Effects of dapagliflozin and empagliflozin on 6-min walk distance in heart failure with preserved and reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials involving 2624 patients

Background Dapagliflozin and empagliflozin are antidiabetic medications. They are the first two sodium-glucose cotransporter-2 inhibitors (SGLT2i) to receive the US Food and Drug Administration approval to manage heart failure. Emerging new trials have examined changes in the 6-min walk distance as a clinically significant response to dapagliflozin and empagliflozin in patients with heart failure with reduced ejection fraction (HFpEF) and heart failure with preserved ejection fraction (HFrEF). This meta-analysis aims to evaluate the effects of dapagliflozin and empagliflozin on the 6-min walk distance in patients with HFpEF and HFrEF. To our knowledge, no such meta-analysis has been published. Methods Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) to identify eligible studies reported up to December 16, 2023. Using Review Manager software, we reported outcomes as risk ratios (RRs) or mean difference (MD) and confidence intervals (CIs). A p-value <= 0.05 is considered as statistically significant. Results The meta-analysis included a total of 8 studies with 2624 patients. Overall, the results showed insignificant differences in the 6-min walk between the SGLT2i and placebo (MD 24, 95% CI -0.30 to 18.78, p = 0.06). Results became significant after resolving the heterogeneity (MD 6.72, 95% CI 0.13 to 13.31, p = 0.05). Notably, the results of each drug separately were insignificant. More robust observations occurred in the HFpEF group (MD 10.73, 95% CI 1.08 to 20.39, p = 0.03). Compared to placebo, patients on dapagliflozin reported significant improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary (KCCQ-CS) and Overall Summary (KCCQ-OS) with values of MD 5.18 (95% CI 2.80 to 7.57, p < 0.0001) and MD 4.06 (95% CI 1.66 to 6.46, p = 0.0009), respectively. The dapagliflozin group and patients with HFpEF had reported a significant reduction in their weight compared with the control group (MD -0.59 CI -1.09 to -0.08, p = 0.02) and (MD -0.80 CI -1.47 to -0.13, p = 0.02), respectively. No significant side effects were observed for dapagliflozin or empagliflozin. Conclusion Patients with HFpEF experienced benefits from SGLT2i administration, as evidenced by improved 6-min walk distances and weight reduction. Dapagliflozin demonstrated clinical and overall improvements in KCCQ scores and was more effective in reducing weight than the placebo. Both Dapagliflozin and Empagliflozin were well-tolerated and exhibited favorable safety profiles. Future studies could benefit from a larger patient population, a longer follow-up period, and a broader range of SGLT2i.