Inadequate Response to PCSK9 Inhibitors

BACKGROUND: Suboptimal response to various proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapies has been reported in the literature; however, inadequate response to proprotein convertase subtilisin/kexin type 9 monoclonal antibodies and small interference RNA is rare to our knowledge. CASE SUMMARY: A 68-year-old woman with hypercholesterolemia (baseline low-density lipoprotein cholesterol [LDL-C]: 205 mg/dL), subclinical atherosclerosis (coronary artery calcium: 204 Agatston units), and elevated lipoprotein(a) (217 nmol/L) experienced debilitating muscle aches and other limiting side effects with statins, ezetimibe, and bempedoic acid, leading to the discontinuation of all oral LDL-C lowering agents. Alirocumab reduced LDL-C to 162 mg/dL after 6 doses. Inclisiran resulted in LDL-C levels of 165 and 199 mg/dL after the first and second doses, respectively. Evolocumab plateaued LDL-C to 155 mg/dL after 7 doses. All the PCSK9i therapies were <25% LDL-C lowering. DISCUSSION: The patient's response to multiple forms of PCSK9i was less than expected. Real-world data show a higher rate of suboptimal proprotein convertase subtilisin/kexin type 9 responses than reported in randomized clinical trials (7.5% vs 1%), warranting further research. TAKE-HOME MESSAGES: A higher rate of suboptimal PCSK9i responses have been reported in real-world data than in randomized clinical trials (7.5% vs 1%), warranting further investigation to understand mechanisms. The use of combination therapy based on individual response and tolerance is essential to assure goal attainment and improve residual risk in patients with suboptimal response.