PCSK9 inhibition
A PCSK9 loss-of-function mutation lowers Lp(a) and reduces aortic valve stenosis risk, a Danish study of 103 083 people (J Clin Endocrinol Metab 2016)
Original title: PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis
This study tested whether the PCSK9 R46L loss-of-function mutation, associated with lower LDL cholesterol, is also linked to lower Lp(a) and reduced risk of aortic valve stenosis and myocardial infarction, using 103 083 individuals from two Danish population cohorts and one patient cohort, with Lp(a) measured in 49,617 of them. Median Lp(a) fell from 10 mg/dL in non-carriers to 9 mg/dL in heterozygotes to 8 mg/dL in homozygotes (trend P=.02), while median LDL cholesterol fell from 124 to 104 to 97 mg/dL (trend P=2x10-52). PCSK9 R46L carriers versus non-carriers had lower risk of aortic valve stenosis (odds ratio 0.64, 95% CI 0.44-0.95), myocardial infarction (odds ratio 0.77, 95% CI 0.65-0.92), and the combined outcome (odds ratio 0.76, 95% CI 0.64-0.89). The findings show PCSK9 R46L carriers have lower Lp(a) and LDL cholesterol along with reduced aortic valve stenosis and myocardial infarction risk, indirectly suggesting PCSK9 inhibitors could benefit patients with aortic valve stenosis.
Original abstract
Context: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown.
Objective: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction.
Design: We used two prospective cohort studies of the general population and one patient-based cohort.
Setting: Cohort studies selected at random individuals of Danish descent.
Participants: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study.
Main Outcome Measures: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals.
Results: Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10(-52)). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction.
Conclusions: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.
aortic stenosisgeneticsPCSK9 inhibition
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.