Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab

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.

Trial registration: ClinicalTrials.gov NCT01763827 NCT01763866 NCT01763905 NCT01763918.

Keywords: lipid‐lowering therapy; lipoprotein[a]; low‐density lipoprotein cholesterol; proprotein convertase subtilisin/kexin type 9.

Figure 1

Relationship between percentage reduction in LDL‐C and Lp(a). Relationship between percentage reduction in LDL‐C and Lp(a) at 12 weeks of evolocumab therapy according to baseline Lp(a). A, Baseline Lp(a) >10 mg/dL. B, Baseline Lp(a) >30 mg/dL, C, Baseline Lp(a) >50 mg/dL. The quadrants shaded in pink represent patients with discordant LDL‐C and Lp(a) responses to evolocumab based on response to therapy defined as LDL‐C reduction >35% and Lp(a) reduction >10%. LDL‐C indicates low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); Q2W, every 2 weeks; QM, monthly.

Figure 2

Relationship between percentage reduction in Lp(a) and selected variables. Relationship between percentage reduction in Lp(a) and baseline LDL‐C (A), on‐treatment LDL‐C (B), and baseline Lp(a) concentration (C) for the overall cohort at 12 weeks of evolocumab therapy. LDL‐C indicates low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a).