SGLT2 inhibitors and cardiovascular and renal outcomes: a meta-analysis and trial sequential analysis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events and renal outcomes in patients with diabetes mellitus (DM). This meta-analysis aimed to provide a thorough evaluation regarding the efficacy and safety of SGLT2 inhibitors. Data search of MEDLINE/PubMed, Embase, and Cochrane Library databases and ClinicalTrials.com from inception through November 26, 2020. We included randomized trials, SGLT2 inhibitors compared with placebo, patients with or without diabetes at recruitment, and reporting the incidence of cardiovascular or renal outcomes. Two authors extracted pertinent data into predefined data collection tables. Ten trials were included (71,553 patients). The mean age was 64.7 ± 8.4 years, with 65.1% male. Follow-up durations range 9-50 months. Inhibition of SGLT2 resulted in lower composite outcome of heart failure (HF) hospitalization or cardiovascular death (RR 0.76, 95% CI 0.73-0.81, P < 0.01) and lower risk of renal outcomes (RR 0.68, 95% CI 0.60-0.77, P < 0.01). Furthermore, SGLT2 inhibitors were associated with lower major adverse cardiovascular events (MACEs), HF hospitalization, cardiovascular mortality, all-cause mortality, myocardial infarction, and serious adverse events, compared with placebo (P < 0.05). Sensitivity analyses revealed lower MACE events also in patients with HF, and a lower HF hospitalization and cardiovascular mortality in non-diabetic patients (P < 0.05). While the amputation risk was comparable between the two groups, the risk of diabetic ketoacidosis was higher in the SGLT2 inhibitor group. Inhibition of SGLT2 in patients with DM and prevalent ASCVD reduces the risk of HF hospitalization, cardiovascular mortality, all-cause mortality, MACE, and renal outcomes without increasing the risk of serious adverse events or amputation.