What is the best treatment approach for a patient with non-alcoholic fatty liver disease (NAFLD) grade 1/2 who has been taking saroglitazar (a peroxisome proliferator-activated receptor (PPAR) agonist) for 3 months?

Treatment After 3 Months of Saroglitazar for NAFLD Grade 1/2

Transition from saroglitazar to evidence-based first-line therapy with either pioglitazone 30-45 mg daily (if diabetic) or vitamin E 800 IU daily (if non-diabetic without cirrhosis), as saroglitazar is not recommended by major hepatology guidelines for NAFLD treatment. 1

Critical Context: Saroglitazar Lacks Guideline Support

• The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and American Gastroenterological Association (AGA) do not recommend saroglitazar for NASH treatment 1
• Saroglitazar improves transaminases but does not improve liver stiffness or fat content unless accompanied by ≥5% weight reduction 2
• Major guidelines recommend pioglitazone or vitamin E as first-line pharmacotherapy for biopsy-proven NASH, not saroglitazar 1

Recommended Treatment Algorithm

Step 1: Assess Diabetes Status and Biopsy Confirmation

• If diabetic with biopsy-proven NASH: Switch to pioglitazone 30-45 mg daily, which achieves NASH resolution in 47% versus 21% with placebo (P<0.001) and addresses both glycemic control and liver disease simultaneously 3, 1
• If non-diabetic without cirrhosis with biopsy-proven NASH: Switch to vitamin E 800 IU daily (rrr α-tocopherol formulation), which achieves the primary histologic endpoint in 43% versus 19% with placebo (P<0.001) 3, 1
• If no biopsy confirmation: Do not initiate pharmacotherapy, as guidelines require biopsy confirmation before starting pioglitazone or vitamin E since only biopsy-proven NASH patients are at greatest risk of progression to cirrhosis 3, 1

Step 2: Mandatory Lifestyle Modifications (Non-Negotiable)

• Target 7-10% weight loss through dietary modifications, as this improves necroinflammation and fibrosis and is essential to accompany any pharmacotherapy 3, 1, 4
• Implement Mediterranean diet with reduced carbohydrate and fructose intake 1, 4, 5
• Prescribe 150-300 minutes per week of moderate-intensity physical activity 1, 4
• Weight loss of ≥5% decreases intrahepatic fat content and inflammation, with greater weight loss correlating with greater histologic improvement 5

Step 3: Monitor Treatment Response

• For pioglitazone: Expect improvement in steatosis, lobular inflammation, ballooning, and NASH resolution in 47% of patients, though weight gain of 2.5-4.7 kg is common 3
• For vitamin E: Expect improvement in steatosis, inflammation, ballooning, and NASH resolution in approximately one-third of patients with number needed to treat of 4.4 3
• Reassess at 24 weeks based on reduction in liver stiffness, fat content, metabolic parameters, and absence of adverse effects 4

Critical Pitfalls to Avoid

• Do not continue saroglitazar as monotherapy, since it only improves transaminases without improving liver stiffness or controlled attenuation parameter values unless accompanied by significant weight reduction 2
• Do not use metformin to treat NASH histology, as it has no effect on liver pathology despite improving insulin resistance 3, 1
• Do not initiate pioglitazone if ALT exceeds 2.5 times the upper limit of normal or if active liver disease is present 1
• Do not use vitamin E in cirrhotic patients due to lack of safety data in this population 1
• Do not use pioglitazone or vitamin E without biopsy confirmation of NASH, as these agents should not be used for simple steatosis 3, 1

Pioglitazone-Specific Considerations

• Discuss risks including weight gain (2.5-4.7 kg expected), potential bone loss in women, though bladder cancer risk is not statistically significant with long-term use 3
• Pioglitazone improves liver histology in patients with and without type 2 diabetes with biopsy-proven NASH 3
• Resolution of NASH occurs in 47% versus 21% with placebo (P<0.001), making it highly effective for the key secondary endpoint 3

Vitamin E-Specific Considerations

• Use only the pure rrr α-tocopherol formulation at 800 IU daily for 96 weeks 3
• Vitamin E results in improvement in steatosis, inflammation, ballooning, and resolution of steatohepatitis in non-diabetic adults with NASH 3
• Vitamin E does not improve hepatic fibrosis 3