Non-alcoholic fatty liver disease medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]Parth Vikram Singh, MBBS[3]

Overview

Clinical practice guidelines from NICE and the American Association for the Study of Liver Diseases (AASLD) direct management. The available guidelines have been compared and summarized.

Weight loss, withdrawal of hepatotoxic agents, and management of underlying insulin resistance/metabolic syndrome is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).

The primary goals of MASLD treatment are resolution of MASH, prevention of fibrosis progression, and reduction of long-term liver-related events, including cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver-related death. Management of metabolic comorbidities, including obesity, type 2 diabetes, hyperlipidemia, and hypertension, is also important to reduce cardiometabolic and extrahepatic complications.

Medical Therapy

There is no FDA approved specific treatment for NAFLD. Behavioral modification, including a weight-reducing diet, increased physical activity, avoidance of alcohol, and effective management of type 2 diabetes, hyperlipidemia, hypertension, and obesity, as well as withdrawal of hepatotoxic agents, is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).

Resmetirom and semaglutide are conditionally approved by the US Food and Drug Administration for the treatment of adults with noncirrhotic MASH and moderate to severe fibrosis, corresponding to fibrosis stages F2 to F3. No randomized clinical trial has compared combination therapy with resmetirom and semaglutide for MASH with moderate to advanced fibrosis.

Systematic reviews, using network analyses, by the Cochrane Collaboreation made no conclusion, whereas a non-Cochrane review made the following conclusions:

• ≥1 stage of fibrosis improvement: "Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively.
• NASH resolution: "semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively."

The combination of vitamin E (400 IU b.i.d.) and pioglitazone has been studies in one trial.

Resmetirom

Resmetirom is a liver-directed thyroid hormone receptor beta-selective agonist. In a phase 3 trial of 966 patients with obesity and biopsy-confirmed MASH with fibrosis stages F1 to F3, resmetirom 80 mg/day or 100 mg/day for 52 weeks resulted in histological resolution of MASH without worsening of fibrosis in 25.9% and 29.9% of patients, respectively, compared with 9.7% in the placebo group.

Improvement in fibrosis by at least 1 stage without worsening of MASH occurred in 24.2% of patients receiving 80 mg/day and 25.9% receiving 100 mg/day, compared with 14.2% receiving placebo.

Resmetirom was associated with reductions in serum ALT, liver stiffness, LDL cholesterol, triglycerides, and lipoprotein(a). Resmetirom did not have a significant effect on body weight, suggesting that its hepatoprotective effect was not mediated by weight loss.

Resmetirom, in the MAESTRO-NASH randomized controlled trial, was better than placebo at causing resolution of NASH and improvement in fibrosis (improvement in fibrosis stage 24% versus 14 for placebo).

Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA)

Randomized controlled trials have been executed of:

• Liraglutide in the LEAN trial in 2016
  • "Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04)"
• In a phase 3 placebo-controlled trial of patients with obesity and biopsy-confirmed MASH with fibrosis stage F2 or F3, semaglutide 2.4 mg weekly for 72 weeks resulted in MASH resolution without worsening of fibrosis in 62.9% of patients compared with 34.3% of patients receiving placebo. Improvement in fibrosis by at least 1 stage without worsening of MASH occurred in 36.8% of patients receiving semaglutide compared with 22.4% receiving placebo. Semaglutide was associated with greater weight loss than placebo, reductions in serum ALT, improvement in liver stiffness, and improvements in plasma lipid levels.
• Semaglutide in the Newsome trial in 2021:
  • "An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48)" over 6 years of treatment.
• Semaglutide in the Loomba trial in 2023
  • "Improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06–1·24; p=0·087)."
• Semaglutide in the Romero trial in 2023
  • Fibrosis change results were not included in their journal article, but are available at in the trial registration at https://classic.clinicaltrials.gov/ct2/show/NCT02970942. The results do not show a dose-response relationship.

