Is the effect of Saroglitazar (a peroxisome proliferator-activated receptor (PPAR) agonist) biopsy-proven in Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) trials?

Saroglitazar's Effect on NAFLD/NASH: Lack of Biopsy-Proven Evidence

Saroglitazar does not have biopsy-proven efficacy in NAFLD/NASH clinical trials, unlike established treatments such as pioglitazone and vitamin E which have demonstrated histological improvements in randomized controlled trials with liver biopsy endpoints. 1

Current Evidence for Saroglitazar

Saroglitazar, a dual PPAR-α/γ agonist, has been evaluated in several studies for NAFLD/NASH treatment, but lacks the robust histological evidence that defines standard of care:

• The most recent randomized trial (SVIN trial, 2024) evaluated saroglitazar alone and in combination with vitamin E, but relied on surrogate markers rather than liver biopsy 2:

  • Showed improvements in ALT levels and CAP scores
  • Only the combination therapy significantly reduced liver stiffness measurements
  • No histological confirmation through biopsy was performed

• A 2021 phase 2 trial assessed saroglitazar in NAFLD/NASH patients but used ALT reduction as the primary endpoint and MRI proton density fat fraction for liver fat content rather than histological assessment 3

• A 2023 meta-analysis of saroglitazar studies showed improvements in liver enzymes and stiffness measurements but did not include histological endpoints from liver biopsies 4

Established Biopsy-Proven Treatments

In contrast, several treatments have established histological efficacy through liver biopsy:

1. Pioglitazone:

   • Multiple randomized controlled trials with biopsy endpoints show histological improvement
   • PIVENS trial demonstrated resolution of NASH in 47% vs 21% in placebo group 1
   • Improves steatosis, inflammation, and ballooning with some evidence for fibrosis improvement 1

2. Vitamin E (800 IU/day):

   • Achieved primary histological endpoint in 43% vs 19% in placebo group in the PIVENS trial 1
   • Recommended by guidelines for non-diabetic adults with biopsy-proven NASH 5

Clinical Implications

When considering treatment options for NAFLD/NASH:

• For biopsy-proven NASH: Pioglitazone and vitamin E remain the most evidence-backed options with histological confirmation
• For saroglitazar: Currently lacks the gold-standard biopsy evidence that would position it alongside established treatments
• Monitoring requirements: If using saroglitazar, regular assessment of liver enzymes, metabolic parameters, and non-invasive fibrosis markers is needed 5

Limitations of Current Evidence

The absence of biopsy-proven efficacy for saroglitazar represents a significant limitation:

• Liver biopsy remains the gold standard for diagnosing NASH and assessing treatment response 1
• Surrogate markers (ALT, imaging) may not accurately reflect histological improvements
• Major guidelines (AASLD, EASL) have not incorporated saroglitazar into recommendations due to insufficient histological evidence 5

While saroglitazar shows promise in improving biochemical and imaging parameters in NAFLD/NASH patients, particularly those with diabetic dyslipidemia 6, it lacks the biopsy-proven efficacy that would establish it as a definitive treatment for histologically confirmed NASH.