Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are significantly effective in reducing cardiovascular events in patients with type 2 diabetes mellitus (T2DM). However, the magnitude of the effect of SGLT-2i on cardiovascular outcomes in established heart failure (HF) patients with T2DM remains undefined. Methods We systematically searched the PubMed, Embase, Cochrane Central and Web of Science databases for articles published prior to 09 April 2020 to identify randomized controlled trials that compared SGLT-2i with placebo in patients with heart failure concomitant with T2DM. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled across trials by using the generic inverse variance method. Sensitivity analyses were conducted by excluding specific studies or using risk ratios (RRs) with 95% CIs as measures of the effect size. Serious adverse events served as safety outcomes. Results A total of 5 large trials comprising 6945 patients with HF and T2DM were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for the primary composite outcome of CVD or HHF by 13% (HR: 0.87, 95% CI: 0.83–0.91, I2: 0%, P < 0.00001) in patients with HF concomitant with T2DM. Similarly, the use of SGLT-2i was associated with a statistically significant 14% reduction in HHF (pooled HR: 0.86, 95% CI: 0.81–0.91, I2: 0%, P < 0.00001) and a 10% reduction in ACM (pooled HR: 0.90, 95% CI: 0.86–0.96, I2: 16%, P < 0.0005) but was not significantly associated with a reduction in CVD (HR: 0.91, 95% CI: 0.81–1.02, I2: 60%, P = 0.11). Sensitivity analyses indicted consistent results. Compared with placebo plus standard care, the SGLT-2i group had a lower proportion of serious adverse events (weighted proportions: 44.3% vs 50.3%; RR 0.88, 95% CI 0.82–0.95, I2: 22%, p = 0∙006). Conclusions SGLT-2i significantly reduced the risk of HHF and ACM in a broad range of HF patients concomitant with T2DM. Compared with standard care, SGLT-2i plus standard therapy was associated with a reduction in serious adverse events.