Venous thromboembolism with modern glucose-lowering agents in diabetes: active-comparator evidence beyond placebo-based meta-analyses

Abstract The influence of newer glucose-lowering agents on venous thromboembolism (VTE) risk has important therapeutic implications. This meta-analysis compared sodium-glucose cotransporter-2 inhibitors (SGLT2—i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) with dipeptidyl peptidase-4 inhibitors (DPP-4i) and evaluated head-to-head SGLT2i versus GLP1-RA comparisons. Eligible studies enrolled adults with diabetes and reported adjusted relative risks for VTE, pulmonary embolism (PE), or deep vein thrombosis (DVT) using new-user cohort, target-trial emulation, nested case–control, or randomized controlled designs. Pooled estimates were derived using inverse-variance meta-analysis on the log scale, with random-effects sensitivity analyses. Six studies met inclusion criteria, all of moderate risk of bias. Compared with DPP-4i, both SGLT2—i (HR 0.72; 95% CI 0.62–0.82) and GLP1-RA (HR 0.78; 95% CI 0.73–0.83) were associated with significantly reduced VTE risk, whereas no difference was observed between SGLT2—i and GLP1-RA (HR 1.02; 95% CI 0.84–1.23). Component analyses were directionally consistent: for PE, SGLT2—i versus DPP-4i HR 0.44 (95% CI 0.30–0.64) and GLP1-RA versus DPP-4i HR 0.74 (95% CI 0.68–0.82); for DVT, SGLT2—i versus DPP-4i HR 0.82 (95% CI 0.68–0.99) and GLP1-RA versus DPP-4i HR 0.81 (95% CI 0.75–0.88). In adults with diabetes, SGLT2—i and GLP1-RA were each associated with a lower risk of VTE compared with DPP-4i, while head-to-head comparisons showed no clear difference and were limited by imprecision. These findings should be interpreted with caution given the limited evidence base. Overall, they suggest that concerns regarding VTE risk should not be a primary driver of treatment selection between these agents in clinical practice. Trial registration: PROSPERO CRD4201149607. Graphical abstract In a meta-analysis of six observational studies, both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of venous thromboembolism compared with DPP-4 inhibitors, while no significant difference was observed between SGLT2 inhibitors and GLP-1 receptor agonists in head-to-head comparisons.