Incremental effects of SGLT2 inhibitors, GLP-1 receptor agonists, and pioglitazone in type 2 diabetes and MASLD across Asian study settings: a systematic review and meta-analysis

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The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abstract

[OBJECTIVE] We evaluated the incremental hepatic and metabolic effects of adding sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), or pioglitazone to comparable background glucose-lowering therapy in Asian adults with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). [METHODS] We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science through 30 June 2026. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Eligible trials evaluated the addition of a study drug to background glucose-lowering management that was comparable between randomized groups and either remained stable or followed a prespecified adjustment protocol. Changes from baseline in alanine aminotransferase (ALT) and glycated hemoglobin (HbA1c) were coprimary outcomes. Secondary outcomes included aspartate aminotransferase, gamma-glutamyl transferase, magnetic resonance imaging-proton density fat fraction, liver stiffness, fibrosis-4 index, fasting plasma glucose, lipid parameters, body mass index, serum adiponectin, and systolic blood pressure. Random-effects pairwise meta-analyses were performed, and GRADE certainty was assessed for the two coprimary outcomes. Safety outcomes were synthesized narratively because reporting was heterogeneous and frequently incomplete. [RESULTS] We included eleven randomized trials: 692 participants were randomized into eligible comparisons, of which 642 participated in the coprimary efficacy analyses. Moderate certainty was found for a reduction in ALT with the addition of an SGLT2 inhibitor compared with background therapy alone (mean difference [MD], - 7.56 U/L; 95% confidence interval [CI], - 11.24 to - 3.88); however, there was little or no clinically important further benefit observed for HbA1c (MD, - 0.09%; 95% CI, - 0.27 to 0.08; moderate certainty). Modest reductions in ALT were suggested by moderate certainty for GLP-1RAs (MD, - 6.71 U/L; 95% CI, - 11.53 to - 1.89) while low certainty indicated an HbA1c reduction (MD, - 0.48%; 95% CI, - 0.83 to - 0.14). Secondary exploratory findings favoring add-on therapy existed, although they are unadjusted for multiplicity. The comparative safety could not be assessed reliably. [CONCLUSION] In short-term randomized trials conducted in Asian study settings, adding SGLT2 inhibitors or GLP-1RAs may improve selected hepatic and metabolic surrogate outcomes. The available evidence does not support a treatment-class ranking, and the durability and clinical significance of these changes remain uncertain because follow-up was short and several comparisons were based on sparse evidence. Comparative safety also remains uncertain because adverse-event reporting was heterogeneous and incomplete. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251231137.

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