Drug	Class	Dose in JAMA review	Population	Key outcome
Resmetirom	Liver-directed thyroid hormone receptor beta-selective agonist	80 mg/day or 100 mg/day	Adults with noncirrhotic MASH and moderate to severe fibrosis	MASH resolution without worsening fibrosis: 25.9%-29.9% vs 9.7% with placebo
Semaglutide	GLP-1 receptor agonist	2.4 mg/week	Adults with noncirrhotic MASH and F2-F3 fibrosis	MASH resolution without worsening fibrosis: 62.9% vs 34.3% with placebo

Weight management

• Lifestyle modifications to achieve weight loss is a central aspect of management of NAFLD in obese patients.
• Lifestyle-induced weight loss improves hepatic steatosis, MASH, and fibrosis. In a prospective study with paired liver biopsy results, weight loss of 5% decreased hepatic steatosis, while weight loss of 7% to 10% improved MASH and liver fibrosis.
  • MASH resolution occurred in 64% of patients with 7% to 10% weight loss compared with 10% of patients with less than 5% weight loss. Weight loss of 10% or greater was associated with MASH resolution in 90% of patients and fibrosis reduction in 45% at 52 weeks.
  • Low-carbohydrate and low-fat hypocaloric diets have similar effectiveness in reducing liver fat and serum aminotransferase levels. A Mediterranean-type diet rich in fruits, vegetables, whole grains, fish, and olive oil, with limitation of ultraprocessed foods, saturated fats, and refined sugars, may be used for MASLD management.
  • Regular physical activity is recommended, preferably 150 minutes per week of moderate-intensity aerobic exercise or 75 to 150 minutes per week of vigorous-intensity exercise, to reduce hepatic steatosis.

Bariatric surgery

Bariatric surgery, including Roux-en-Y gastric bypass or sleeve gastrectomy, should be considered in selected patients with MASLD and obesity with a body mass index greater than 35, particularly in those without improvement in imaging-detected hepatic steatosis or fibrosis after behavioral modification or medication therapy.

In a bariatric surgery cohort of 180 patients with severe obesity and biopsy-proven MASH, histological resolution of MASH occurred in 84% of patients and fibrosis reduction occurred in 70% of patients at 5-year follow-up.

In an observational study of 1158 adults with histologically confirmed MASH and fibrosis stages F1 to F3, bariatric surgery was associated with a lower 10-year cumulative incidence of major adverse liver-related events compared with nonsurgical care and a lower 10-year cumulative incidence of cardiovascular disease events.

In a non-randomized cohort study of patients with liver fibrosis (histological stages 1-3) and he prevention of "major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality)":

• Bariatric surgery: 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).

• No surgery: 9.6% (95% CI, 6.1%-12.9%)

...resulting in an adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).

Management of hyperlipidemia

• The direct effect of anti-lipid agents on NAFLD and liver histology has not been clearly understood; however, trials suggest no harm and observational studies suggest benefit.
• Statins are the drugs of choice, however statins should not be administered as primary treatment of NAFLD, but rather as treatment of hyperlipidemia.
• The goal is to get the LDL down to < 100 mg/dl.
  • Preferred regimen: Atorvastatin 40 mg PO q24h.

Management of Insulin resistance

• Rosiglitazone is recommended among all patients who develop NAFLD.
• Long term treatment with rosiglitazone in patients with NAFLD shows significant improvement.
  • Preferred regimen: Rosiglitazone 4 mg PO/OD q24h .
  • Alternative regimen: Pioglitazone 4mg PO/OD.
  • Alternative regimen: Liraglutide 1.2 mg PO/OD.

Anti-oxidants

• Antioxidants offer hepatocyte protection from free radical damage.

• Patients with NAFLD are recommended to use ursodeoxycholic acid (UDCA) in combination with vitamin E.
• Vitamin E alone or in combination with vitamin C is also recommended in patients without any side effects in fibrosis score.
  • Preferred regimen (1) : Vitamin E 800 mg PO /OD.
  • Preferred regimen (1) : Vitamin C 30 mg/Kg/PO/OD.
  • Note: Avoid high dose of vitamin E which increases the fatality rate.

The combination of vitamin E (400 IU b.i.d.) and pioglitazone has been studies in one trial.

Miscellaneous

• Moringa Oleifera (MO), a plant from the family Moringacea is a major crop in Asia and Africa, the leaves of these plant have been studied extensively and it has shown to be beneficial in NAFLD and in prevention and alleviation of NAFLD.