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 (SGLT2i) 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 SGLT2i 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 SGLT2i 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, SGLT2i 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 SGLT2i and placebo groups in drug related discontinuations, amputations, severe hypoglycemia, hypotension, volume depletion, keto-acidosis and genital infections. By contrast, a protective role of SGLT2i against placebo was found for serious adverse events and acute kidney injury. CONCLUSIONS In patients with HF, regardless of LVEF phenotype, all SGLT2i 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.