SGLT-2 inhibitor add-on to DPP-4 inhibitor therapy significantly reduces HbA1c and body weight without increasing hypoglycaemia risk in type 2 diabetes inadequately controlled on metformin: a systematic review and meta-analysis

PURPOSE: This study evaluates the efficacy of combination therapy with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) versus DPP-4i monotherapy in patients with type 2 diabetes mellitus (T2DM) who remained inadequately controlled on metformin. METHODS: Randomized controlled trials (RCTs) investigating adults with T2DM inadequately controlled on metformin, comparing the combination of SGLT-2i plus DPP-4i versus DPP-4i add-on therapy alone were systematically reviewed. PubMed/Medline, Google Scholar, Embase, and CENTRAL were searched without language restriction. The primary outcomes were change in HbA1c and in fasting plasma glucose (FPG) from baseline, proportion of patients attainting HbA1c < 7.0%, and body weight reduction. Secondary outcomes included hypoglycemia risk, genital infection, urinary tract infection (UTI), and overall and serious adverse events (AEs). Pooled analyses were carried out using the random-effects model. RESULTS: Eleven RCTs (3662 patients) were pooled. Compared with DPP-4i alone, adding a combination of SGLT-2i plus DPP-4i after metformin significantly reduced HbA1c (MD: - 0.47%; 95% CI (- 0.54, - 0.41); GRADE: high), increased the proportion of patients attaining HbA1c < 7.0% (RR: 1.71; 95% CI (1.52, 1.93); GRADE: moderate), reduced FPG (MD: - 15.75 mg/dL; 95% CI (- 21.56, - 9.93); GRADE: moderate), increased genital infection (RR: 2.83 (95% CI 1.02, 7.87; GRADE = moderate), and produced greater body weight reduction (MD: - 1.46 kg; 95% CI (- 1.93, - 0.99); GRADE: moderate). The risk of UTI and overall and serious AEs were insignificantly different between arms. CONCLUSION: The combinatorial therapy using SGLT-2i and DPP-4i produces a significantly better glycemic control and body weight compared with DPP-4i therapy alone, without increasing the overall safety burden. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13340-026-00934-1.