Could metformin modulate cardiovascular outcomes differently with DPP-4 inhibitors compared with SGLT2 inhibitors?

AIMS: Preliminary data have suggested that metformin might potentiate cardiovascular (CV) protection by dipeptidyl peptidase-4 inhibitors (DPP-4is), but reduce CV protection by sodium-glucose cotransporter type-2 inhibitors (SGLT2is), in patients with type 2 diabetes (T2DM) at high CV-related risk. For this reason, the present meta-analyses aimed to compare metformin moderation of the CV effects of the two pharmacological classes. METHODS: Major adverse CV events (3-point MACEs) were counted in high-risk patients with T2DM treated with or without metformin as background therapy in five CV outcome trials with DPP-4is (SAVOR-TIMI 53, EXAMINE, TECOS, CARMELINA, CAROLINA) involving 24,821 patients (17,870 with and 6951 without metformin) and 2550 events (1696 with and 854 without metformin), and four trials with SGLT2is (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, VERTIS CV) involving 24,563 patients (19,090 with and 5473 without metformin) and 1829 events (1300 with and 529 without metformin). RESULTS: DPP-4is failed to reduce 3-point MACEs in both metformin users (OR: 0.96, 95% CI: 0.89-1.03) and non-users (OR: 1.05, 95% CI: 0.95-1.16), with no heterogeneity between trials and no significant between-subgroup differences (P = 0.4074), whereas SGLT2is significantly reduced 3-point MACEs in both patients with (OR: 0.91, 95% CI: 0.84-0.98) and without (OR: 0.81, 95% CI: 0.71-0.91) metformin, but again with no heterogeneity between trials and no significant between-subgroup differences (P = 0.2977). Overall, metformin non-users had a poorer risk profile than metformin users. CONCLUSION: Our meta-analyses involving a larger number of trials than before have revealed that background metformin therapy has no significant influence on either the neutral impact of DPP-4is or the positive impact of SGLT2is on CV events (3-point MACEs) in T2DM patients at high CV risk.