Joseph Cencetti, PharmD, BCACP, CLSa; Callie Abramowitz, PharmDb; Heather Spoonhower, PharmDa Correspondence: Joseph Cencetti (joseph.cencetti@va.gov)
aWilkes-Barre Veterans Affairs Medical Center, Pennsylvania
bPhiladelphia Veterans Affairs Medical Center, Pennsylvania
Author contributions
Conception and design, final approval, and accountable for all aspects of the work (all); data analysis and interpretation (JC, CA); manuscript writing (JC, CA).
Author disclosures
The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Ethics and consent
All authors completed education requirements through the Collaborative Institutional Training Initiative program. This study was approved by the Coatesville Veterans Affairs Institutional Review Board (VISN 4 M/S), Coatesville Veterans Affairs Medical Center.
In our study, only 6 patients (4.4%) discontinued PCSK9i therapy. This low discontinuation rate is largely attributable to our unique study design, which allowed for a dose reduction in patients who experienced muscle-related AEs. The earlier ODYSSEY-ALTERNATIVE trial evaluated the safety and efficacy of alirocumab compared with ezetimibe in confirmed statin-intolerant subjects after 24 weeks. This trial did not use a dose-reduction strategy and found 15.9% of patients discontinued alirocumab due to a muscle-related AE.24 This is notably higher than our discontinuation rate of 4.4%. If patients with a muscle-related AE discontinued PCKS9i instead of reducing the dose, they would likely return to their baseline LDL-C, which would increase the risk of MACE.
In general, myalgias due to antihyperlipidemic medications are not completely understood. One possible mechanism for statin-induced myalgias is the depletion of ubiquinone. However, this theory cannot explain muscle-related AEs associated with PCSK9i or ezetimibe, which have not been shown to deplete ubiquinone. We also found that the onset of muscle-related AEs associated with PCSK9i tends to appear later in therapy than what we know about statin therapy. Our study showed that the onset of a muscle-related PCSK9i AEs occurred a mean (SD) 8 (5.3) months after initiation (range, 1-19). Statin muscle-related AEs typically occur within the initial 4 to 8 weeks of treatment, although they can occur at any time.28
Limitations
The results of this study should be considered with the following limitations. First, this was a retrospective chart review performed over a prespecified period. Any muscle-related AEs or LDL-C lowering effects from PCSK9i that occurred outside the review period were not captured. Our study was small and only included 137 patients, though it was similar in size to the GAUSS-2, GAUSS-3, and ODYSSEY-ALTERNATIVE trials.22-24 Additionally, the study was primarily composed of White men and may not be representative of other populations. Some muscle-related PCSK9i AEs may be attributed to the nocebo. Last, our study did not capture patients on a PCSK9i who were not followed in the PACT clinic.
Conclusions
We found that muscle-related PCSK9i AEs occurred at a similar rate as those reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe had a higher likelihood of developing a muscle-related PCSK9i AE. In our study, only 1 patient developed a muscle-related PCSK9i AE who did not have a prior history of muscle-related intolerance to either a statin or ezetimibe. However, in our study, a substantial percentage of patients with statin and/or ezetimibe intolerances tolerated the full PCSK9i dose well, proving that PCSK9i are still a reasonable alternative for patients with prior intolerances to statins and/or ezetimibe.
Acknowledgments
This material is the result of work supported with resources and the use of facilities at the US Department of Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania.
