Among patients with type 2 diabetes mellitus (T2DM), the worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are estimated to be 55% and 17%, respectively.^1,2 When considering the NAFLD treatment, Dr. Diana Barb, Clinical Assistant Professor of the Division of Endocrinology, Diabetes and Metabolism of the University of Florida, United States, recommended three drug classes, namely glucagon-like peptide-1 receptor agonist (GLP-1ra), peroxisome proliferator-activated receptor (PPAR) agonist and selective thyroid hormone receptor-beta agonist, with proven effectiveness in resolving NAFLD without worsening of fibrosis.^5-9

The first drug class suitable for the treatment of NAFLD in diabetic patients is GLP-1ra such as semaglutide and liraglutide.^5-6 Both have been proven to resolve biopsy-confirmed NAFLD without worsening of fibrosis in overweight or obese individuals with T2DM.5-6 In a 72-week doubleblind phase 2 trial, 320 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were randomly assigned to different doses of semaglutide (i.e., 0.1mg, 0.2mg, or 0.4mg daily) versus placebo.5 The percentage of NASH resolution was 40% with 0.1mg semaglutide, 36% with 0.2mg semaglutide, 59% with 0.4mg semaglutide and 17% with placebo, respectively.⁵ Likewise, similar results were reported in a 26-week trial involving 75 patients with both T2DM and NAFLD who are receiving liraglutide or sitagliptin.⁶ By the end of the study, patients receiving liraglutide or sitagliptin had 15.4% and 15.5% reduction of fat composition in the intrahepatic fluid, respectively, which was significantly greater than the placebo group receiving insulin glargine.⁶

Another option is PPAR agonists which mediate hepatological protective effect by inhibiting the mitochondrial pyruvate carrier in the hepatocytes.^7-8 Two PPAR agonists, pioglitazone and lanifibranor, were investigated in two separate studies.^7-8 In a prospective study involving biopsy-proven NASH, the use of pioglitazone reduced NAFLD activity score by 2 points or more in 48% of patients with T2DM and 46% of non-diabetic NASH patients.⁷ Likewise, the 24-week treatment with lanifibranor (800mg or 1,200mg/day) conferred significant reduction of NAFLD activity score by 2 points or more.⁸ In addition, lanifibranor decreased hepatic collagen deposition and preserved hepatic function among NAFLD patients.8 Both studies revealed a significant reduction in plasma alanine aminotransferase in patients receiving lanifibranor treatment.^7,8

Resmetirom (formerly known as MGL-3196), a selective thyroid hormone receptor-beta agonist, is also an option for treating NAFLD.⁹ In a 36-week phase 2 open-label study, patients receiving 80mg or 100mg oral resmetirom daily had 55% reduction of liver fat deposition comparing to baseline as revealed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF).⁹

When considering treatment of NAFLD in patients with T2DM, Dr. Barb summarized that “Semaglutide, pioglitazone, lanifibranor, liraglutide and resmetirom are antidiabetic agents which can resolve NASH without fibrosis worsening.”