Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody
نویسندگان
چکیده
BACKGROUND Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
منابع مشابه
PCSK9 Inhibition: Does Lipoprotein Size Matter?
I n order to assess the risk of cardiovascular diseases in patients, fasting plasma lipids levels are usually measured as total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) and combined to estimate lowdensity lipoprotein cholesterol (LDL-C) levels using the Friedewald formula. While this indirect measure is strongly correlated with the risk of cardiovascular dise...
متن کاملSo Far, PCSK9 Inhibitors Work for All Heterozygous FH Patients.
T wo proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have obtained approval by the United States Food and Drug Administration: evolocumab (Amgen) and ali-rocumab (Sanofi/Regeneron). Per their package inserts, both are "indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (FH) or clinic...
متن کاملProprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.
OBJECTIVE Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? APPROACH AND RESUL...
متن کاملFamilial Hypercholesterolemia: From Diagnosis to Treatment
Familial hypercholesterolemia (FH) is an inherited common autosomal Mendelian disorder of lipoprotein metabolism with a population prevalence of 1 in 500. FH is characterized by severely elevated levels of low-density lipoprotein cholesterol (LDL-C), which result in surplus deposition of cholesterol in tissues. This condition leads to premature at hero sclerosis and early-onset of coronary hear...
متن کاملPCSK9 and Lipoprotein(a)
Proprotein convertase subtilisin kexin type 9 (PCSK9) has rapidly become a focus of intensive investigation worldwide because of its linkage to multiple clinically important facets of hepatic lipoprotein metabolism. To facilitate secretion and proper folding, the zymogen pro-PCSK9 must undergo autocatalytic cleavage. Once in the extracellular space, mature PCSK9 does not engage in proteolytic a...
متن کامل