J Am Heart Assoc. 2026;15(7):e047533.

Angiotensin-Neprilysin Inhibition and Renal Outcome in Men and Women With Heart Failure.

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제1저자 윤민재, 김원세 · 교신저자 박진주

PMID 41878850 PMC13279094 DOI 10.1161/JAHA.125.047533 IF 6 순환기내과

소속 (4)

Department of Mathematical Sciences, RIMS, and AIIS Seoul National University Seoul Republic of Korea.
MetaEyes Seoul Republic of Korea.
Cardiovascular Center, Division of Cardiology, Department of Internal Medicine Seoul National University Bundang Hospital, Seoul National University College of Medicine Seongnam Republic of Korea.
Cardiology Department University of California San Diego La Jolla CA USA.

Abstract

BACKGROUND Sacubitril/valsartan is known to reduce adverse renal outcomes and slow the decline in estimated glomerular filtration rate (eGFR) compared with renin-angiotensin system (RAS) inhibitors across the entire spectrum of heart failure. However, whether these renoprotective effects differ by sex has not been elucidated. Thus, we aimed to evaluate whether the treatment effect of sacubitril/valsartan versus RAS inhibitors on renal outcomes differs by sex.

METHODS Data sets from the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; ejection fraction ≤40%, n=8399) and PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; ejection fraction ≥45%, n=4796) trials were integrated in a prespecified pooled analysis. We evaluated the treatment effect (sacubitril/valsartan versus RAS inhibitors) on the prespecified renal composite outcome (death from renal failure, end-stage renal disease, or ≥50% reduction in eGFR) and changes in eGFR slope in female (n=4311) and male (n=8884) patients to determine whether sex modified the effect of sacubitril/valsartan on renal outcomes.

RESULTS At baseline, women exhibited lower eGFR values than men (67.2±19.7 versus 72.6±20.4 mL/min/1.73 m², P<0.001). Compared with RAS inhibitors, sacubitril/valsartan reduced the renal composite outcome similarly in women (1.1% versus 2.2%, hazard ratio [HR], 0.51 [95% CI, 0.31-0.83]) and in men (1.0% versus 1.7%, HR, 0.60 [95% CI, 0.41-0.86]; P for interaction=0.60). Sacubitril/valsartan attenuated the decline in eGFR compared with RAS inhibitors similarly in women (-1.8 versus -2.2 mL/min/1.73 m² per year, P=0.006) and men (-1.6 versus -2.3 mL/min/1.73 m² per year, P<0.001) (P for interaction for difference in eGFR slopes=0.19).

CONCLUSIONS Sacubitril/valsartan significantly reduces the incidence of renal composite outcome and decelerates the decline in eGFR compared with RAS inhibitors. The renoprotective effects of this drug are uniformly observed in both women and men.

Keywords

estimated glomerular filtration rateheart failurerenal outcomesacubitril/valsartansex

Figures

**Figure 1** Kaplan–Meier analysis of composite renal outcome by sex. Estimates are shown for the probability of a first occurrence of the composite renal outcome, defined as a ≥50% reduction in estimated glomerular filtration rate from baseline, development of end‐stage renal disease, or death due to renal failure, in (A) all patients, (B) the PARADIGM‐HF trial, and (C) the PARAGON‐HF trial. ARNI indicates angiotensin receptor‐neprilysin inhibitor; HR, hazard ratio; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RAS, renin‐angiotensin system.

**Figure 2** Change in eGFR over time in female and male. The eGFR was calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. Error bars indicate 95% CIs. Estimates are shown for (A) all patients, (B) the PARADIGM‐HF trial, and (C) the PARAGON‐HF trial. *P ‐values are reported for differences in eGFR change between patients treated with ARNI and those treated with RASi. †P for interaction are reported to assess whether the treatment effects of sacubitril/valsartan (compared with RASi) on eGFR changes over time varied between women and men. ARNI indicates angiotensin receptor‐neprilysin inhibitor; eGFR, estimated glomerular filtration rate; PARADIGM‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON‐HF, Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; and RASi, renin‐angiotensin system inhibitor.

**Figure 3** Continuous treatment effect of sacubitril/valsartan versus RAS inhibitors on the renal composite outcome according to LVEF, eGFR, NT‐proBNP levels, and SBP. Estimated hazard ratios and 95% CIs are displayed for men (blue) and women (red) separately, according to (A) LVEF, (B) eGFR, (C) NT‐proBNP levels, and (D) SBP. eGFR indicates estimated glomerular filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; RAS, renin‐angiotensin system; and SBP, systolic blood pressure.

그림 출처: PubMed Central 공개 논문 (PMC13279094)

Conflict of interest statement

None.

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