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

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

Andrew J Sauer  1 , Joycie Chang  1 , Zhuxuan Fu  2 , Carla Valenzuela Ripoll  3 , Yoonje Cho  3 , Zhen Guo  3 , Philip Jones  2 , Senthil Selvaraj  4 , Sheryl L Windsor  2 , Mansoor Husain  5 , Silvio E Inzucchi  6 , Darren K McGuire  7 , Bertram Pitt  8 , Benjamin M Scirica  9 , Bethany A Austin  1 , Guillermo Umpierrez  10 , Sinh Tran  11 , Björn Dahlbäck  11 , Ali Javaheri  12 , Mikhail N Kosiborod  13 ; DEFINE-HF Investigators
Affiliations

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

Andrew J Sauer et al. JACC Adv. 2025 Jun.

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.

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Conflict of interest statement

Funding support and author disclosures DEFINE-HF was an investigator-initiated trial funded by AstraZeneca Pharmaceuticals LP (Wilmington, DE) and conducted by Saint Luke's Mid America Heart Institute (Kansas City, MO) independent of the funding source. AstraZeneca AB (Mölndal, Sweden) provided funding to Washington University in St. Louis (St. Louis, MO) for the ApoM testing. Dr Sauer has received grant/research support from AstraZeneca, CSL Vifor, Rivus, Pfizer, Bayer, and Boehringer Ingelheim; has received honoraria from Bayer, Abbott, Impulse Dynamics, Boston Scientific, Medtronic, Edwards Lifesciences, Biotronik, General Prognostics, Story Health, and Acorai; and has stock ownership with ISHI. Dr Kosiborod has received grant/research support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has served as a consultant for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Roche, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support (data analytic center fees) from AstraZeneca and Vifor Pharma; has stock options with Artera Health and Saghmos Therapeutics; and reports employment by AstraZeneca R&D, effective January 6, 2025. Dr Javaheri has received grant/research support from AstraZeneca and Bitterroot Bio; has advisory board and ownership interest for Mobius Scientific; and holds patents on ApoM fusion-protein nanodiscs for treatment of HF and eye diseases. Dr Inzucchi has received grant/research support from NIDDK; has served as a consultant/advisor for AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Bayer, Merck, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Baseline and 12-Week Apolipoprotein M Levels in Dapagliflozin and Placebo Groups (A) Individual patient-level ApoM values at baseline and 12 weeks are displayed for the dapagliflozin (red) and placebo (blue) groups. Vertical lines connecting baseline (BL) and 12-week values illustrate the within-patient change in ApoM levels over time. The median change (with IQR) for each group is displayed at the top of the figure. Box plots on the left and right summarize baseline and week 12 distributions. (B) Box plots represent the distribution of ApoM level changes from baseline to week 12 for each treatment group. Box edges indicate the IQR, with horizontal lines representing the median. Whiskers extend to the upper and lower adjacent values, and dots represent individual outliers. ApoM = apolipoprotein M.
Figure 2
Figure 2
Association Between Change in Apolipoprotein M and Log-Transformed N-Terminal Pro-B-Type Natriuretic Peptide at 12 Weeks in Dapagliflozin and Placebo Groups This forest plot illustrates the estimated association between a 0.1 μM increase in ApoM and the corresponding change in log-transformed NT-proBNP at 12 weeks. Results are presented separately for the dapagliflozin group (N = 121), placebo group (N = 115), and overall cohort. Black dots represent the point estimates, with horizontal lines indicating the 95% CIs. The red vertical line at zero serves as a reference for no association. A statistically significant inverse association was observed in the dapagliflozin group (−0.19; 95% CI: −0.28 to −0.09), while the placebo group showed no significant association (0.04; 95% CI: −0.09 to 0.16). The overall cohort demonstrated a moderate inverse relationship (−0.11; 95% CI: −0.18 to −0.03). NT-proBNP = N-terminal pro-B-type natriuretic peptide; other abbreviation as in Figure 1.
Figure 3
Figure 3
Change in Log-Transformed N-Terminal Pro-B-Type Natriuretic Peptide From Baseline to Week 12 Among Patients With Decreased Urine Albumin-Creatinine Ratio (A) Individual patient-level log NT-proBNP values at baseline (BL) and 12 weeks are displayed for the dapagliflozin (red) and placebo (blue) groups, specifically among patients who experienced a decrease in UACR over 12 weeks. Vertical lines connecting baseline and week 12 values illustrate within-patient changes in NT-proBNP over time. The median change (with IQR) for each group is displayed at the top of the figure. Box plots on the left and right summarize the baseline and week 12 distributions. (B) Box plots represent the distribution of NT-proBNP level changes from baseline to week 12 for each treatment group. Box edges indicate the IQR, with horizontal lines representing the median. Whiskers extend to the upper and lower adjacent values, and dots represent individual outliers. UACR = urine albumin-creatinine ratio; other abbreviation as in Figure 2.
Central Illustration
Central Illustration
Proposed Mechanism Linking Dapagliflozin, Apolipoprotein M, and Cardiorenal Benefits in Heart Failure With Reduced Ejection Fraction With Albuminuria In patients with albuminuria (urinary albumin-to-creatinine ratio [UACR] >25 mg/g), treatment with dapagliflozin was associated with an inverse relationship between ApoM and N-terminal pro-B-type natriuretic peptide (NT-proBNP), suggesting a potential dapagliflozin-mediated effect. This relationship may be mediated by ApoM-related protective mechanisms, including enhanced endothelial cell chemotaxis, wound healing, and angiogenesis via the sphingosine-1-phosphate (S1P) signaling pathway, which contribute to favorable cardiac remodeling and the attenuation of kidney fibrosis and nephropathy. The significant interaction with dapagliflozin supports further investigation into ApoM as a potential mediator of its cardiorenal benefits. HFrEF = heart failure with reduced ejection fraction; other abbreviations as in Figures 1 to 3.
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