Initiation of SGLT2 inhibitors versus mineralocorticoid receptor antagonists as third-line therapy in heart failure with reduced ejection fraction: a nationwide cohort study.

Background: Heart failure with reduced ejection fraction (HFrEF) guidelines recommend early initiation of four foundational therapies-renin-angiotensin system inhibitors (RASI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In clinical practice, these drugs are usually introduced sequentially, and optimal sequencing remains uncertain. This study investigated the effectiveness of initiating SGLT2 inhibitors versus MRAs as the third foundational therapy following RASI and beta-blockers. Methods: This was a nationwide non-interventional study in Denmark, July 2020-2023. Patients with HFrEF (left ventricular ejection fraction ≤40%) aged ≥45 years on background RASI and beta-blockers were included. An active-comparator new-user design was used to emulate a trial-like comparison. Baseline characteristics were balanced using inverse-probability of treatment weighting based on propensity scores. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, heart failure hospitalization, and their composite. Weighted hazard ratios (wHRs) were estimated using proportional hazards regression. Findings: The study included 4185 new MRA users (63% spironolactone, 37% eplerenone) and 2565 new SGLT2 inhibitor users (74% dapagliflozin, 26% empagliflozin). All-cause mortality occurred in 423 MRA users (unweighted rate 6.3 per 100 person-years) and 155 SGLT2 inhibitor users (5.8 per 100 person-years). In weighted analysis comparing SGLT2 inhibitors to MRAs, the wHR was 0.70 (95% CI 0.57-0.86; absolute risk difference -2.1 per 100 person-years, 95% CI -0.9 to -3.2). For the composite secondary outcome, the wHR was 0.83 (95% CI 0.71-0.97); for cardiovascular death, 0.65 (95% CI 0.49-0.87); and for heart failure hospitalization, 0.89 (95% CI 0.74-1.07). Interpretation: Initiating SGLT2 inhibitors as the third foundational therapy after RASI and beta-blockers was associated with significantly lower risk of all-cause mortality compared to MRAs. These findings support the prioritization of SGLT2 inhibitors in treatment sequencing for HFrEF. Funding: This study was supported by the Novo Nordisk Foundation and Karolinska Institutet.