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.
Data were collected using the VA Computerized Patient Record System (CPRS) and stored in a secure, locked spreadsheet. Baseline patient demographic characteristics collected included age (at PCSK9i start); sex; race; and PCSK9i name, dose, and frequency. We recorded when a patient switched PCSK9i, whether or not it was due to a muscle-related AE, and the name of the original PCSK9i. Also collected were lipid therapy intolerances prior to PCSK9i initiation (ie, intolerance to statin, ezetimibe, or both).
Patients were considered statin intolerant due to a muscle-related AE in accordance with the VA PCSK9i Criteria for Use, which requires trial of at least 3 statins, one of which was trialed at the lowest dosage approved by the US Food and Drug Administration (FDA) and resulted in intolerable skeletal muscle AEs that worsened during treatment and resolved when the statin was stopped. For our study purposes, patients taking alternative day dosing of statins due to muscle-related AEs (ie, 2- or 3-times weekly dosing) were not considered statin intolerant; however, patients taking once-weekly statin dosing were considered statin intolerant. Patients were considered ezetimibe intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when ezetimibe was stopped. Patients were considered PCSK9i intolerant due to a muscle-related AE if the intolerance was due to skeletal muscle concerns that worsened during treatment and resolved when the PCSK9i was stopped. Patients with non–muscle-related intolerances to statins, ezetimibe, and PCSK9i were not considered statin, ezetimibe, and PCSK9i intolerant.
Alirocumab was initiated at 75 mg subcutaneous (SQ) once every 2 weeks or evolocumab 140 mg SQ once every 2 weeks in our study. The protocol allowed for a dose reduction of alirocumab 75 mg SQ once monthly if a patient experienced AEs, but this dose reduction strategy was not used for any patients on evolocumab in this study. Of note, alirocumab 75 mg SQ once monthly is not an FDA-approved dosing strategy. However, it is similar in concept to the alternative statin dosing (ie, alternate day dosing, once-weekly dosing) and may avoid the need to discontinue PCSK9i therapy altogether.
A review of the CPRS also documented whether a muscle-related AE occurred while the patient was on a PCSK9i (if yes, the specific AE was recorded), the result of PCSK9i therapy (tolerated full dose, required a dose reduction, switched medication, or discontinued), and management strategies taken for patients who did not meet their LDL-C goal while on a reduced (monthly) PCSK9i dose. Prior lipid therapy intolerances, PCSK9i-related AEs, results of PCSK9i therapy, and management strategies for patients who did not meet LDL-C goal while on a reduced PCSK9i dose were obtained by reviewing the PACT pharmacist’s clinic notes and assessment, along with clinic notes and medication history listed within the CPRS.
Statistical Analysis
Descriptive statistics were used for the demographic characteristics of study patients. The primary outcome was calculated as a binary measure (yes/no) of whether the patient developed a muscle-related AE while on a PCSK9i. The secondary outcome of statin, ezetimibe, or statin and ezetimibe intolerances in subgroups also was calculated as a binary measure.
