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

Abstract

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.

Diabetes, metformin and glucose lowering therapies after myocardial infarction: Insights from the SWEDEHEART registry

“…25 In a recent meta-analysis on treatment with SGLT2i the reduction in CV and renal complications was consistent regardless of concomitant metformin or not. 26 Interestingly, in the present observational study, although marginal and could be due to unmeasured confounding, we found lower rates of CV complication in diabetes patients treated with metformin (mono-therapy) than with diet alone. Furthermore, non-diabetes patients treated with metformin had a similar risk for future CV event than non-diabetes patients.…”

“… 25 In a recent meta-analysis on treatment with SGLT2i the reduction in CV and renal complications was consistent regardless of concomitant metformin or not. 26 …”

Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs Sulfonylureas in Patients With Type 2 Diabetes

“…54 Increasingly, second-line antihyperglycemics are often initiated without first-line metformin therapy. 55 In the SGLT2 inhibitors trials involving patients with type 2 diabetes, baseline metformin use ranged from 58% to 82%. 56 In this study, we designed a per-protocol analysis to gain a better understanding whether continued metformin use with the addition of SGLT2 inhibitors was contributing to risk reduction.…”

Sodium–glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes

“…It is anticipated that novel indications may be issued in the near future as the results of ongoing trials become available. The accumulated evidence suggests that SGLT-2i should be considered for control of hyperglycemia in patients with T2D, particularly in those with established CVD, given that they reduce the risk of MACE, hospitalization for HF and progression of DKD, regardless of whether patients are receiving or not metformin [66]. The remarkable reduction in risk of HF seen across CVOTs, as well as other intervention trials (Fig.…”