Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an overview of 36 systematic reviews

The recently published randomized trials (RCTs) evaluating the effect of Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) led researchers to perform a plethora of systematic reviews (SRs), often providing contradictory conclusions. This overview of reviews was aimed at summarizing the evidence of these SRs, quantifying the overlap, re-analyzing the evidence in case new studies that were identified, and mapping knowledge gaps. Literature search was conducted through Medline, Scopus, and Cochrane until March 22, 2023. Overall, 36 SRs synthesizing results from 18 RCTs were identified. A substantial overlap was identified among the SRs synthesizing large heart failure or cardiovascular outcome trials (CVOTs). Regarding the composite outcome of cardiovascular (CV) mortality or hospitalization for heart failure (HHF), all authors reported a significant favorable effect. A beneficial effect was also noted for CV and all-cause mortality, albeit not significant. Our meta-analysis demonstrated a significant improvement in health-related quality-of-life (HRQoL) as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS, MD = 1.97, p < 0.001), Total Symptom Score (KCCQ-TSS, MD = 2.29, p < 0.001), Clinical Summary Score (KCCQ-CSS, MD = 1.59, p < 0.001), and the 6-min walking distance (MD = 10.78 m, p = 0.032). Regarding safety, SGLT2i were associated with a significantly lower risk of serious adverse events compared to placebo (RR = 0.94, p = 0.002). The use of SGLT2i in HFpEF is both efficient and safe. Further research is required to clarify the impact of SGTL2i on different subphenotypes of HFpEF and the cardiorespiratory capacity of these patients.