Data from clinical care: less LDL-c reduction with PCSK9 antibodies in women than men

Sex differences in efficacy and safety of PCSK9 monoclonal antibodies: A real-world registry

Literature - Galema-Boers AMH, Mulder JWCM, Steward K, et al. - Atherosclerosis. 2023 Mar 30;S0021-9150(23)00115-6 [Online ahead of print]. doi: 10.1016/j.atherosclerosis.2023.03.013

Introduction and methods

Background

Sex-specific analyses of the FOURIER and ODYSSEY clinical trials showed that treatment with PCSK9 monoclonal antibodies results in slightly less LDL-c reduction in women than men [1-3]. However, real-world studies have reported conflicting results, with some confirming the trial findings [4-8], while others presented no sex differences [9,10]. These real-world studies did have limitations such as a small population size, a short follow-up duration, and an unbalanced sex distribution.

Aim of the study

The study aim was to assess sex differences in the effectiveness and safety of PCSK9 monoclonal antibodies in a clinical real-world setting using a large registry.

Methods

Data were extracted from a prospective open-cohort registry that included consecutive adult patients who started subcutaneous treatment with evolocumab (140 mg per 2 weeks) or alirocumab (75 or 150 mg per 2 weeks), as part of clinical care, at the outpatient lipid clinic of the Erasmus Medical Center in Rotterdam, the Netherlands. According to Dutch reimbursement criteria, patients qualify for reimbursement of PCSK9 inhibitor therapy if they do not meet the LDL-c target level despite maximum-tolerated lipid-lowering therapy and are at very high CVD risk.

For the current study, patients who had homozygous familial hypercholesterolemia, received treatment with inclisiran), or had participated in a previous PCSK9 inhibitor trial were excluded, leaving 436 patients (of whom 209 women (48%)) to be included in the analysis.

Outcomes

Main outcomes were percentage LDL-c change compared with baseline and reported side effects at 6 months. Secondary outcomes were absolute and percentage changes in LDL-c reduction over time, specific side effects, and treatment discontinuation.

Main results

Effectiveness

  • At baseline, women had a higher mean (± SD) LDL-c level compared with men (4.7 ± 1.6 vs. 4.1 ± 1.4 mmol/L; P<0.01). After 6 months, the mean LDL-c level was still higher in women compared with men (2.4 ± 1.4 vs. 1.6 ± 1.0 mmol/L; P<0.001). Mean LDL-c levels remained stable throughout the follow-up (up to 24 months) in both women and men .
  • Although the mean absolute (± SD) LDL-c reduction with the PCSK9 inhibitor therapy at 6 months did not differ between women and men (2.3 ± 1.3 vs. 2.5 ± 1.1 mmol/L; P=0.087), the mean relative reduction was smaller in women (50% ± 25% vs. 61% ± 18%; P<0.001). Mean LDL-c decrease also remained stable over time in both sexes.
  • Overall, no differences were observed in mean LDL-c reduction between patients treated with alirocumab and those receiving evolocumab.
  • Women less often reached LDL-c target levels than men (50% vs. 72%; P<0.001). Women were also more frequently hypo- or nonresponders (i.e., LDL-c decrease ≤25%) (13% vs. 3%; P<0.001) and less frequently hyperresponders (i.e., LDL-c decrease >75%) (12% vs. 20%; P=0.044).
  • In a multivariable linear regression model, percentage LDL-c change was associated with female sex (β: 12.0; P=0.001) and concomitant use of high-intensity statin (β: −13.7; P<0.001).

Safety

  • No differences were observed in the reporting of side effects by women and men at 6 months (32% vs. 27%; P=0.26) or discontinuation of treatment (13% vs. 10%; P=0.46).
  • Women and men with statin intolerance experienced more side compared with patients on statin therapy (36% vs. 19%; P=0.005). In a multivariable logistic regression model, statin intolerance was associated with reporting of any side effect (β: 0.6; P=0.014 ).

