Dapagliflozin & pioglitazone combination therapy in T2DM with or without MASLD - a systematic review and meta-analysis: PRO-2 study

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Aims: To evaluate the efficacy and safety of dapagliflozin plus pioglitazone versus comparators on metabolic control and hepatic steatosis in adults with type 2 diabetes mellitus (T2DM), with or without metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We conducted a systematic review and meta-analysis of randomized and observational studies in PubMed, Embase, Cochrane Central, Scopus, Web of Science with a search updated through January 2026, following peer review. Eligible studies enrolled adults with T2DM with or without MASLD, receiving dapagliflozin plus pioglitazone in comparison with standard care or monotherapy, or as pooled-arm exploratory estimates. The primary outcome was glycemic control (HbA1c and fasting and postprandial glucose levels). Secondary outcomes included body weight, insulin resistance indices, related liver outcomes (liver fat content, NAFLD activity score [NAS], and steatohepatitis resolution), liver enzymes, non-invasive fibrosis indices, lipid parameters, and safety outcomes. Results: Thirteen studies (n = 1411) met the inclusion criteria. Dapagliflozin-pioglitazone significantly improved glycemic control, with a reduction in HbA1c (mean difference -0.49%; 95% CI -0.64 to -0.34), and Fasting Blood Glucose (-11.96 mg/dL; 95% CI -16.30 to -7.62) and Post-Prandial Glucose (-21.54 mg/dL; 95% CI -30.84 to -12.24). Hepatic outcomes also improved, with reductions in liver fat content (standardized mean difference -0.42; 95% CI -0.61 to -0.22) and NAS (standardized mean difference -0.39; 95% CI -0.56 to -0.22), and higher rates of steatohepatitis resolution (risk ratio 1.48; 95% CI 1.13-1.92). Certainty of evidence was moderate for glycemic and steatosis outcomes and low for histological endpoints. Conclusions: Dapagliflozin-pioglitazone combination therapy was associated with improvements in glycemic control and non-invasive markers of hepatic steatosis in adults with T2DM, with or without MASLD, while maintaining a favorable safety profile. Certainty of evidence was moderate for metabolic and steatosis outcomes and low for histological endpoints. Given the predominance of surrogate hepatic endpoints and limited biopsy-confirmed data, these findings should be interpreted with appropriate caution. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1117019, identifier CRD420251117019.

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