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Case series Patients: Male, 44-year-old • Female, 71-year-old Final Diagnosis: Resistance to PCSK9I overcomed by adding statin Symptoms: Dyslipidemia Medication: — Clinical Procedure: — Specialty: Cardiology Objective: Unusual or unexpected effect of treatment Background: Real-life data on the efficacy of monotherapy with PCSK9 inhibitors are scarce. Most cohort studies have examined populations that are not severely dyslipidemic and are receiving combined therapy rather than monotherapy. Case Reports: From a series of 167 alirocumab prescriptions, we present a case of complete nonresponse and one of low response to monotherapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in 2 patients with heterozygous familial hypercholesterolemia and abnormalities of the low-density lipoprotein cholesterol (LDL-C) receptor. In these cases, PCSK9 inhibitors were ineffective when used alone to reduce the LDL-C level, but the addition of statin led to a dramatic improvement. Conclusions: As PCSK9 inhibitors become more commonly prescribed, more cases of nonresponse to PCSK9 inhibitors will be identified. Prospective studies are needed to investigate the efficacy of treatment with the monoclonal antibodies PCSK9 inhibitors in the context of LDL-C receptor abnormalities and to determine whether a genetic explanation exists for interindividual differences in response.