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. 2023 Jun 2;9(4):337-342.
doi: 10.1093/ehjcvp/pvad009.

LDL lowering effect of PCSK9 inhibition is reduced in women

Veronika A Myasoedova  1 , Antoine Rimbert  2 , Marina Camera  1   3 , Cedric Le May  2 , Romain Capoulade  2 , Bertrand Cariou  2 , Paolo Poggio  1
Affiliations

LDL lowering effect of PCSK9 inhibition is reduced in women

Veronika A Myasoedova et al. Eur Heart J Cardiovasc Pharmacother. .

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.

Keywords: Genetics; LDL reduction; PCSK9 inhibitors; Sex difference.

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Conflict of interest statement

B.C. reports grants and/or personal fees from Akcea, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead, Eli Lilly, Novartis, Novo Nordisk, Sanofi, and Regeneron, outside the submitted work. V.A.M., A.R., M.C., C.L., R.C., and P.P. have nothing to declare.

Figures

Figure 1
Figure 1
Sex differences in LDL-C reduction induced by PCSK9 monoclonal antibodies in a real-life setting. Forest plot of the difference in LDL-C reduction between men and women. LDL-C reduction was evaluated with a mean difference expressed in mg/dL. The diamond represents the estimated overall effect, while the squares represent each study with 95% CI. LDL-C, low-density lipoprotein cholesterol; RCT, randomized clinical trial; CI, confidence interval.
Figure 2
Figure 2
Plasma LDL-cholesterol levels according to the genetic inhibition of PCSK9 (as a function of PCSK9-R46L variant) in the UK Biobank. The plot depicts data from 382 813 individuals from the UK Biobank [219 301 women (pink symbols), 163 512 men (blue symbols)] free for lipid-lowering therapies. The y-axis showed LDL-C plasma levels (mmol/L) of individuals and the x-axis show groups of individuals based on their sex and genetic status. PCSK9, proprotein convertase subtilisin/kexin type 9; REF (0/0), non-carriers of the PCSK9-R46L variant; HET (0/1), heterozygous carriers of the PCSK9-R46L variant; HOM (1/1), homozygous carriers of the PCSK9-R46L variant; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation to the mean.
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