There are limited data on the beneficial effects of antihyperglycemic drugs for nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Most of the available evidence relates to the use of pioglitazone in these patients, which shows some efficacy in reducing liver disease progression and related outcomes, according to study results published in Diabetes & Metabolism.

Although many randomized controlled trials have explored the possible effect of antihyperglycemic drugs on NAFLD, the management of this liver disease is mainly based on lifestyle modifications, and there are no currently approved medications for this indication. In the current systematic review, the goal was to assess the efficacy and safety of different antihyperglycemic agents in NAFLD or NASH specifically.

After a systematic search in PubMed, ClinicalTrials.gov, and the Cochrane Database of Systematic Reviews from January 1990 to September 2019, the researchers identified 29 placebo-controlled or active-controlled randomized trials with a total of 2617 participants (45% with established type 2 diabetes) who received metformin (6 studies), glitazones (8 studies), glucagon-like peptide-1 receptor agonists (6 studies), dipeptidyl peptidase-4 inhibitors (4 studies), or sodium-glucose cotransporter 2 inhibitors (7 studies) to treat NAFLD.


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Metformin was investigated in 4 trials that included patients with biopsy-proven NAFLD and in 2 trials involving patients with imaging-defined NAFLD. The trials that focused on biopsy-proven NAFLD reported small beneficial effects on liver steatosis and inflammation, but no significant effects on liver fibrosis or NASH. The trials that included participants with imaging-defined NAFLD showed neutral effects on liver steatosis.

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Glitazones were investigated in 8 trials, including 6 studies of pioglitazone and 2 studies of rosiglitazone. All studies included participants with biopsy-proven NAFLD, with the exception of 1 study that included patients with imaging-defined NAFLD. Both pioglitazone and rosiglitazone significantly improved liver fat content and NASH. However, in most studies, there was no significant beneficial effect on liver fibrosis. Pioglitazone was also linked to greater weight gain than placebo or other reference treatment.

Of the glucagon-like peptide-1 receptor agonists assessed in the included studies, liraglutide was found to improve liver fat, serum aminotransferase levels, and body weight. Data on liver fibrosis were limited to a single study, which found that liraglutide had no significant effect on liver fibrosis.

Although dipeptidyl peptidase-4 inhibitor vildagliptin had a marginal effect on liver fat, no data on liver histology were available, and therefore the researchers could not assess the effect of these agents on NASH.

Sodium-glucose cotransporter 2 inhibitors were assessed in 7 studies, all of which included participants with imaging-defined NAFLD. There were mixed reports on the effect of these medications on liver fat content.

Overall, the data show that antihyperglycemic agents may improve serum liver enzymes, but the effects on histologic features of NAFLD or NASH are limited. Pioglitazone use in patients with NASH was found to have beneficial effects on liver function, liver fat content, and NASH resolution in patients with and without type 2 diabetes. However, pioglitazone treatment was also associated with increased body weight and lower-limb edema, which may limit its use.

The researchers acknowledged several limitations of this systematic review, including the restriction to randomized controlled trials, lack of head-to-head trials, and variable mechanisms of actions of the different medications assessed.

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Reference

Mantovani A, Byrne CD, Scorletti E, Mantzoros CS, Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: an updated systematic review of randomized controlled trials [published online January 7, 2020]. Diabetes Metab. doi:10.1016/j.diabet.2019.12.007