Dapagliflozin's Association With Cardiorenal Outcomes and Apolipoprotein M Levels in HFrEF Patients: Insights From DEFINE-HF

Background: Apolipoprotein M (ApoM) is associated with lower mortality in heart failure (HF) patients and protects against cardiac and kidney injury in mice. Objectives: The authors investigated dapagliflozin's cardiorenal effects by studying its association with ApoM in patients with HF with reduced ejection fraction. Methods: We performed a secondary analysis of DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with HF with Reduced Ejection Fraction) to assess dapagliflozin's effects on ApoM, N-terminal pro B-type natriuretic peptide (NT-proBNP), and urine albumin-creatinine ratio (UACR) changes from baseline to 12 weeks. Results: Of 263 randomized patients, 236 had ApoM values at baseline (mean 0.641 ± 0.181 μM) and 12 weeks. Dapagliflozin did not significantly affect ApoM vs placebo. However, each 0.1 μM increase in ApoM was associated with a significant decrease in log-transformed NT-proBNP overall (β = −0.11, P = 0.006), particularly in dapagliflozin-treated patients (β = −0.19, P < 0.001; P interaction = 0.025). The inverse relationship between ApoM and NT-proBNP varied by changes in UACR. Dapagliflozin-treated patients with reduced UACR at 12 weeks (n = 53, 22%) experienced a mean NT-proBNP reduction of −0.28 per 0.1 μM increase in ApoM (P < 0.001), compared to a smaller reduction in those without UACR change (−0.07, P = 0.47). Placebo-treated patients with reduced UACR over 12 weeks did not show significant NT-proBNP changes (β = −0.17, P = 0.11). Conclusions: Dapagliflozin did not significantly alter ApoM overall; however, an inverse association between ApoM and NT-proBNP was observed in dapagliflozin-treated patients with albuminuria. While some NT-proBNP reductions were seen in the placebo group, the significant interaction with treatment allocation suggests a potential dapagliflozin-mediated effect.