Comparison of sodium-glucose cotransporter-2 (SGLT2) inhibitors to reduce cardiovascular and renal outcomes: a network meta-analysis of randomized controlled trials

Abstract

Abstract Background Although the cardio- and reno-protective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established, the differences across agents in various populations have yet to be elucidated. Purpose To investigate the profiles of each SGLT2 inhibitor in patients from various backgrounds. Methods MEDLINE and EMBASE databases were searched in November 2022 to identify randomized controlled trials (RCTs) comparing SGLT2 inhibitor to placebo. To compare each SGLT2 inhibitor, a network meta-analysis was performed. The primary efficacy endpoint was the composite of cardiovascular (CV) mortality and hospitalisations for heart failure (HHF). The secondary efficacy endpoints were all-cause mortality, CV mortality, HHF, kidney disease progression, and acute kidney injury (AKI). We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease (CKD). Safety endpoints were also assessed between SGLT2 inhibitors in all cohorts. Results This study included 19 RCTs with a total of 94,495 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. Although there were consistent tendencies favouring SGLT2 inhibitors over placebo, no significant difference between SGLT2 inhibitors was manifested for the primary outcome (Figures 1-2). Compared to placebo, empagliflozin and dapagliflozin improved all studied efficacy outcomes in overall population and demonstrated consistent benefits on reduction in primary outcome, HHF, kidney disease progression, and AKI independent of diabetic status. Among patients without CKD, empagliflozin were associated with lower risks of the primary outcome compared to ertugliflozin (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.60-0.98), CV mortality compared to canagliflozin (HR, 0.62; 95% CI, 0.40-0.96) and dapagliflozin (HR, 0.59; 95%CI, 0.39-0.89), and all-cause mortality compared to dapagliflozin (HR, 0.72; 95% CI, 0.52-0.99). All SGLT2 inhibitors increased the occurrence of genital infections. As compared to a placebo, canagliflozin increased the risks of limb amputation (HR, 1.58; 95% CI 1.07-2.35) and fracture (HR, 1.19; 95%CI 1.01-1.40). Conclusions SGLT2 inhibitors have comparable efficacy profiles in reducing cardiovascular and renal events. Whilst empagliflozin and dapagliflozin are beneficial even in patients without diabetes, empagliflozin may be an especially reasonable opiton in patients without CKD.Figure 1Figure 2