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Early Initiation of SGLT2 inhibitor and Mortality in Heart Failure With Reduced Ejection Fraction: A Target Trial
George Frederick Mkoma1,2,3, Anders Hviid1, Björn Pasternak1,4
1Department of Data Science and AI in Health, Statens Serum Institut, Copenhagen, Denmark.
Background And Aims:
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF), yet the optimal timing of initiation in routine clinical practice remains uncertain. We investigated the impact of early initiation of SGLT2i within 30 days of HFrEF diagnosis on mortality and HF hospitalization.
Methods:
Using Danish nationwide register data from July 2020 to August 2024, adults with incident HFrEF eligible for SGLT2i therapy were identified. A target trial comparing initiation of SGLT2i within 30 days of HFrEF diagnosis versus no SGLT2i initiation during this 30-day period was emulated. The analysis used a clone-censor-weight design with follow-up starting at HFrEF diagnosis. The primary outcome was one-year all-cause mortality, and HF hospitalization was assessed as a secondary outcome.
Results:
Among 10,346 patients with incident HFrEF, 3268 (31.6%) initiated an SGLT2i within 30 days of HFrEF diagnosis and 7078 (68.4%) did not initiate the treatment during this 30-day window. About 226 deaths occurred among SGLT2i initiators and 637 deaths among non-initiators. Compared with non-initiation, initiation of SGLT2i within 30 days was associated with lower one-year risks of both death (RD -1.1 percentage points; 95% CI (-2.0 to -0.2)) and HF hospitalization (RD -3.4 percentage points; 95% CI (-3.9 to -2.9)).
Conclusions:
Initiation of an SGLT2i within 30 days of HFrEF diagnosis was associated with lower one-year mortality and HF hospitalization compared with no initiation. These findings support prioritizing early SGLT2i initiation as part of foundational therapy for HFrEF in routine clinical practice.