Key result
SGLT2 inhibitors cut MACE ~18% in patients without baseline metformin, with consistent benefits regardless of use.
Why the study?
It was unknown whether the effects of SGLT2 inhibitors on cardiovascular, kidney, and mortality outcomes are consistent with and without concomitant metformin use.
Do SGLT2 inhibitors reduce cardiovascular, kidney, and mortality outcomes consistently with and without concomitant metformin use in patients with type 2 diabetes, kidney disease, or heart failure?
Meta-Analysis (n=51,743)
Placebo-controlled
Randomized
Yes
Do SGLT2 inhibitors reduce cardiovascular, kidney, and mortality outcomes consistently with and without concomitant metformin use in patients with type 2 diabetes, kidney disease, or heart failure?
This meta-analysis demonstrates that SGLT2 inhibitors consistently reduce cardiovascular, heart failure, kidney, and mortality outcomes regardless of concomitant metformin use, supporting their use independent of background metformin therapy.
Answers are grounded in this paper and cite their sources.
Supports SGLT2 inhibitor initiation independent of metformin; extends RCT evidence to metformin-naive subgroups.
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.
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Neuen et al. (2020) conducted a meta-analysis in Type 2 diabetes mellitus, chronic kidney disease, or heart failure with reduced ejection fraction (n=51,743). Sodium-glucose co-transporter-2 (SGLT2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin) with or without concomitant metformin vs. Placebo with or without concomitant metformin was evaluated on Major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in patients without concomitant metformin vs with concomitant metformin (HR 0.82 (without metformin); HR 0.93 (with metformin), 95% CI 0.71-0.96, p=0.14 for heterogeneity). SGLT2 inhibitors reduced MACE both with (HR 0.93, 95% CI 0.87-1.00) and without (HR 0.82, 95% CI 0.71-0.96; P-heterogeneity=0.14) concomitant metformin.
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