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

Brendon L. Neuen, Clare Arnott, Vlado Perkovic, Gemma Figtree, Dick de Zeeuw, Greg Fulcher, Min Jun, Meg J. Jardine, Sophia Zoungas, Carol Pollock, Kenneth W. Mahaffey, Bruce Neal, Hiddo J.L. Heerspink

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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.

Original languageEnglish
Pages (from-to)382-390
Number of pages9
JournalDiabetes, Obesity and Metabolism
Issue number2
Publication statusPublished - Feb 2021


  • cardiovascular disease
  • clinical trial
  • diabetic nephropathy
  • heart failure
  • meta-analysis
  • SGLT2 inhibitor

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