Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events

Boekholdt, S. Matthijs; Hovingh, G. Kees; Mora, Samia; Arsenault, Benoit J.; Amarenco, Pierre; Pedersen, Terje R.; LaRosa, John C.; Waters, David D.; DeMicco, David A.; Simes, R. John; Keech, Antony C.; Colquhoun, David; Hitman, Graham A.; Betteridge, D. John; Clearfield, Michael B.; Downs, John R.; Colhoun, Helen M.; Gotto, Antonio M.; Ridker, Paul M.; Grundy, Scott M.; Kastelein, John J.P.

doi:10.1016/j.jacc.2014.02.615

Cited by 581Lipoproteins and Cardiovascular HealthCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events

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Boekholdt, S. Matthijs, Hovingh, G. Kees, Mora, Samia, Arsenault, Benoit J., Amarenco, Pierre, Pedersen, Terje R., LaRosa, John C., Waters, David D. +13 more·2014·Journal of the American College of Cardiology

DOI 10.1016/j.jacc.2014.02.615PMC PMC4443441

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Abstract

Background Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.Objectives The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.Methods This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.Results Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.Conclusions The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.

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These trials are consistent in showing that the higher the initial LDL-C level, the greater the absolute reduction in risk, while the relative risk reduction remains constant at any given baseline LDL-C level.
“These trials are consistent in showing that the higher the initial LDL-C level, the greater the absolute reduction in risk, while the relative risk reduction remains constant at any given baseline LDL-C level.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [61]
This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels.
“This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels. 61-71”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [61]
There is considerable individual variability in LDL-C response to dietary and drug treatments.
“There is considerable individual variability in the LDL-C response to dietary and drug treatments, 61 which is traditionally taken to support a tailored approach to management.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [61]
There is considerable interindividual variation in LDL cholesterol reduction with the same dose of a statin.
“There is also considerable interindividual variation in LDL-C reduction with the same dose of drug. 61”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [61]
There is considerable individual variability in LDL-C response to dietary and drug treatments.
“There is considerable individual variability in the LDL-C response to dietary and drug treatments, 61 which is traditionally taken to support a tailored approach to management.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [61]

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Authors: Boekholdt, S. M., Hovingh, G. K., Mora, S., Arsenault, B. J., Amarenco, P., Pedersen, T. R., LaRosa, J. C., Waters, D. D., DeMicco, D. A., Simes, R. J., Keech, A. C., Colquhoun, D., Hitman, G. A., Betteridge, D. J., Clearfield, M. B., Downs, J. R., Colhoun, H. M., Gotto, A. M., Ridker, P. M., Grundy, S. M., & Kastelein, J. J. P.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
Brigham and Women's Hospital (US)
Hôpital Bichat-Claude-Bernard (FR)
Oslo University Hospital (NO)
State University of New York (US)
San Francisco General Hospital (US)
Pfizer (United States) (US)
The University of Sydney (AU)
Wesley Hospital (AU)
University of London (GB)
University College Hospital (GB)
Touro University California (US)
The University of Texas at San Antonio Health Science Center (US)
University of Dundee (GB)
Cornell University (US)
The University of Texas Southwestern Medical Center (US)
ORCID: Boekholdt, S. