Is saroglitazar (a peroxisome proliferator-activated receptor (PPAR) agonist) safe to use in a patient with non-alcoholic steatohepatitis (NASH) or toxic-mediated liver damage?

Saroglitazar for NASH and Toxic-Mediated Liver Damage

Saroglitazar is NOT recommended for NASH or toxic-mediated liver damage in standard clinical practice, as it lacks endorsement from major North American and European liver disease guidelines, which instead recommend pioglitazone (for diabetic and non-diabetic patients) or vitamin E (for non-diabetic patients only) as first-line pharmacotherapy for biopsy-proven NASH. 1

Why Saroglitazar Is Not the Preferred Choice

Absence from Major Guidelines

• The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and American Gastroenterological Association (AGA) guidelines do not include saroglitazar as a recommended treatment option for NASH 1

• These guidelines specifically endorse pioglitazone (15-45 mg daily) for biopsy-proven NASH, which achieves NASH resolution in 47-58% of patients versus 19-21% with placebo (P<0.001) 1

• For non-diabetic patients without cirrhosis, vitamin E (800 IU daily) is recommended, achieving the primary histologic endpoint in 43% versus 19% with placebo (P<0.001) 1

Limited Evidence Quality

• While saroglitazar shows promise in research studies, the evidence comes primarily from small trials and observational studies, predominantly from India 2, 3, 4

• A 2023 meta-analysis showed saroglitazar reduced ALT by 26 U/L and improved liver stiffness by 2.22 kPa, but this was based on moderate-quality GRADE evidence with high heterogeneity (I² = 97-100%) 2

• The largest Western study was a proof-of-concept trial, not a definitive phase 3 registration study 3

Established First-Line Therapies Instead

For Patients WITH Type 2 Diabetes

• Use pioglitazone 30-45 mg daily for biopsy-proven NASH, as it addresses both glycemic control and liver disease simultaneously 1

• Pioglitazone improves steatosis (P<0.001), lobular inflammation (P=0.004), and achieves NASH resolution in 47% of patients 1

• It also provides cardiovascular risk reduction, which is critical since cardiovascular disease is the leading cause of death in diabetic patients with NAFLD 1

• Common side effects: Weight gain of 2.5-4.7 kg, peripheral edema 1

• Contraindications: Active heart failure, bladder cancer history, increased bone loss risk 1

For Patients WITHOUT Diabetes

• Use vitamin E 800 IU daily for biopsy-proven NASH without cirrhosis 1

• Vitamin E achieves NASH resolution in approximately one-third of patients and significantly improves NAS scores (P<0.001) 1

• Do not use in diabetic patients due to lack of proven efficacy and potential safety concerns 1

• Safety concerns: Possible increased all-cause mortality (RR 1.04), increased prostate cancer risk (1.6 per 1000 person-years), and increased hemorrhagic stroke risk (RR 1.22) 1

Critical Treatment Prerequisites

Biopsy Confirmation Required

• Only treat biopsy-proven NASH with pharmacotherapy, as these patients are at greatest risk of progression to cirrhosis 1

• Do not initiate pharmacotherapy based solely on elevated liver enzymes or imaging findings 1

Mandatory Lifestyle Modifications

• Weight loss of 7-10% is essential and must accompany any pharmacotherapy 1

• Weight loss of 3-5% improves steatosis, but 7-10% is needed to improve necroinflammation and fibrosis 1

• Mediterranean diet with reduced carbohydrate and fructose intake 1, 5

• Exercise: 150-300 minutes per week of moderate-intensity physical activity 1, 5

Regarding Toxic-Mediated Liver Damage

• Saroglitazar has no established role in toxic-mediated liver injury (drug-induced liver injury, toxin exposure, etc.) 2, 3

• For toxic liver damage, the primary management is immediate cessation of the offending agent and supportive care

• Pharmacotherapy for NASH (including saroglitazar, pioglitazone, or vitamin E) is not indicated for acute toxic liver injury

Common Pitfalls to Avoid

• Do not use metformin to treat NASH histology—it has no effect on liver pathology despite improving insulin resistance 1

• Do not initiate pioglitazone if ALT exceeds 2.5 times the upper limit of normal or if active liver disease is present 6

• Do not use vitamin E in cirrhotic patients due to lack of safety data in this population 1

• Do not rely on liver enzymes alone to diagnose NASH or monitor treatment response—histologic confirmation is required before starting pharmacotherapy 1