Differential cardiovascular benefits of SGLT2 inhibitors, sacubitril/valsartan, omecamtiv mecarbil, and vericiguat across heart failure phenotypes: a systematic review and meta-analysis

Aim: The study evaluated the cardiovascular outcomes associated with pharmacological treatments in heart failure (HF) patients and explored whether the benefits/risks associated with these drugs for HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were consistent with HF with reduced EF (HFrEF). Methods: Several online databases were searched. All studies explored the cardiovascular effects of sodium glucose cotransporter-2 inhibitor (SGLT2i), sacubitril/valsartan, omecamtiv mecarbil and vericiguat were screened and reviewed. Results: A total of 39 studies were included. Compared with placebo therapy, SGLT2i significantly reduced cardiovascular death and hospitalization for HF (HHF) in both HFrEF and HFmrEF/HFpEF patients (approximately 13%-27% risk reduction). SGLT2i reduced serious adverse events across all HF types. Sacubitril/valsartan demonstrated significant benefits in HFrEF patients, reducing cardiovascular death by 19%, all-cause mortality by 22%, and HHF by 22%. However, these benefits were not observed in HFmrEF/HFpEF patients. In contrast, sacubitril/valsartan substantially increased hypotension risk in HFmrEF/HFpEF patients. Omecamtiv mecarbil and vericiguat tended to improve cardiovascular outcomes in patients with HF, but the difference was not statistically significant. Conclusion: SGLT2i represents an effective and safe treatment strategy across the HF spectrum. Sacubitril/valsartan significantly improves outcomes in HFrEF but requires careful benefit-risk evaluation in HFmrEF/HFpEF patients. Current evidence does not support routine use of omecamtiv mecarbil or vericiguat. Large-scale randomized trials are warranted to validate these findings. Systematic review registration: CRD42023455966.