Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Abstract

Background The cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT 2 (sodium–glucose cotransporter 2) inhibitors have not been well documented. Methods and Results For cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT 2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [ HR ]: 0.80; 95% confidence interval [ CI ], 0.69–0.92; P =0.002), all‐cause mortality ( HR : 0.67; 95% CI , 0.54–0.84; P <0.001), cardiovascular mortality ( HR : 0.77; 95% CI, 0.60–0.98; P =0.03), nonfatal myocardial infarction ( HR : 0.86; 95% CI , 0.76–0.98; P =0.02), hospitalization for heart failure ( HR : 0.62; 95% CI , 0.55–0.69; P <0.001), and progression of albuminuria ( HR : 0.68; 95% CI , 0.58–0.81; P <0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT 2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT 2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections. Conclusions SGLT 2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.