What are the FDA-approved drugs for metabolic liver disease, specifically Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)?

FDA-Approved Drugs for Metabolic Liver Disease (NAFLD/NASH)

Resmetirom (REZDIFFRA) is currently the only FDA-approved drug for treating noncirrhotic NASH with moderate to advanced liver fibrosis (F2-F3), approved in 2024 under accelerated approval based on improvement of NASH and fibrosis. 1

Current FDA-Approved Treatment

Resmetirom (REZDIFFRA)

• Indicated for adults with noncirrhotic NASH with moderate to advanced liver fibrosis (F2-F3 stages) 1
• Must be used in conjunction with diet and exercise 1
• Critical limitation: Avoid use in patients with decompensated cirrhosis 1
• This is an accelerated approval; continued approval depends on confirmatory trial results demonstrating clinical benefit 1

Off-Label Pharmacotherapy with Strong Guideline Support

While not FDA-approved specifically for NASH, the following medications have strong guideline recommendations:

For Non-Diabetic Patients with Biopsy-Proven NASH

• Vitamin E 800 IU daily is recommended for non-diabetic adults with biopsy-confirmed NASH and significant fibrosis (F2-F3) 2, 3, 4
• Improves liver histology through antioxidant properties 3, 4
• Do NOT use in diabetic patients or those with cirrhosis 4
• Potential concerns include increased risk of all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term use 3

For Diabetic Patients with Biopsy-Proven NASH

• Pioglitazone 30 mg daily is the first-line pharmacotherapy for diabetic patients with NASH 2, 3, 4
• Effective for patients with or without diabetes, improving all histological features except fibrosis 2, 3, 4
• Led to resolution of steatohepatitis in 47% of patients versus 21% with placebo 2
• Side effects include weight gain, bone fractures in women, and rarely congestive heart failure 3, 4

GLP-1 Receptor Agonists (Emerging Evidence)

• Semaglutide has the strongest evidence for liver histological benefit among GLP-1 receptor agonists 4
• Achieves 8-21% weight reduction and reduces hepatic steatosis 5
• Considered for diabetic NASH patients, particularly those with significant fibrosis 4
• Liraglutide also shows promise but with less robust evidence than semaglutide 5

Treatment Algorithm Based on Disease Stage

Simple Steatosis or Minimal Fibrosis (F0-F1)

• No liver-directed pharmacotherapy recommended 3, 4
• Focus exclusively on lifestyle modifications: 7-10% weight loss, Mediterranean diet, 150-300 minutes moderate-intensity exercise weekly 3, 4

Significant Fibrosis (F2-F3)

• Intensive lifestyle modifications PLUS pharmacotherapy 3
• Non-diabetic: Vitamin E 800 IU daily 3, 4
• Diabetic: Pioglitazone 30 mg daily OR consider GLP-1 receptor agonists 3, 4
• This is the population where resmetirom is FDA-approved 1

Cirrhosis (F4)

• Limited evidence for pharmacotherapy; avoid resmetirom 3, 1
• Focus on lifestyle modifications with careful monitoring 3
• Hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months 3, 5
• Esophagogastroduodenoscopy screening for esophageal varices 5

Critical Pitfalls to Avoid

• All pharmacologic treatments (except resmetirom) require histologic diagnosis via liver biopsy prior to initiation 3
• Never prescribe vitamin E to diabetic patients or those with cirrhosis 4
• Metformin is NOT effective for treating NASH despite being first-line for diabetes 2, 4
• Statins are safe in NASH patients and should be used for dyslipidemia 2, 4
• Ursodeoxycholic acid and orlistat are NOT recommended due to lack of significant histological benefit 4

Lifestyle Modifications Remain Cornerstone

• Weight loss of 7-10% significantly improves liver histology and can reverse NASH 2, 3, 4
• Even 5-7% weight loss improves hepatic steatosis 3
• Mediterranean diet is the most strongly recommended dietary pattern 3
• Vigorous exercise (≥6 METs) provides greater benefit than moderate exercise for NASH and fibrosis 3, 5
• Bariatric surgery leads to histologic resolution in up to 85% of morbidly obese patients with NASH at one year 3, 5