Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes – A systematic review

Karin Rådholm, Jason Hy Wu, Muh Geot Wong, Celine Foote, Gregory Fulcher, Kenneth W Mahaffey, Vlado Perkovic, Bruce Neal

Sodium glucose co-transporter 2 (SGLT2) inhibitors appear to protect against increased risks of cardiovascular and kidney disease in patients with type 2 diabetes but also cause some harms. Whether effects are comparable across drug class or specific to individual compounds is unclear. This meta-analysis assessed the class and individual compound effects of SGLT2 inhibition versus control on cardiovascular events, death, kidney disease and safety outcomes in patients with type 2 diabetes. MEDLINE, EMBASE, the Cochrane Library and regulatory databases were systematically searched for data from randomized clinical trials that included reporting of cardiovascular events, deaths or safety outcomes. We used fixed effects models and inverse variance weighting to calculate relative risks with the 95% confidence intervals. The analyses included data from 82 trials, four overviews and six regulatory reports and there were 1,968 major cardiovascular events identified for analysis. Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77 to 0.93), heart failure (RR 0.67, 95%CI 0.55 to 0.80), all-cause death (RR 0.79, 95%CI 0.70 to 0.88) and serious decline in kidney function (RR 0.59, 0.49 to 0.71). Significant adverse effects were observed for genital infections (RR 3.06, 95%CI 2.73 to 4.43), volume depletion events (RR1.24, 95%CI 1.07 to 1.43) and amputation (RR 1.44 95%CI 1.13 to 1.83). There was a high likelihood of differences in the associations of the individual compounds with cardiovascular death, hypoglycaemia and amputation (all I2> 80%) and a moderate likelihood of differences in the associations with non-fatal stroke, all-cause death, urinary tract infection and fracture (all I2> 30%). There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated with infections, volume depletion effects and amputation. Some associations appear to differ between compounds.