Sodium-glucose co-transporter-2 inhibitors with and without metformin: A meta-analysis of cardiovascular, kidney and mortality outcomes

Aim: To assess whether the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use.

Material and methods: We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects, reported as hazards ratios (HRs) and 95% confidence intervals (CIs), were pooled using random-effects meta-analysis. The main outcomes in this analysis were (i) major adverse cardiovascular events (MACE) and (ii) hospitalization for heart failure (HHF) or cardiovascular death.

Results: We included six trials of four SGLT2 inhibitors that enrolled a total of 51 743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86, respectively; P-heterogeneity = 0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors, irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87, respectively; P-heterogeneity = 0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity > 0.40).

Conclusion: Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin.