Outcomes of sacubitril/valsartan plus SGLT2 inhibitors versus SGLT2 inhibitors in heart failure with reduced ejection fraction: a propensity-matched real-world analysis

Background In heart failure with reduced ejection fraction (HFrEF), both angiotensin receptor–neprilysin inhibitors (ARNI) and sodium–glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes. The PARADIGM-HF trial establishing the benefit of sacubitril/valsartan (ENTRESTO) in HFrEF preceded SGLT2i foundational therapy. Consequently, contemporary real-world data evaluating the incremental benefit of combining ENTRESTO with SGLT2i versus SGLT2i alone remain limited. Purpose To compare 1-year clinical outcomes between HFrEF patients treated with ENTRESTO plus SGLT2i versus SGLT2i alone. Methods We conducted a retrospective cohort study using the TriNetX US Collaborative Network (64 healthcare organizations). Adults (≥18 years) with HFrEF receiving ENTRESTO plus SGLT2i or SGLT2i alone were identified. Patients with end-stage renal disease, eGFR ≤20 mL/min/1.73m², pregnancy, heart transplantation, and type 1 diabetes were excluded. Outcomes evaluated were 1-year all-cause mortality, major adverse cardiovascular events (MACE), acute kidney injury (AKI), and ventricular arrhythmias. A propensity score–matched model (1:1) was used to adjust for baseline characteristics between the study groups. Cox proportional hazard regression analysis was used to evaluate the outcomes. P-value <0.05 indicated statistical significance. Results Before matching, 8,824 patients received combination therapy and 12,565 received SGLT2i alone. After matching (n=13,724) were included (i.e. 6,862 patients per group). The study population had a mean age was 66 years, 27% were female, 76% White, 48% had diabetes, and 32% chronic kidney disease. Compared with SGLT2i alone, combination therapy of ENTRESTO and SGLT2i was associated with lower all-cause mortality (8.7% vs 9.8%; HR 0.81, 95% CI 0.73–0.91; p<0.001) and lower MACE (28.4% vs 30.6%; HR 0.87, 95% CI 0.82–0.92; p=0.002). However, ENTRESTO plus SGLT2i was associated with higher AKI and ventricular arrhythmias. Conclusion In this large real-world HFrEF cohort, the combined use of ENTRESTO and SGLT2i was associated with lower mortality and MACE but higher risks of AKI and ventricular arrhythmias compared with SGLT2i alone. Our findings warrant careful patient selection for guideline-directed medical therapy in HFrEF.