Case Series: Patients with Hypo-Responsiveness to PCSK9 Inhibitor Therapy

Abstract

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Proprotein convertase subtilisin/Kexin type 9 inhibitors (PCSK9i) [alirocumab, evolocumab] are fully human monoclonal antibodies that bind to plasma PCSK9 and prevent LDL receptor degradation. They reduce LDL-C by 50-70% and improve cardiovascular morbidity and mortality by 50% (Gouni-Berthold I.,2017). They are indicated as an adjunct to diet and maximally tolerated statin in individuals with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional LDL-C lowering. Evolocumab reduced LDL-C by 30% or greater in 99.8% patients, and alirocumab reduced LDL-C by atleast 15% in 98.9% patients (Qamar et al.,2019, Bays et al.,2018). About 87-98% achieve LDL-C goal with PCSK9i (Gouni-Berthold I.,2017). Hence, majority of patients on PCSK9i are expected to have a substantial and consistent LDL-C reduction. But, hypo-responsiveness to PCSK9i (less than 30% LDL-C reduction from baseline at all time points, i.e., beyond two standard deviations of mean for expected LDL-C reduction [Qamar et al.,2019]) are encountered more commonly in the clinical setting than expected. <h3>Objective/Purpose</h3> Assess factors contributing to hypo-responsiveness to PCSK9i. <h3>Methods</h3> A case series of five patients with hypo-responsiveness to PCSK9i reported in table 1. <h3>Results</h3> Unusual response to PCSK9i occur 3-fold higher in real-world than reported in clinical trials (Warden et al.,2020). Maximal PCSK9i LDL-C reduction occurs in 14-days (Chaudhary et al.,2017). In clinical trials, LDL-C was obtained at the end of dosing interval. Evolocumab reduces LDL-C by 85% at midpoint and by 60% at end of dosing interval (Qamar et al.,2019). Less than 15% LDL-C reduction in ODYSSEY trials was reported due to poor adherence to PCSK9i or concurrent lipid-lowering therapy (Bays et al.,2018). All our patients were adherent to treatment and had accurate injection techniques. Our patients have unique genetics and co-morbidities, which might have contributed to interindividual variation and hypo-responsiveness to PCSK9i. Elevated Lp(a) co-measured with LDL-C can contribute to suboptimal response as PCSK9i can lower Lp(a) by 15-30% only (Ruscica et al.,2020). PCSK9 and Lp(a) levels increase in nephrotic syndrome (Pavlakou et al.,2017, Hopewell et al.,2018). Disorders with very low LDL receptor activity can influence response to PCSK9i. There is a potential for immunogenicity, but anti-drug antibodies impact on clinical response to PCSK9i is unknown. There is no evidence of insufficient PCSK9 blockade, difference with switching PCSK9i, or changing injection site. <h3>Conclusions</h3> Careful medication reconciliation and injection technique assessment are the initial steps in evaluating hypo-responsiveness to PCSK9i. Understanding possible etiologies for hypo-responsiveness to PCSK9i might help advance lipid-lowering pharmacology.