Sodium-glucose Cotransporter 2 Inhibitors Association with Risk of Heart Failure Hospitalization in Preserved and Mildly Reduced Ejection Fraction, Regardless of Diabetes Mellitus: A Systematic Review and Meta-Analysis

Introduction: There are strong guidelines regarding the importance of SGLT-2 inhibitors (SGLT2i) in reducing mortality in patients with heart failure with reduced ejection (HFrEF). However, the role of SGLT2i in the management of patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) remains ambiguous. Methods: A systematic review and meta-analysis of SGLT2i randomized controlled trials (RCTs) in HFpEF and HFmrEF, with and without diabetes was conducted (Prospero ID - CRD42023464479). Databases including Clinicaltrials.gov, PubMed, Biomed Central, Scopus, and Science Direct were searched from 2018 to 2024. Hospitalization due to heart failure (HFH) with HFpEF and HFmrEF was the primary outcome analyzed, followed by a subgroup analysis of HFH in HFpEF only. Secondary outcomes analyzed included cardiovascular (CV) death, all-cause mortality, and serious adverse effects. Results: In seven RCTs involving 31,057 participants, meta-analysis using random effects models showed that SGLT2i treated patients had a statistically significant reduction in HFH risk (OR=0.74, p<0.00001) compared to placebo or standard of care (SOC). A subgroup analysis, in HFpEF only patients, also showed a statistically significant reduction (OR=0.72, p<0.0001) in HFH odds. Statistical analysis of secondary outcomes showed a statistically non-significant difference in CV death risk (OR=0.92, p=0.13), all-cause mortality (OR=0.94, p=0.13), and any serious adverse events (OR=0.92, p=0.10). Discussion: This meta-analysis demonstrates that SGLT2i significantly reduce the risk of heart failure hospitalization in patients with preserved and mildly reduced ejection fraction, regardless of diabetes status. While reductions in cardiovascular and all-cause mortality, as well as serious adverse events, were observed, these did not reach statistical significance. These findings align with emerging evidence suggesting a broader cardioprotective role for SGLT2i across the heart failure spectrum, although further studies are needed to clarify their mortality benefit and long-term safety in HFpEF and HFmrEF populations. Conclusions: This meta-analysis found a significant reduction in HFH with the use of SGLT2i in patients with HFpEF and HFmrEF. Secondarily, there was a statistically non-significant reduction in allcause mortality, CV death risk, and serious adverse events with the use of SGLT2i.