Cardiovascular Outcomes With Empagliflozin and Dapagliflozin in Patients Without Diabetes

Abstract

While the cardiovascular (CV) benefits with sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes mellitus (DM) are well known, their effects in patients without DM continue to be explored. We provide a meta-analysis of the available evidence. Online databases were searched for randomized controlled trials (RCTs) comparing SGLT2i to placebo/control in patients without DM. The endpoints of interest were composite CV death/hospitalization for heart failure (HF) with individual components, all cause death, major adverse CV events (MACE) and serious adverse events. Subgroup analysis was performed according to the type of SGLT2i. Pooled odds ratios (OR) and 95% confidence intervals (CI) were generated via a random-effects model. A total of 6 RCTs with 12,984 patients (6,501 in the SGLT2i group and 6,483 in the placebo group) were included, followed over a mean duration of 17.7 months. Four RCTs had patients with HF, 1 with chronic kidney disease (CKD) and 1 with myocardial infarction (MI). The mean age was 64 years, 72% patients were men and mean HbA1C was 5.7%. As compared to placebo, SGLT2i treatment was associated with significant reduction in composite CV death or hospitalization for HF (OR 0.77, 95% CI 0.68 - 0.87, p < 0.0001), primarily due to decrease in hospitalization for HF (OR 0.70, 95% CI 0.60 - 0.81, p < 0.00001). No significant differences were found pertaining to CV death (OR 0.86, 95% CI 0.74 - 1.01, p = 0.06), all cause death (OR 0.89, 95% CI 0.71 - 1.11, p = 0.29) and MACE (OR 0.95, 95% CI 0.68 - 1.32, p = 0.75). Serious adverse events were lower with use of empagliflozin vs placebo. In conclusion, this study shows significant CV benefits in terms of reduction in CV death or hospitalization for HF in non-diabetic patients treated with SGLT2i as compared to placebo. The underlying heterogeneity of patients in terms of comorbidities (HF, CKD or MI) needs to be considered while interpreting the results.