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

BackgroundThe cardiovascular and long-term noncardiovascular safety and efficacy of SGLT2 (sodium-glucose cotransporter 2) inhibitors have not been well documented. Methods and ResultsFor cardiovascular outcomes, we performed a meta-analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26weeks and 2000patient-years of follow-up. For long-term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2years and 1000patient-years of follow-up. Five studies with 351476 patients were included in cardiovascular outcomes analysis. Meta-analyses showed that SGLT2 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 SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long-term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections. ConclusionsSGLT2 inhibitors showed remarkable cardiovascular- and renal-protective effects and good long-term noncardiovascular safety with sustained efficacy.