What is the role of saroglitazar in managing fatty liver disease, specifically Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)?

Role of Saroglitazar in Fatty Liver Disease

Saroglitazar is not recommended as a standard treatment for NAFLD/NASH based on current major international guidelines, which instead endorse pioglitazone (30 mg daily) and vitamin E (800 IU daily) as first-line pharmacotherapy for biopsy-proven NASH with significant fibrosis. 1, 2

Guideline-Endorsed Pharmacotherapy

The established treatment options for NAFLD/NASH according to major guidelines include:

• Pioglitazone 30 mg daily is recommended for patients with biopsy-confirmed NASH with or without diabetes, showing significant improvement in steatosis (P<0.001), lobular inflammation (P=0.004), and NASH resolution (47% vs 21% placebo, P<0.001) 3, 1

• Vitamin E 800 IU daily is recommended for non-diabetic patients with biopsy-proven NASH without cirrhosis, demonstrating histologic improvement in 43% versus 19% with placebo (P=0.001) 3, 1

• GLP-1 receptor agonists (liraglutide, semaglutide) are preferred for patients with type 2 diabetes and NASH/fibrosis 1, 2

Saroglitazar: Research Evidence Without Guideline Support

While saroglitazar shows promise in research studies, it is notably absent from all major international NAFLD/NASH guidelines including AASLD, EASL, KASL, AGA, and ACG recommendations 3, 1, 2.

Research Findings on Saroglitazar:

• A randomized controlled trial (n=106) demonstrated that saroglitazar 4 mg significantly reduced ALT by 45.8% versus 3.4% with placebo (P<0.001) and decreased liver fat content by 19.7% versus 4.1% increase with placebo at 16 weeks 4

• The same trial showed improvements in insulin resistance (HOMA-IR decreased by 6.3 vs -1.3 with placebo), triglycerides (decreased 68.7 mg/dL vs -5.3 mg/dL), and adiponectin levels (P<0.05 for all) 4

• Observational studies reported improvements in liver stiffness measurement (LSM decreased from 8.4 to 7.5 kPa, P=0.0261) and controlled attenuation parameter (CAP) after 24 weeks 5

• However, one study found that LSM and CAP improvements occurred only when saroglitazar was accompanied by ≥5% weight loss, suggesting the drug alone may not be sufficient 6

Critical Limitations:

• No long-term histologic data: Unlike pioglitazone which has demonstrated fibrosis improvement in meta-analyses 3, saroglitazar lacks biopsy-proven histologic endpoints in human trials 4

• Short study duration: Most saroglitazar trials are 16-24 weeks, compared to 96-week trials for pioglitazone 3, 4

• Weight gain concern: Saroglitazar 4 mg caused mean weight gain of 1.5 kg versus 0.3 kg with placebo, though not statistically significant (P=0.27) 4

• Regulatory approval limited: Saroglitazar is approved only for diabetic dyslipidemia in select countries (primarily India), not specifically for NAFLD/NASH 5, 7

Clinical Algorithm for NAFLD Pharmacotherapy

For patients requiring pharmacologic treatment (biopsy-proven NASH with ≥F2 fibrosis):

1. Without diabetes or cirrhosis: Consider vitamin E 800 IU daily as first-line 1, 2

2. With or without diabetes, without cirrhosis: Consider pioglitazone 30 mg daily, accepting 2.5-4.7 kg weight gain 3, 1

3. With type 2 diabetes and NASH/fibrosis: Prefer GLP-1 receptor agonists (liraglutide, semaglutide) 1, 2

4. Saroglitazar: May be considered off-guideline in patients with diabetic dyslipidemia and NAFLD where approved, but should not replace guideline-endorsed therapies 5, 4

Important Caveats

• Pharmacotherapy should be restricted to biopsy-proven NASH with significant fibrosis (≥F2), not simple steatosis, as these patients have the highest risk of progression and mortality 3, 2

• Lifestyle modification remains the cornerstone: Target 7-10% weight loss through Mediterranean diet and ≥150 minutes weekly vigorous exercise (≥6 METs), as this improves both steatosis and fibrosis 3, 1, 2

• Avoid rapid weight loss (>1 kg/week) as it may worsen portal inflammation and fibrosis 3, 2

• Pioglitazone is contraindicated in decompensated cirrhosis and should be avoided in patients with heart failure 3

In summary, saroglitazar lacks the robust long-term histologic data and guideline endorsement necessary to recommend it as standard therapy for NAFLD/NASH. Clinicians should prioritize pioglitazone, vitamin E, or GLP-1 receptor agonists based on patient characteristics, as these have established efficacy for improving morbidity and mortality-related outcomes in NASH.