Relationship Between Low‐Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab
Open accessAbstract
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.
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Lp(a) is not cleared predominantly through the LDL receptor.
“Unlike LDL, Lp(a) is not cleared predominantly through the LDL receptor[27].”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [27]
The Discussion (page unavailable) suggests that some Lp(a) isoforms may use clearance routes other than the LDL receptor and says Lp(a) clearance is partly regulated by that receptor. It does not establish that the LDL receptor is not the predominant clearance route overall; the claim states that stronger conclusion as fact. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe apo(a) moiety likely shifts clearance toward non-LDLR pathways that are less responsive to PCSK9 inhibition, while any reduction in secretion appears modest.
“The apo(a) moiety likely also shifts clearance toward non-LDLR pathways that are less responsive to PCSK9 inhibition [27], while any reduction in secretion appears modest.”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [27]
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- Authors
- Shapiro, M. D., Minnier, J., Tavori, H., Kassahun, H., Flower, A., Somaratne, R., & Fazio, S.
- Affiliations
- Oregon Health & Science University (US)
- Amgen (United States) (US)
- Syneos Health Dunedin FL
- NGM Biopharmaceuticals (United States) (US)
- Corresponding author
- Shapiro, Michael D.
- Venue
- Journal of the American Heart Association
- Published
- 2019-02-19
- Volume
- 8
- Issue
- 4
- Pages
- e010932-e010932
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC6405654
- OpenAlex
- W2912156356
- Cited by
- 70
- References
- 34
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 18 · 2019: 9
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043488)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- evolocumab, PCSK9 inhibition, lipoprotein(a), LDL cholesterol lowering, familial hypercholesterolemia, hypercholesterolemia, statin intolerance
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Aged, Anticholesteremic Agents, Female, Follow-Up Studies, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Biomarkers, Treatment Outcome, Antibodies, Monoclonal, Humanized
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