Efficacy of Antihyperglycemic Drugs for the Treatment of NAFLD and NASH

A person holding 2 white pills in their hand.
Investigators examined the effects of certain antihyperglycemic drugs as treatment for NAFLD or NASH in patients with or without type 2 diabetes.

Peroxisome proliferator-activated receptor (PPAR) agonists, glucagon-like peptide-1 receptor (GLP-1R) agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors may be effective treatment options for individuals with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), according to a study published in The Lancet Gastroenterology & Hepatology.

There are currently no licensed treatments for NAFLD or NASH. With incidence of type 2 diabetes closely linked to these liver diseases, 3 different classes of antihyperglycemic drugs — PPAR agonists, GLP-1R agonists, and SGLT2 inhibitors — have demonstrated potential in their treatment. Researchers conducted a systematic review of active-controlled or placebo-controlled randomized trials to examine the efficacy and safety of PPAR agonists, GLP-1R agonists, or SGLT2 inhibitors to specifically treat NAFLD and NASH in adults with or without type 2 diabetes.

Investigators identified a total of 25 (n=8 for PPAR agonists; n=10 for GLP-1R agonists; n=7 for SGLT2 inhibitors) active-controlled or placebo-controlled trials that met inclusion criteria. In total, 2597 patients (1376 [53%] men and 1221 [47%] women) with a mean age of 52 years and a mean body mass index (BMI) of 32 kg/m² were included. Of these patients, 1610 (62%) had type 2 diabetes.

Based on these studies, the researchers found that pioglitazone, lanifibranor, and GLP-1R agonists (eg, liraglutide and semaglutide) appeared to improve individual features of NASH, including steatosis, ballooning, and lobular inflammation. Additionally, these treatments were associated with resolution of NASH without worsening of fibrosis. SGLT2 inhibitors (eg, empagliflozin and dapagliflozin) were associated with reduced liver fat content when examined using magnetic resonance-based techniques.

This review is limited by the small sample sizes and limited treatment durations of studies included in the analysis. Additionally, very few trials using GLP-1R agonists and SGLT2 inhibitors included data on histological liver outcomes. Future head-to-head trials are needed in order to provide recommendations on which drug class is most effective for treatment of NAFLD and NASH.

The researchers concluded, “Because of the different mechanisms of actions of each of these three classes of drugs, combination therapy would seem to be a particularly effective therapeutic option.”


Mantovani A, Byrne CD, Targher G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. Lancet Gastroenterol Hepatol. Published online January 11, 2022. doi: 10.1016/S2468-1253(21)00261-2