What is the evidence for using Saroglitazar in treating fatty liver disease, specifically Non-Alcoholic Fatty Liver Disease (NAFLD) or Non-Alcoholic Steatohepatitis (NASH)?

Saroglitazar in Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

Saroglitazar shows promising results in treating NAFLD/NASH with significant improvements in liver enzymes, steatosis, and metabolic parameters, but it is not yet included in major international guidelines for NAFLD/NASH management and requires more robust clinical evidence before becoming a first-line recommendation.

Mechanism of Action and Current Status

Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist that:

• Targets both lipid and glucose metabolism pathways
• Reduces insulin resistance and improves lipid profile
• Currently approved in India for diabetic dyslipidemia, but not widely approved for NAFLD/NASH in most countries

Evidence for Saroglitazar in NAFLD/NASH

Liver Enzyme Improvement

• Recent meta-analysis shows significant reduction in ALT (mean difference: 26.01 U/L) and AST (mean difference: 19.68 U/L) with moderate GRADE evidence 1
• Prospective observational study demonstrated ALT reduction from 94 U/L to 39 U/L and AST from 89 U/L to 37 U/L after 24 weeks of treatment 2

Liver Stiffness and Steatosis

• Significant improvement in liver stiffness measurement (LSM) (mean difference: 2.22 kPa) 1
• Controlled attenuation parameter (CAP) values improved significantly in multiple studies 2, 3
• However, one study found that LSM and CAP improvements were only observed when saroglitazar was combined with ≥5% weight reduction 4

Metabolic Parameters

• Significant improvements in:
  • Glycated hemoglobin (mean difference: 0.59%) 1
  • Total cholesterol (mean difference: 19.20 mg/dL) 1
  • Triglycerides (mean difference: 105.49 mg/dL) 1

Comparative and Combination Therapy

• Recent randomized trial (SVIN trial) compared saroglitazar, vitamin E, and combination therapy:
  • Only combination therapy showed significant reduction in liver stiffness 3
  • Both saroglitazar alone and in combination improved CAP and liver enzymes 3

Current Guideline Recommendations for NAFLD/NASH

Major hepatology guidelines do not yet include saroglitazar as a recommended therapy for NAFLD/NASH. Current guideline-recommended treatments include:

1. Lifestyle modifications - Cornerstone of NAFLD treatment 5

   • Weight loss of 5-10% of total body weight
   • Regular aerobic exercise
   • Minimization of alcohol consumption

2. Pioglitazone - Currently the most evidence-backed pharmacological option

   • Improves liver histology in patients with and without T2DM with biopsy-proven NASH 5, 6
   • Resolution of NASH in 47% vs 21% in placebo group in the PIVENS trial 5
   • Recommended by AASLD for biopsy-proven NASH 5

3. Vitamin E (800 IU/day)

   • Recommended for non-diabetic adults with biopsy-proven NASH 5
   • Achieved primary endpoint in 43% vs 19% in placebo group in the PIVENS trial 5

Limitations of Current Saroglitazar Evidence

1. Study Quality:

   • Most studies are observational or small-scale
   • Limited randomized controlled trials with histological endpoints
   • Lack of long-term safety and efficacy data

2. Guideline Recognition:

   • Not yet included in major international guidelines like AASLD 5
   • No FDA or EMA approval for NAFLD/NASH indication

3. Comparative Efficacy:

   • Limited head-to-head comparisons with established treatments
   • One study suggests combination with vitamin E may be more effective than monotherapy 3

Clinical Approach to Using Saroglitazar

Based on current evidence, saroglitazar may be considered in:

1. Patients with NAFLD/NASH who also have diabetic dyslipidemia
2. Patients who cannot tolerate or have contraindications to pioglitazone (heart failure, bladder cancer risk)
3. As part of combination therapy, particularly with vitamin E

Monitoring Recommendations

For patients receiving saroglitazar:

• Liver enzymes (ALT, AST) every 3 months
• Liver stiffness measurement and CAP (if available) at baseline and 6 months
• Lipid profile and glycemic parameters every 3 months
• Weight monitoring and continued emphasis on lifestyle modifications

Conclusion

While saroglitazar shows promise in improving liver enzymes, steatosis, and metabolic parameters in NAFLD/NASH patients, it has not yet been incorporated into major treatment guidelines. Pioglitazone and vitamin E remain the most evidence-backed pharmacological options for biopsy-proven NASH. More robust clinical trials with histological endpoints and long-term outcomes are needed before saroglitazar can be recommended as a first-line treatment for NAFLD/NASH.