Impact of SGLT2 inhibitors on major clinical events and safety outcomes in heart failure patients: a meta-analysis of randomized clinical trials

BACKGROUND Sodium-glucose co-transporter-2 inhibitors(SGLT2 i) significantly reduce the risk of cardiovascular(CV) and renal adverse events in patients with diabetes mellitus, heart failure(HF) and/or chronic kidney disease. We performed a metaanalysis to explore the impact of several different SGLT2 i on all-cause mortality, CV mortality, HF hospitalizations and the combined outcome CV death/HF hospitalization in HF patients across the spectrum of left ventricular ejection fraction(LVEF) phenotypes.METHODS A systematic search in MEDLINE database and Cochrane library through March 2021 was performed without limitations. Randomized clinical trials that provided data about the impact of SGLT2 i on all-cause mortality, CV mortality, HF hospitalizations or the combined outcome of CV death/HF hospitalization in HF patients were included. A random effects model was used for calculating the effect estimates.RESULTS Nine studies(n = 16,723 patients, mean age: 65.9 years, males: 70.7%) were included in the quantitative synthesis.Compared to placebo, SGLT2 i use was associated with 14% lower risk of all-cause mortality [hazard ratio(HR) = 0.86, 95% CI:0.78-0.94, I~2 = 0, P = 0.0008], 32% lower risk of HF hospitalizations(HR = 0.68, 95% CI: 0.62-0.74, I~2 = 0, P < 0.001), 14% lower risk of CV mortality(HR = 0.86, 95% CI: 0.77-0.95, I~2 = 0, P = 0.003) and 26% lower risk of CV death/HF hospitalization(HR = 0.74,95% CI: 0.68-0.80, I~2 = 0, P < 0.001). Regarding the safety outcomes, our data revealed no significant differences between SGLT2 i and placebo groups in drug related discontinuations, amputations, severe hypoglycemia, hypotension, volume depletion, ketoacidosis and genital infections. By contrast, a protective role of SGLT2 i against placebo was found for serious adverse events and acute kidney injury.CONCLUSIONS In patients with HF, regardless of LVEF phenotype, all SGLT2 i had an excellent safety profile and significantly reduced the risk of all-cause mortality, CV mortality, HF hospitalizations and CV deaths/HF hospitalizations compared to placebo.