Cardiac And Kidney Benefits Of Dapagliflozin Are Associated With ApoM Levels In Patients With Heart Failure With Reduced Ejection Fraction

Document Type

Article

Publication Date

1-9-2024

Publication Title

J Card Fail

Abstract

Background: Apolipoprotein M (ApoM) is protective in the heart and kidney via interactions with sphingosine-1 phosphate in the myocardium and endothelium. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) increase ApoM levels, reduce inflammation, and improve cardiac function. SGLT2i improve outcomes for patients with heart failure (HF); however, the mechanisms are not fully understood. We aimed to investigate the effect of the SGLT2i dapagliflozin in the heart and kidney by examining its association with ApoM in patients with HF with reduced ejection fraction (HFrEF) in the DEFINE-HF Trial.

Objective: To explore the relationship between ApoM and cardiac and renal biomarkers and its association with dapagliflozin treatment in patients with HFrEF. Methods: We performed a secondary analysis of the DEFINE-HF trial, which included 263 patients with HFrEF randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. We examined the effects of dapagliflozin on change in ApoM from baseline to 12 weeks. We also evaluated the association between changes in ApoM and NT-proBNP and urine albumin-creatinine ratio (UACR) from baseline to 12 weeks using multivariable linear regression adjusted for baseline value of the respective covariate, baseline ApoM, age, race, sex, eGFR, and type 2 diabetes mellitus; additional models included change in ApoM*treatment interaction terms.

Results: 236 (89.7%) patients had available ApoM values (mean 0.641 ± 0.181 uM). In the overall population, dapagliflozin vs. placebo had no significant effect on change in ApoM (-0.002 uM, 95% CI -0.029 to 0.247; P = 0.89 for the dapagliflozin group). However, each 0.1 uM increase in ApoM level at 12 weeks was associated with a significantly decreased log-transformed NT-proBNP in the overall cohort (-0.11, 95% CI -0.18 to -0.03, P = 0.006). This association was evident in the dapagliflozin group (-0.19; 95% CI -0.28 to -0.09, P<0.001) but not in the placebo group (0.04; 95% CI -0.09 to 0.16, P = 0.57; P for interaction = 0.025). The inverse relationship between ApoM and log-transformed NT-proBNP levels also varied by change in UACR. Dapagliflozin-treated patients with a reduction in UACR at 12 weeks (n = 53, 22%) experienced a mean reduction in log-transformed NT-proBNP of -0.28 per 0.1 uM increase in ApoM (95% CI -0.41 to -0.15; P < 0.001); versus -0.07 (95% CI -0.19 to - 0.06; P = 0.47) for dapagliflozin-treated patients without a change or increase in UACR. Placebo-treated patients with reduced UACR over twelve weeks did not have a significant reduction in log-transformed NT-proBNP per 0.1 uM increase in ApoM (-0.17, -0.37 to 0.035, P = 0.11).

Conclusion: In the DEFINE-HF trial of patients with HFrEF, dapagliflozin did not significantly affect overall ApoM levels. However, an increase in ApoM at 12 weeks was associated with a decline in log-transformed NT-proBNP levels. This relationship was only seen in dapagliflozin-treated patients, especially if significant albuminuria was present at baseline and was reduced over 12 weeks. These data suggest that favorable effects of SGLT2i in HFrEF may be associated with increases in ApoM.

Volume

30

Issue

1

First Page

236

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