PCSK9 inhibitors are monoclonal antibodies that target the PCSK9 serum proteins.12 Their mechanism of action is to inactivate PCSK9, thereby preventing it from binding to the LDLR. In turn, this upregulates LDL on the surface of hepatocytes, thereby promoting an increase in the uptake of circulating LDL-C and ultimately leading to a reduction in plasma LDL-C concentrations.1 Two agents, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) in July and August of 2015 respectively. Alirocumab is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH and atherosclerotic CVD who require additional LDL-C lowering.13 Evolocumab has been approved for this indication, as well as for those patients with HoFH who are receiving other cholesterol-lowering therapies.14

Numerous clinical trials have demonstrated the efficacy of this class of agents. For example, evolocumab monotherapy lowered LDL-C by 55% to 57% from baseline, compared with placebo, and up to 38% to 40%, compared to ezetimibe.15 A pooled analysis from three double-blind, randomized, placebo-controlled Phase II studies, including 88 control patients and 108 patients treated with alirocumab, found that it reduced LDL-C from baseline by 68.4%, compared with 10.5% of controls. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab, versus 8% of controls.16

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Both agents have been found to reduce LDL-C when used in conjunction with statins, regardless of baseline statin type, dose, or intensity.17 A meta-analysis of 24 RCTs, including 10,159 patients with FH, non-familial or unspecified hypercholesterolemia, statin-intolerant hypercholesterolemia, or mixed FH and non-FH hypercholesterolemia compared PCSK9 inhibitors to placebo or ezetimibe. The analysis found reduction in all-cause mortality with use of PCSK9 inhibitors and a small reduction in CV mortality.18 However, results of this meta-analysis should be “interpreted with some caution” because of the wide range of populations, the use of two different PCSK9 inhibitors, and the inclusion of differing comparators.1

Both PCSK9 inhibitors are well tolerated. Injection site reactions are the most commonly reported adverse effects, as well as a higher incidence of nasopharyngitis and influenza.1


PCSK9 inhibition “seems to be the most promising emerging treatment option” for patients with FH.19 Clinicians treating this population should emphasize lifestyle modifications (eg, a cardioprotective diet, exercise regimen, weight management, limited alcohol consumption, and smoking cessation) to be used in conjunction with pharmacologic interventions.1