What medications can be used to treat non-alcoholic fatty liver disease (NAFLD)?

Pharmacological Treatment of Non-Alcoholic Fatty Liver Disease

For patients with biopsy-proven NASH without diabetes or cirrhosis, vitamin E (800 IU/day) is the first-line pharmacological treatment, achieving 43% histological improvement versus 19% with placebo. 1 For patients with biopsy-proven NASH regardless of diabetes status, pioglitazone (30 mg daily) is equally effective, achieving 47% NASH resolution versus 21% with placebo. 1, 2

Treatment Algorithm Based on Patient Characteristics

Non-Diabetic Patients with Biopsy-Proven NASH

Vitamin E (800 IU/day) should be the preferred agent, as it achieved the primary endpoint in the landmark PIVENS trial with 42% of patients showing histological improvement compared to 19% with placebo (P < 0.001, number needed to treat = 4.4). 1 This represents resolution of steatohepatitis with significant improvements in steatosis, inflammation, and ballooning. 1, 2

• Vitamin E demonstrated similar efficacy in children with NAFLD, achieving 58% NASH resolution versus 28% with placebo (P < 0.006). 1
• Critical caveat: Vitamin E has been associated with increased all-cause mortality and excess hemorrhagic stroke and prostate cancer at high doses, requiring informed discussion with patients before initiation. 1
• Vitamin E does not improve fibrosis. 1

Diabetic or Non-Diabetic Patients with Biopsy-Proven NASH

Pioglitazone 30 mg daily is the treatment of choice, particularly when diabetes coexists or when vitamin E is contraindicated. 1, 2 Pioglitazone achieved 47% NASH resolution versus 21% with placebo (P < 0.001) and demonstrated improvement across all histological parameters including potential fibrosis regression. 1

• Five randomized controlled trials with meta-analysis confirm pioglitazone's efficacy, showing resolution of NASH (odds ratio 3.22; 95% CI 2.17-4.79; P < 0.001) and reversal of advanced fibrosis (odds ratio 3.15; 95% CI 1.25-7.93; P = 0.01). 1
• Expected weight gain of 2.5-4.7 kg is the most common side effect, which can be mitigated through nutritional counseling or combination with SGLT2 inhibitors or GLP-1 receptor agonists. 1
• Contraindications include decompensated cirrhosis, congestive heart failure risk, and bladder cancer history. 1
• Bone loss may occur in women treated with thiazolidinediones. 1

Lean Patients with Biopsy-Proven NASH

The same treatment principles apply: vitamin E for non-diabetics without cirrhosis, and pioglitazone 30 mg daily for those with or without diabetes but without cirrhosis. 1

Emerging Therapies with Strong Evidence

GLP-1 Receptor Agonists

Semaglutide represents the most promising emerging therapy, achieving 59% NASH resolution with the highest dose (0.4 mg/day) versus 17% with placebo (P < 0.001) in 320 patients with biopsy-proven NASH. 1, 2 This is the highest resolution rate among all tested pharmacotherapies. 2

• Liraglutide demonstrated 39% NASH resolution versus 9% placebo in earlier trials, with reversal of steatohepatitis and amelioration of fibrosis progression after 12 months. 1, 3
• The American Diabetes Association recommends prioritizing GLP-1 receptor agonists as first-line glucose-lowering agents for diabetic patients with NAFLD, combined with aggressive lifestyle intervention. 3
• Dose-dependent gastrointestinal adverse effects (nausea, constipation, vomiting) occur more frequently than placebo. 1
• GLP-1 receptor agonists have not been widely tested in decompensated cirrhosis and should be used cautiously in this setting. 1

Treatments WITHOUT Proven Efficacy

Metformin

Metformin should NOT be used to treat NASH, as it has no major effect on steatohepatitis or liver histology in randomized controlled trials. 1, 2, 4 However, metformin remains safe and effective for treating diabetes in patients with NAFLD when clinically indicated. 1

SGLT2 Inhibitors

SGLT2 inhibitors lack robust liver biopsy-proven histological improvement data and their therapeutic role in NAFLD is not fully defined. 1, 3 Randomized controlled trials with dapagliflozin, canagliflozin, and empagliflozin reported approximately 20% placebo-subtracted reduction in steatosis by imaging, but effects on liver histology remain unknown. 1

• SGLT2 inhibitors should be reserved for managing comorbid conditions (cardiovascular disease, heart failure, chronic kidney disease) rather than as primary NAFLD therapy. 1, 3
• They can be used safely in compensated cirrhosis (Child-Pugh Class A or B) but must be avoided in decompensated cirrhosis. 3

Critical Prerequisites for Pharmacotherapy

Pharmacological treatment should be reserved exclusively for patients with biopsy-proven NASH, not for simple steatosis (NAFL). 1, 2 The distinction is critical because:

• NAFL has negligible risk of progression and does not warrant pharmacotherapy. 1
• NASH carries higher risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma, justifying treatment risks. 1
• Liver biopsy remains the reference standard when uncertainty exists regarding disease stage or contributing causes. 1

Mandatory Concurrent Interventions

All pharmacological interventions must be accompanied by lifestyle modifications targeting 7-10% weight loss through Mediterranean diet and 150-300 minutes weekly of moderate-intensity exercise. 3, 2 Weight loss of 3-5% improves steatosis, while 10% weight loss improves NASH histology. 1

Management of Cardiovascular Risk Factors

Statins are safe in NAFLD and should be used for dyslipidemia management as clinically indicated, with beneficial effects including 37% reduction in hepatocellular carcinoma risk and 46% reduction in hepatic decompensation. 1, 3 Statins can be prescribed to patients with F2-F3 fibrosis and Child A or B cirrhosis but should be avoided in Child class C cirrhosis. 1

Monitoring and Follow-Up

Risk stratification using FIB-4 score should be performed at baseline, with values <1.3 indicating low risk, 1.3-2.67 indicating intermediate risk, and >2.67 indicating high risk requiring hepatology referral. 3 Noninvasive tests should be repeated at 6-month to 2-year intervals depending on fibrosis stage and treatment response. 1, 3