Comparative Real-World Effectiveness of Sacubitril/Valsartan and SGLT2 Inhibitors in Patients with HFrEF: A Retrospective Cohort Study

Purpose Sacubitril/valsartan (S/V) and SGLT2 inhibitors (SGLT2i) are guideline-recommended (Class I) for HFrEF, yet direct comparative data are limited. We evaluated their relative effectiveness in routine care. Methods Retrospective cohort of 626 HFrEF patients (LVEF ≤ 40%) followed 2017–2024, all with ≥ 12 months of optimized β-blocker and RAAS inhibition. Three strategies: Group 1 (n = 200) ACEI/ARB→S/V; Group 2 (n = 190) ACEI/ARB→+SGLT2i (often because of S/V affordability); Group 3 (n = 220) on S/V then + SGLT2i. Outcomes were compared in the 12 months before (T0) and after (T1) treatment change. Results Switching to S/V was associated with greater improvement than adding SGLT2i to ACEI/ARB. HF hospitalizations fell 61% (1.8→0.7 per patient-year; p < 0.001) with S/V vs 25% (1.6→1.2; p = 0.048) with SGLT2i. NT-proBNP decreased 48% (1820→940 pg/mL; p < 0.001) with S/V vs 15% (2395→2020; p = 0.047) with SGLT2i. LVEF rose by 7.1% (28.7→35.8%; p < 0.001) with S/V vs 2.3% (30.5→32.8%; p = 0.06) with SGLT2i. Outpatient visits and emergency department admissions showed parallel reductions. Adding SGLT2i on background S/V (Group 3) provided modest incremental benefits, particularly for visits and NYHA class. Conclusions In well-treated HFrEF, initiating S/V after ACEI/ARB was linked to larger gains across hospitalizations, biomarkers, and function than adding SGLT2i to ACEI/ARB, while SGLT2i on top of S/V offered smaller complementary improvements. These real-world data support S/V as the backbone therapy, with SGLT2i providing additional—though less pronounced—benefits.