LDL lowering effect of PCSK9 inhibition is reduced in women

Author:

Myasoedova Veronika A1,Rimbert Antoine2ORCID,Camera Marina13,Le May Cedric2,Capoulade Romain2ORCID,Cariou Bertrand2ORCID,Poggio Paolo1ORCID

Affiliation:

1. Centro Cardiologico Monzino IRCCS , Via Carlo Parea 4, 20138, Milan , Italy

2. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax , F- 44000 Nantes , France

3. Department of Pharmaceutical Sciences, Università degli Studi di Milano , Milan , Italy

Abstract

Abstract Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of plasma low-density lipoprotein cholesterol (LDL-C) concentration, and its inhibition reduces the risk of atherosclerotic cardiovascular disease (ASCVD). We aimed to assess the sex-differential effect of either pharmacological or genetic inhibition of PCSK9 on LDL-C levels. Methods and results We meta-analyzed six real-life studies (1216 men and 641 women) that investigated the effects of PCSK9 monoclonal antibodies (mAbs) on LDL-C reduction in men and women. Despite higher LDL-C levels in women at baseline [mean difference (MD) = 17.4 mg/dL, P < 0.0001, women = 175 mg/dL vs. men = 152 mg/dL], the LDL-C reduction under PCSK9 mAb treatment was significantly greater in men (MD = 7.6 mg/dL, 95% confidence interval: 2.7–12.4, P = 0.002) than in women. We tested the sex-related association of the loss-of-function variant PCSK9-R46L with LDL-C plasma levels in 382 813 individuals (219 301 women and 163 512 men) free of lipid-lowering drugs from the UK Biobank general population cohort. The magnitude of LDL-C reduction was larger in men than in women (mean LDL-C difference: –35 mg/dL vs. –26 mg/dL, when comparing homozygous carriers with non-carriers in men and women, respectively). The relationship between PCSK9-R46L and LDL-C was significantly dependent on sex (P for interaction = 7.2e–04). Conclusion These results demonstrate by complementary approaches that the decrease in LDL-C mediated by PCSK9 inhibition is slightly, but significantly, less marked in women than in men. These data reinforce the need for specific studies to develop sex-specific recommendations for the management of ASCVD in women.

Funder

Fondation pour la Recherche Médicale

Agence Nationale de la Recherche

Italian Ministry of Health funds

Publisher

Oxford University Press (OUP)

Subject

Pharmacology (medical),Cardiology and Cardiovascular Medicine

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