Muscle-Related Adverse Events Associated With PCSK9 Inhibitors in a Veteran Population
Background: Statins and PCSK9 inhibitors (PCSK9i) are used to lower low-density lipoprotein cholesterol and reduce cardiovascular events, yet some patients are unable to tolerate statin therapy due to muscle-related adverse events (AEs). The effect of PCSK9i on muscle-related AEs is not well studied, and available data show inconsistent incidence rates.
Methods: The primary study outcome was to determine the percentage of patients who developed muscle-related PCSK9i AEs. A secondary outcome was to analyze data based on 4 subgroups: tolerated a full PCSK9i dose; tolerated alternative PCSK9i following initial intolerance; required a PCSK9i dose reduction, or discontinued PCSK9i. In addition, the percentage of statin- and/or ezetimibe-intolerant patients in these 4 groups was determined. Another secondary outcome was the management strategies taken for patients who were on a reduced (monthly) dose of PCSK9i who did not reach their low-density lipoprotein cholesterol goal. Statin intolerance was defined as intolerable skeletal muscle AEs on at least 3 different statins. We conducted a single-center, retrospective review of patients prescribed a PCSK9i between December 1, 2017, and September 1, 2021, at a patient aligned care team clinic at the Wilkes-Barre Veterans Affairs Medical Center.
Results: The study included 137 veterans. Twenty-four patients (17.5%) developed a muscle-related AE while on a PCSK9i. In predefined subgroups studied, statin intolerance ranged from 68.1% to 100%, ezetimibe intolerance ranged from 41.6% to 83.3%, and both statin and ezetimibe intolerance ranged from 36.3% to 83.3%.
Conclusions: In this study, muscle-related PCSK9i AEs occurred at a similar incidence rate to that reported in previous clinical trials and exceeded the incidence rate reported in the prescribing information for alirocumab and evolocumab. It also appears that patients who have a prior muscle-related intolerance to a statin and/or ezetimibe have a higher likelihood of developing a muscle-related AE to a PCSK9i.
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.