Conclusion

In this Dutch, single-center, real-world study of patients at very high CVD risk who received maximum-tolerated lipid-lowering therapy, PCSK9 monoclonal antibody therapy resulted in less relative LDL-c reduction at 6 months in women compared with men. Although the mean absolute LDL-c reduction was similar in both sexes, women had a higher mean baseline LDL-c level. During the remainder of follow-up (up to 24 months), mean LDL-c levels remained stable in both women and men. In addition, women were less likely to reach LDL-c targets than men. No sex differences in reported side effects or treatment discontinuation were observed.

Although further research is needed, the authors point out that “[a]n explanation for the unequal relative LDL-c reduction between sexes could be the sex difference in circulating levels of PCSK9.” Based on their results, they also offer some recommendations for clinical practice, for example, to start with a full dose of the PCSK9 monoclonal antibody and uptitrate statins in all patients in whom this therapy is initiated, especially women.

References

1. P. Sever, et al., LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial, Eur. J. Prev Cardiol. 28 (8) (Jul 23 2021) 805–812, https://doi.org/10.1177/2047487320902750.

2. A.J. Vallejo-Vaz, et al., Lower on-treatment low-density lipoprotein cholesterol and major adverse cardiovascular events in women and men: pooled analysis of 10 ODYSSEY phase 3 alirocumab trials, J. Am. Heart Assoc. 7 (18) (Sep 18 2018), e009221, https://doi.org/10.1161/jaha.118.009221.

3. J.G. Robinson, et al., Efficacy and safety of alirocumab in reducing lipids and cardiovascular events, N. Engl. J. Med. 372 (16) (2015) 1489–1499, https://doi.org/10.1056/NEJMoa1501031.

4. T. Hollstein, et al., Treatment with PCSK9 inhibitors reduces atherogenic VLDL remnants in a real-world study, Vasc. Pharmacol. 116 (May 2019) 8–15, https://doi.org/10.1016/j.vph.2019.03.002.

5. D.R. Leitner, et al., Efficacy and tolerability of alirocumab in Austrian clinical practice – results of the non-interventional PEARL-AT study, Curr. Med. Res. Opin. 36 (9) (2020/09/01 2020) 1419–1425, https://doi.org/10.1080/03007995.2020.1786678.

6. A. Cordero, et al., Sex differences in low-density lipoprotein cholesterol reduction with PCSK9 inhibitors in real-world patients: the LIPID-REAL registry, J. Cardiovasc. Pharmacol. 79 (4) (Apr 1 2022) 523–529, https://doi.org/10.1097/fjc.0000000000001205.

7. J. Vicente-Valor, et al., PCSK9 inhibitors revisited: effectiveness and safety of PCSK9 inhibitors in a real-life Spanish cohort, Biomed. Pharmacother. 146 (Feb 2022), 112519, https://doi.org/10.1016/j.biopha.2021.112519.

8. M. Paquette, S. Faubert, N. Saint-Pierre, A. Baass, S. Bernard, Sex differences in LDL-C response to PCSK9 inhibitors: a real world experience, J. Clin. Lipidol. 17 (1) (2022) 142–149.

9. O. Oren, E.L. Kludtke, S.L. Kopecky, Characteristics and outcomes of patients treated with Proprotein convertase subtilisin/kexin type 9 inhibitors (the mayo clinic experience), Am. J. Cardiol. 124 (11) (Dec 1 2019) 1669–1673, https://doi.org/10.1016/j.amjcard.2019.08.016.

10. K. Yokote, et al., 12-Week effectiveness and safety of low-density lipoprotein cholesterol-lowering therapy by Proprotein convertase subtilisin/kexin type 9 inhibition in patients with familial hypercholesterolemia and hypercholesterolemia - data from a real-world observational study of evolocumab in Japan, Circ Rep. 1 (5) (May 8 2019) 219–227, https://doi.org/10.1253/circrep.CR-19-0027.

Find this article online at Atherosclerosis.

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