Comparative Effectiveness of Sacubitril/Valsartan Versus Sodium-Glucose Cotransporter 2 Inhibitors among Patients with Heart Failure with Reduced Ejection Fraction with or without Diabetes: A Cohort Study

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and sacubitril/valsartan (SAC/VAL), an angiotensin receptor-neprilysin inhibitor, are both US Food and Drug Administration-approved and guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF). While each has demonstrated significant reductions in cardiovascular morbidity and mortality, direct comparative evidence remains limited, particularly in relation to patients’ diabetes status. Objective To compare the effectiveness of SAC/VAL versus SGLT2i in preventing HF-related and all-cause hospitalizations among patients with HFrEF, with or without diabetes, using real-world data from the MarketScan® Research databases. Methods This new-user, active-comparator cohort study using MarketScan® Commercial and Medicare databases (2019–2023) identified patients with HFrEF by using International Classification of Diseases codes. Patients who initiated SAC/VAL or SGLT2i treatment were included, with the index date defined as the first prescription fill. Continuous health plan enrollment ≥ 6 months prior to HFrEF diagnosis through the index date was required. To balance baseline characteristics between groups, we applied stabilized inverse probability of treatment weighting (IPTW). Cox proportional hazards models compared risks of HF-related and all-cause hospitalizations in cohort analyses defined by diabetes status, diagnosis, and antidiabetic medications. Results After IPTW, the study included 7406 patients initiating SAC/VAL and 5101 patients initiating SGLT2i. Among patients with diabetes, there were no significant differences in the risks of HF-related hospitalization (adjusted hazard ratio [aHR] 1.13, 95% confidence interval [CI] 0.98–1.30) or all-cause hospitalization (aHR 0.99, 95% CI 0.90–1.09) between medication groups. In contrast, among patients without diabetes, initiation of SAC/VAL was associated with significantly lower risks of HF-related hospitalization (aHR 0.65, 95% CI 0.56–0.76) and all-cause hospitalization (aHR 0.69, 95% CI 0.62–0.77). Conclusions In a real-world cohort of patients with HFrEF and without diabetes, but not those with diabetes, SAC/VAL initiation was associated with reduced risks of HF-related and all-cause hospitalizations compared with SGLT2i initiation. These findings provide supportive evidence that may inform clinicians when selecting therapy for patients with HFrEF.