Sex differences in leptin levels but not in the leptin response to sacubitril/valsartan in patients with heart failure with reduced ejection fraction

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Background Leptin is an adipokine involved in metabolic regulation and neurohormonal activation and has been implicated in the pathophysiology of heart failure. Sacubitril/valsartan (angiotensin receptor–neprilysin inhibitor, ARNI) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) and may also influence metabolic pathways. However, it remains unclear whether ARNI therapy affects circulating leptin levels differently in men and women. Methods In this observational study, patients with HFrEF from two clinical centres were evaluated before and after initiation of sacubitril/valsartan therapy. Serum leptin levels, N-terminal pro-B-type Natriuretic Peptide (NT-proBNP), echocardiographic parameters and New York Heart Association (NYHA) class were assessed at baseline and follow-up. Sex-specific differences in leptin levels and leptin dynamics were analysed. Results A total of 74 patients (20 women and 54 men) were included. Women exhibited significantly higher leptin levels compared with men at baseline (39.78 ± 31.95 vs. 10.39 ± 17.04 ng/mL, p < 0.001) despite similar body mass index (BMI) values (ns). Following initiation of ARNI therapy, leptin levels increased significantly in both women (39.78 ± 31.95 to 50.10 ± 41.28, p = 0.041) and men (10.39 ± 17.04 to 12.49 ± 16.62, p = 0.006). However, the magnitude of absolute and relative leptin change did not differ significantly between sexes. Improvements in left ventricular ejection fraction (LVEF) were observed in both groups, while changes in NT-proBNP and NYHA class showed different within-group patterns but did not differ significantly between sexes. Conclusion Women with HFrEF showed markedly higher circulating leptin levels than men at both baseline and follow-up. Leptin levels increased significantly in both sexes. However, there were no significant differences in absolute or relative leptin changes between women and men. Sex influences baseline leptin concentrations, but not the response to ARNI therapy. Further prospective studies are needed to clarify the mechanisms and clinical significance of leptin changes during sacubitril/valsartan treatment.

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