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Target of action PCSK9, a protein (protease) secreted primarily by liver, binds to LDL receptors on hepatocytes and promotes internalization and lysosomal degradation of LDL receptors, thereby reducing the number of LDL receptors. Reduction in LDL receptors result in elevated serum LDL-C levels. Mechanism of action PCSK9 inhibitors are monoclonal antibodies against PCSK9, thereby preventing internalization and lysosomal degradation of LDL receptors. This increases LDL receptor density, thereby reducing serum LDL-C levels. Available products Evolocumab and alirocumab are two commercially available PCSK9 inhibitors that are FDA approved for human use. Mode of administration Both evolocumab and alirocumab are administered as subcutaneous injection once a month or every 2 weeks Storage Should be stored in refrigerator and warmed to room temperature before use. PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; FDA, Federal Drug Administration.
LDL-C reduction Treatment with evolocumab or alirocumab results in approximately 55% or 53% reduction in LDL-C levels, respectively. Effect on lipid panel Evolocumab and alirocumab results in 7.6% and 8% increases in HDL-C, respectively. There was reduction in non-HDL-C, total cholesterol, triglycerides, and lipoprotein(a) levels. Effect on clinical outcomes PCSK9 inhibitor results in 15% to 48% lower hazard of a composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization (1.5% absolute reduction of events) compared with standard medical therapy. Long-term outcome data are not available. Plaque regression Significantly more plaque volume reduction seen with PCSK9 inhibitor treatment as compared with statin therapy. PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CV, cardiovascular; MI, myocardial infarction; UA, unstable angina.
Safety Profile Evolocumab Alirocumab Common side effects Upper respiratory tract infection, influenza, gastroenteritis, nasopharyngitis, injection site reactions. Upper respiratory tract infection, influenza, nasopharyngitis, gastroenteritis, injection site reactions. Pregnancy No data available on use in pregnant women to inform a drug-associated risk. No available data on use in pregnant women to inform a drug-associated risk. Lactation No information on its presence in human milk, effects on the breastfed infant, or on milk production. No information on its presence in human milk, effects on the breastfed infant, or on milk production. Pediatric use The safety profile of Repatha in these adolescents was similar to that described for adult patients with HoFH. Safety and efficacy not established in HoFH patients <13 years with HoFH and in pediatric patients with primary hyperlipidemia or HeFH. Safety and efficacy in pediatric patients have not been established. Geriatric use Safety profile similar to younger adults. Safety profile similar to younger adults. Renal impairment No dose adjustment is needed. No dose adjustment is needed for mild or moderately impaired renal function. No data are available in severe renal impairment. Hepatic impairment No dose adjustment in mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in severe impairment. No dose adjustment in mild to moderate hepatic impairment. No data are available in severe impairment. PCSK9, proprotein convertase subtilisin/kexin type 9; HoFH, homozygous familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia.
Disease States Patients with ASCVD, HoFH, HeFH. Prerequisite for treatment Decision to start PCSK9 inhibitor would depend on achieving specific target LDL-C levels in various conditions that increase ASCVD risk or in presence of ASCVD.
PCSK9 inhibitors are started in addition to maximum tolerated statin with or without ezetimibe.
PCSK9 inhibitors are started in statin-intolerant patients for achieving specific target LDL-C levels in various conditions that increase ASCVD risk or in presence of ASCVD.
Lipid levels in ACVD for treatment Stable with risk factors and in progressive LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL. Lipid levels in HeFH for treatment Age 40 years to 79 years and controlled ASCVD risk factors, with baseline LDL-C ≥190 mg/dL, and LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL with statin ± ezetimibe.
Age 40 to 79 years and uncontrolled ASVCD risk factors, baseline LDL-C ≥190 mg/dL, and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL with statin ± ezetimibe.
Age 18 to 39 years with uncontrolled ASVCD risk factors, baseline LDL-C ≥190 mg/dL, and LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL with statin ± ezetimibe.
Lipid levels in HoFH for treatment LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL with statin ± ezetimibe. PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; ASCVD, Atherosclerotic cardiovascular disease.
