Medications for Non-Alcoholic Fatty Liver Disease (NAFLD)
No FDA-Approved Drugs Currently Exist for NAFLD
There are currently no FDA-approved pharmacologic agents specifically for treating NAFLD or NASH, and pharmacotherapy should be reserved exclusively for patients with biopsy-proven NASH and significant fibrosis (stage ≥2 or higher), not for simple steatosis. 1, 2
First-Line Approach: Lifestyle Modification Before Medications
Before considering any pharmacotherapy, all NAFLD patients must implement:
- Weight loss of 7-10% through caloric restriction (reducing intake by >500 kcal/day) to improve inflammation and fibrosis 1, 2, 3
- Moderate-intensity exercise for at least 150-300 minutes weekly or 75-150 minutes of vigorous exercise 1, 2
- Mediterranean diet with reduced refined carbohydrates, avoidance of fructose-containing beverages, and increased fiber 2, 3
Weight loss of 5-7% improves steatosis alone, while 7-10% is required to improve inflammation and fibrosis 1, 2
Pharmacotherapy Options (Off-Label Use Only)
Vitamin E: First Choice for Non-Diabetic NASH
Vitamin E at 800 IU daily (RRR-α-tocopherol) is recommended for non-diabetic adults with biopsy-confirmed NASH without cirrhosis. 1, 2, 3
- Improves steatohepatitis, inflammation, and hepatocyte ballooning in the PIVENS trial 1
- Must be restricted to non-diabetic patients only due to mixed results in diabetic populations 1
- Cannot be used in patients with cirrhosis 1, 2
Important caveats: Concerns exist about potential increased all-cause mortality, hemorrhagic stroke, and prostate cancer with long-term use, though evidence is mixed 1, 3
Pioglitazone: Option for Diabetic and Non-Diabetic NASH
Pioglitazone 30 mg daily can be considered for patients with biopsy-proven NASH with or without diabetes, but without cirrhosis. 1, 2, 3
- Improves liver biochemistry, inflammation, and steatosis in patients with or without type 2 diabetes 1
- In the PIVENS trial, achieved 47% resolution of steatohepatitis vs. 21% with placebo 1
- Does not consistently improve fibrosis, the most clinically important outcome 1, 3
Significant side effects include: 1, 4
- Weight gain (common and problematic in already obese patients)
- Peripheral edema
- Increased risk of congestive heart failure
- Bone fractures, particularly in women
- Potential bladder cancer risk with long-term use
GLP-1 Receptor Agonists: Emerging Option for Diabetic Patients
For NAFLD patients with type 2 diabetes, GLP-1 receptor agonists (liraglutide, semaglutide) should be considered based on American Diabetes Association guidelines for diabetes management, with potential liver benefits. 1, 2
- Liraglutide improves steatosis in small studies 1
- Evidence for lean NAFLD patients is insufficient and premature 1
- Primary indication remains diabetes management, with liver improvement as secondary benefit 1
SGLT2 Inhibitors: Insufficient Evidence
SGLT2 inhibitors are not recommended specifically for NAFLD treatment, though they may be used for comorbid type 2 diabetes management. 1
- Therapeutic role in lean NAFLD is not fully defined and requires further investigation 1
- Should only be considered for managing metabolic comorbidities, not as NAFLD-specific therapy 1
Medications NOT Recommended
Metformin: No Benefit
Metformin is not recommended as a specific treatment for NAFLD as it has no significant effect on liver histology. 1, 2
- In the TONIC trial, metformin 500 mg twice daily showed no improvement in liver biochemistries or histology in children with NAFLD 1
Treatment Algorithm Based on Disease Severity
Simple Steatosis (NAFL) or Minimal Fibrosis (F0-F1):
NASH with Significant Fibrosis (F2-F3):
- Intensive lifestyle modifications PLUS 2, 3
- Vitamin E 800 IU daily if non-diabetic 1, 2, 3
- Pioglitazone 30 mg daily if diabetic or if vitamin E contraindicated 1, 2, 3
NASH with Cirrhosis (F4):
- Lifestyle modifications with careful monitoring 3
- Limited evidence for pharmacotherapy 3
- Vitamin E and pioglitazone are contraindicated in cirrhosis 1, 2
- HCC surveillance with ultrasound ± AFP every 6 months required 1, 3
Critical Management Principles
All NAFLD patients require aggressive management of cardiovascular risk factors: 1
- Statins are safe and should be used for dyslipidemia despite liver disease 1, 2
- Glucose-lowering medications should optimize glycemic control in diabetic patients 1
Bariatric surgery should be considered for appropriate candidates with obesity and NAFLD, as it can achieve NASH resolution in up to 85% of patients 2
Avoid rapid weight loss (>1 kg/week) as it may worsen portal inflammation and fibrosis 2