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

Andrew J Sauer; Joycie Chang; Zhuxuan Fu; Carla Valenzuela Ripoll; Yoonje Cho; Zhen Guo; Philip Jones; Senthil Selvaraj; Sheryl L Windsor; Mansoor Husain; Silvio E Inzucchi; Darren K McGuire; Bertram Pitt; Benjamin M Scirica; Bethany A Austin; Guillermo Umpierrez; Sinh Tran; Björn Dahlbäck; Ali Javaheri; Mikhail N Kosiborod; DEFINE-HF Investigators

doi:10.1016/j.jacadv.2025.101800

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

JACC Adv. 2025 Jun;4(6 Pt 2):101800. doi: 10.1016/j.jacadv.2025.101800.

Authors

Andrew J Sauer¹, Joycie Chang¹, Zhuxuan Fu², Carla Valenzuela Ripoll³, Yoonje Cho³, Zhen Guo³, Philip Jones², Senthil Selvaraj⁴, Sheryl L Windsor², Mansoor Husain⁵, Silvio E Inzucchi⁶, Darren K McGuire⁷, Bertram Pitt⁸, Benjamin M Scirica⁹, Bethany A Austin¹, Guillermo Umpierrez¹⁰, Sinh Tran¹¹, Björn Dahlbäck¹¹, Ali Javaheri¹², Mikhail N Kosiborod¹³; DEFINE-HF Investigators

Affiliations

¹ Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.
² Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA.
³ Washington University in St. Louis, St. Louis, Missouri, USA.
⁴ Duke University Medical Center, Duke Molecular Physiology Institute Durham, North Carolina, USA.
⁵ Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada.
⁶ Yale University School of Medicine, New Haven, Connecticut, USA.
⁷ University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas, Texas, USA.
⁸ University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
⁹ Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Emory University, Atlanta, Georgia, USA.
¹¹ Lund University, University Hospital SUS, Malmo, Sweden.
¹² Washington University in St. Louis, St. Louis, Missouri, USA; John Cochran VA, St. Louis, Missouri, USA. Electronic address: ali.javaheri@wustl.edu.
¹³ Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA. Electronic address: mkosiborod@saint-lukes.org.

PMID: 40579063
DOI: 10.1016/j.jacadv.2025.101800

Abstract

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.

Keywords: N-terminal pro B-type natriuretic peptide; apolipoprotein M; cardiorenal effects; dapagliflozin; heart failure with reduced ejection fraction; urine albumin-creatinine ratio.