sensitivity, and anti-inflammatory effects via inhibition of NF-κB and MAPK pathways. 5

Practical Clinical Algorithm

Step 1: Prioritize Guideline-Recommended Therapy

For an overweight adult with NAFLD/MAFLD, type 2 diabetes, and dyslipidemia who has failed lifestyle measures:

1. Initiate a GLP-1 receptor agonist (e.g., semaglutide 0.25 mg weekly, titrate to 1.0-2.4 mg; or liraglutide 0.6 mg daily, titrate to 1.8 mg) 1
2. Add or continue statin therapy for dyslipidemia per cardiovascular risk (e.g., atorvastatin 20-40 mg daily) 1
3. Consider pioglitazone 30 mg daily if significant fibrosis (F2-F3) is documented by FIB-4 >2.67, liver stiffness >8 kPa, or biopsy 1

Step 2: Assess Fibrosis Risk

• Calculate FIB-4 score at baseline and annually 1
• If FIB-4 >1.3 (age <65) or >2.0 (age ≥65), obtain liver stiffness measurement by elastography 1
• Refer to hepatology if liver stiffness ≥8 kPa or FIB-4 >2.67 for consideration of resmetirom (where approved) 1

Step 3: Saroglitazar as Off-Guideline Option

If saroglitazar is locally available and guideline-recommended agents are contraindicated, not tolerated, or inaccessible:

• Dose: 4 mg once daily 4, 2, 3
• Monitor: ALT, AST, lipid panel, HbA1c, and liver stiffness at baseline, 12 weeks, and 24 weeks 4, 3
• Expected timeline: Biochemical improvement (ALT/AST) within 12-24 weeks; liver stiffness reduction by 24 weeks 2, 3
• Safety monitoring: Assess for pruritus, gastrointestinal symptoms, and weight changes 3

Step 4: Lifestyle Foundation (Mandatory for All)

• Weight loss target: 7-10% body weight to achieve NASH resolution in 64% of patients 1, 6
• Mediterranean diet: Hypocaloric (500-1000 kcal deficit), emphasizing vegetables, whole grains, olive oil, fatty fish; eliminate sugar-sweetened beverages and limit red meat to <2.3 servings/week 6
• Exercise: ≥150 minutes/week moderate-intensity aerobic activity plus resistance training 6

Critical Caveats

Compensated Cirrhosis (Child-Pugh A):

• GLP-1 receptor agonists and SGLT2 inhibitors can be used 1
• Metformin is safe if GFR >30 mL/min 1
• Saroglitazar has been studied in compensated cirrhosis with acceptable safety in small observational cohorts, but requires close monitoring 3
• Avoid sulfonylureas due to hypoglycemia risk 1

Decompensated Cirrhosis:

• Do not use metformin (lactic acidosis risk) or saroglitazar (insufficient safety data) 1
• Transition to insulin for glycemic control 1

Monitoring Pitfalls:

• Do not rely on ALT/AST alone for disease assessment; normal transaminases do not exclude advanced fibrosis 6
• Avoid rapid weight loss (>1 kg/week) in patients with advanced fibrosis or cirrhosis, as it may precipitate hepatic decompensation 6

Evidence Quality Summary

The strongest evidence supports GLP-1 receptor agonists (Level A, 2024 ADA guidelines) and resmetirom (Level 2,2024 EASL-EASD-EASO guidelines) for NAFLD/MAFLD with metabolic comorbidities. 1 Saroglitazar evidence consists of moderate-quality observational studies and meta-analyses (Level 2-3) showing biochemical and elastographic improvements but lacking Phase III histological endpoint data required for guideline inclusion. 4, 2, 3

In real-world practice, prioritize guideline-recommended therapies first. Saroglitazar may be considered as an adjunctive or alternative agent in settings where it is approved and first-line options are unavailable, but this represents off-guideline use requiring informed patient discussion and close monitoring.