Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to be efficacious in reducing mortality and heart failure hospitalizations in patients with heart failure and reduced ejection fraction. However, their role in patients with heart failure and preserved ejection fraction (HFpEF) is still unclear. Recently, the results of the EMPEROR-Preserved trial (Empagliflozin in Heart Failure with a Preserved Ejection Fraction) were released and it was the first randomized controlled trial (RCT) evaluating SGLT-2 inhibitors exclusively in patients with HFpEF. However, there have been other studies that have looked at the efficacy of SGLT-2 inhibitors in other populations that included HFpEF patients. Here, we conducted a meta-analysis to evaluate the efficacy of SGLT-2 inhibitors in patients with HFpEF by pooling the results of EMPEROR-Preserved trial with data from post hoc analyses of other trials.
An extensive literature search of multiple databases was conducted on August 29, 2021 to include all published studies that evaluated the role of SGLT-2 inhibitors in patients with HFpEF. The end points of interest were a composite of heart failure hospitalization or cardiovascular mortality (the primary outcome), heart failure hospitalization, cardiovascular mortality, and all-cause mortality. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were extracted from the included studies for all outcomes. These were pooled using a random-effects model. Review Manager (version 5.3, Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for all statistical analyses.
Data from 6 RCTs were included in our analysis. The median follow-up duration was 31.1 months. The included studies are the EMPEROR-Preserved trial, a post hoc study of the CANVAS trials (Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes), a post hoc study of the VERTIS-CV trial (Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes), a post hoc study of the DECLARE-TIMI 58 trial (Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes), a post hoc study of pooled results from SOLOIST-WHF trial (Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure) and SCORED trial (Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease) that was presented by the authors in the American College of Cardiology Conference in 2021. We excluded the CANONICAL trial (Effect of the Sodium-Glucose Cotransporter 2 Inhibitor Canagliflozin for Heart Failure With Preserved Ejection Fraction in Patients With Type 2 Diabetes) as it was designed to evaluate the body weight and changes in plasma B-type natriuretic peptide over relatively shorter follow-up period compared with other included trials (24 weeks) and the HRs for the outcomes of interest were not reported.
The definition of the composite primary outcome was slightly variable among the included studies. In the SOLOIST-WHF and SCORED trials, total heart failure hospitalizations or cardiovascular mortality was the primary composite outcome. In the post hoc analysis of CANVAS program, the primary outcome was total heart failure hospitalizations or all-cause mortality. For all other included studies, the primary outcome was the first heart failure hospitalization or cardiovascular mortality. Given subtle differences between these definitions and the clinical relevance of all of them, they were all included in the analysis.
Compared with placebo, SGLT-2 inhibitors in patients with HFpEF were associated with statistically significant lower risk of the composite primary outcome (HR 0.79, 95% CI 0.71 to 0.88, I 2 0%) ( Figure 1 ), and heart failure hospitalization (HR 0.71, 95% CI 0.61 to 0.82, I 2 0%) ( Figure 1 ). However, there was no significant difference in terms of cardiovascular mortality (HR 1.01, 95% CI 0.80 to 1.28, I 2 23%) ( Figure 1 ) and all-cause mortality (HR 0.95, 95% CI 0.82 to 1.11, I 2 0%) ( Figure 1 ). Heterogeneity was statistically low as I 2 was less than 25% in all outcomes.
