Author information
1 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera, Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy. Electronic address: giovanni.targher@univr.it.
2 Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK; Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK.
3 Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK; Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, USA.
5 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera, Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy.
Abstract
AIM: There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease.
METHODS: We systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH.
RESULTS: We included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n=6 studies), glitazones (n=8 studies), glucagon-like peptide-1 receptor agonists (n=6 studies), dipeptidyl peptidase-4 inhibitors (n=4 studies) or sodium-glucose cotransporter-2 inhibitors (n=7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only.
CONCLUSION: RCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.