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Meta-Analysis
. 2025 Jan 28;151(4):312-321.
doi: 10.1161/CIRCULATIONAHA.124.069556. Epub 2024 Nov 4.

Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis

Harpreet S Bhatia  1 , Simon Wandel  2 , Peter Willeit  3 , Anastasia Lesogor  2 , Keith Bailey  2 , Paul M Ridker  4 , Paul Nestel  5 , John Simes  6 , Andrew Tonkin  7 , Gregory G Schwartz  8 , Helen Colhoun  9 , Christoph Wanner  10 , Sotirios Tsimikas  1
Affiliations
Meta-Analysis

Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis

Harpreet S Bhatia et al. Circulation. .

Abstract

Background: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined.

Methods: A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models.

Results: Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48]).

Conclusions: These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.

Keywords: cholesterol; heart disease risk factors; lipoprotein(a); lipoproteins, LDL.

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Conflict of interest statement

Dr Bhatia received consulting fees from Abbott, Arrowhead, Kaneka Medical, and Novartis Pharmaceuticals. Dr Tsimikas is a coinventor and receives royalties from patents owned by University of California, San Diego and is a cofounder and has an equity interest in Kleanthi Diagnostics, LLC, and has a dual appointment at University of California, San Diego and Ionis Pharmaceuticals. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Drs Lesogor and Wandel, and K. Bailey are employees of Novartis. Dr Wandel holds stocks of Novartis, Alcon, and Sandoz. A. Tonkin has received consulting fees from Novartis and is on the DMC of the ORION-4 study. Dr Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, GSK, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk advisory board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute. Dr Willeit reports consulting fees from Novartis Pharmaceuticals. Dr Colhoun reports grants from IQVIA, JDRF, Chief Scientist Office, Diabetes UK, MRC (UKRI), and EU Commission; speaker bureau fees from Novo Nordisk; advisory roles with Novo Nordisk and Bayer AG; and is a shareholder in Roche Pharmaceuticals and Bayer AG. The other coauthors have nothing to disclose.

Figures

Figure 1.
Figure 1.
Study cohort. The flowchart depicts the number of participants in each trial with available lipoprotein(a) measurements and the number randomized to statin versus placebo. 4D indicates Die Deutsche Diabetes Dialyse; 4S, Scandinavian Simvastatin Survival Study; CARDS, Collaborative Atorvastatin Diabetes Study; JUPITER, Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin; LIPID, Long-Term Intervention With Pravastatin in Ischaemic Disease; and MIRACL, Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering.
Figure 2.
Figure 2.
Association between baseline lipoprotein(a) level and atherosclerotic cardiovascular disease risk in placebo and statin treatment arms. Atherosclerotic cardiovascular disease risk increases log-linearly with increasing lipoprotein(a) (Lp[a]) levels in both the placebo and statin treatment arms. Hazard ratios were calculated using a reference Lp(a) level of 5 mg/dL. Adjusted for age, sex, history of vascular disease, diabetes, smoking, systolic blood pressure, baseline low-density lipoprotein cholesterol level, and high-density lipoprotein cholesterol level, and stratified by trial and treatment assignment.
Figure 3.
Figure 3.
Joint association between baseline lipoprotein(a) level and achieved low-density lipoprotein cholesterol level or change in low-density lipoprotein cholesterol level and atherosclerotic cardiovascular disease risk in statin users. Hazard ratio (HR) adjusted for age, sex, history of vascular disease, diabetes, smoking, systolic blood pressure, baseline low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and stratified by trial. Achieved LDL-C quartiles in mg/dL: quartile 1, 3.09–76.95; quartile 2, 77.34 to 109.44; quartile 3, 109.82 to 140.37; quartile 4, >140.76). Absolute change from baseline in LDL-C quartiles in mg/dL: quartile 1, −192.6 to −52.09; quartile 2, −52.09 to −18.56; quartile 3, −18.56 to 5.99; quartile 4, 5.99 to 115.24. PY indicates person-years.
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