PCSK9 inhibition
PCSK9 inhibition lowers LDL cholesterol and Lp(a) discordantly in 20% of patients, a pooled analysis of 4 phase 3 evolocumab trials in 895 patients (J Am Heart Assoc 2019)
Original title: Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab
This pooled analysis of 4 randomised, 12-week, phase 3 evolocumab trials examined the relationship between LDL cholesterol and Lp(a) lowering with PCSK9 inhibition in 895 patients (438 female, median age 59.0 years) with familial hypercholesterolaemia, nonfamilial hypercholesterolaemia, or statin intolerance. Evolocumab lowered LDL cholesterol by 50-60% and Lp(a) by 25% to 30% overall. Baseline mean LDL cholesterol was 133.6 mg/dL and median Lp(a) was 46.4 mg/dL. Using cutoffs of LDL cholesterol reduction above 35% and Lp(a) reduction above 10% to define a concordant response, a discordant response occurred in 165 patients (19.7%), rising to 26.5% and 28.6% among patients with baseline Lp(a) above 30 mg/dL or 50 mg/dL, respectively. The findings show high discordance between LDL cholesterol and Lp(a) reduction with evolocumab, suggesting Lp(a) lowering involves pathways beyond LDL-receptor-mediated clearance.
Original abstract
Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.