Selective SGLT2 inhibitors in MASLD/MASH: an outcome-specific systematic review and meta-analysis of hepatic and cardiometabolic outcomes

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have established glycaemic, renal and cardiovascular benefits, but their hepatic effects in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) remain incompletely defined. We conducted a PRISMA 2020 systematic review and meta-analysis of randomized controlled trials evaluating selective SGLT2 inhibitors in adults with MASLD, MASH or corresponding earlier non-alcoholic fatty liver disease/non-alcoholic steatohepatitis phenotypes. The protocol was registered in PROSPERO (CRD420261390850). Thirty randomized trials, including 2359 participants contributing to liver-outcome analyses, were included. Most evidence came from T2DM-associated MASLD trials. In a prespecified strict MR-based synthesis of two directly extractable double-blind placebo-controlled trials including 116 participants, SGLT2 inhibition reduced liver fat compared with placebo: mean difference - 2.54% points, 95% confidence interval - 4.39 to - 0.69; I²=41.2%. Certainty was rated as low because of serious indirectness and serious imprecision; publication bias could not be formally assessed because only two trials contributed to the pooled analysis. Additional placebo-controlled magnetic resonance evidence supported liver fat reduction in non-diabetic MASLD but was not pooled because of median-based reporting. Three biopsy-based randomized trials enrolled 245 participants overall, of whom 229 contributed evaluable data to the histological fibrosis-improvement meta-analysis. This analysis suggested a higher likelihood of histological fibrosis improvement: risk ratio 2.21, 95% confidence interval 1.52-3.23; I²=0%, but the finding was judged low certainty and hypothesis-generating. Elastography-based fibrosis-related outcomes were heterogeneous and should not be equated with histological fibrosis regression. SGLT2 inhibitors also improved body weight, body mass index, visceral adiposity and glycaemic control in T2DM-associated MASLD. Current evidence is most consistent with a modest but reproducible reduction in imaging-assessed hepatic steatosis, particularly in T2DM-associated MASLD, whereas evidence for histological disease modification remains preliminary. SGLT2 inhibitors should therefore be regarded primarily as cardiometabolic agents with liver fat-lowering effects and possible adjunctive hepatic relevance, rather than established liver-specific disease-modifying therapies for MASLD/MASH. Registration: PROSPERO CRD420261390850.

Abstract as published, via PubMed.