Additive benefits of combination ARNI and SGLT2 inhibitor therapy in real-world heart failure: a propensity-weighted analysis of 11,483 asian patients
P Amornritvanich, C Ratanatharathorn, P Numthavaj, A Tansawet, P Looareesuwan, A Pattanateepapon, T Yingchoncharoen, A ThakkinstianAbstract
Background
While randomized trials have established the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNI) in heart failure (HF), real-world data on their comparative effectiveness—particularly as combination therapy—remain limited in Asian populations. We evaluated the real-world impact of SGLT2i, ARNI, and their combination on hospitalization and mortality across the HF spectrum.
Methods
We conducted a retrospective cohort study using a large Southeast Asian HF registry (2010–2024) and analyzed 11,483 patients receiving HF medication. Patients were categorized into four groups: guideline-directed medical therapy (GDMT, n=8,362), SGLT2i (n=2,471), ARNI (n=343), and combination ARNI+SGLT2i (n=307). Inverse probability weighting with multinomial propensity scores derived from 12 covariates achieved excellent covariate balance (all SMDs < 0.2). Weighted Cox regression estimated treatment effects on HF hospitalization (HFH) and all-cause mortality.
Results
Over a median follow-up of 2.6 years for HFH and 3.1 years for mortality, SGLT2i therapy was associated with a significant 45% reduction in HFH (HR 0.55, 95% CI 0.39–0.77, p=0.001) and a 40% reduction in all-cause mortality (HR 0.60, 95% CI 0.38–0.94, p=0.027) compared to GDMT. Combination ARNI+SGLT2i therapy demonstrated the most potent effect on HFH (HR 0.48, 95% CI 0.25–0.90, p=0.022) and a numerically favorable but non-significant mortality reduction (HR 0.47, 95% CI 0.21–1.07, p=0.073). ARNI monotherapy showed numerically favorable but non-significant effects on both HFH (HR 0.65, p=0.099) and mortality (HR 0.77, p=0.299). Benefits were most pronounced in patients with HFmrEF/HFpEF, who comprised 82.5% of the cohort.
Conclusion
In this large real-world Asian cohort predominantly comprising HFmrEF and HFpEF, SGLT2i therapy conferred substantial and significant reductions in HFH and all-cause mortality, consistent with randomized trial evidence. Combination ARNI+SGLT2i therapy demonstrated the strongest protection against HFH, supporting the potential additive benefit of concurrent initiation of these therapies. Larger prospective studies are needed to confirm the additive effects of combination therapy, particularly regarding long-term mortality outcomes.KM curves for HFHKM curves for all-cause mortality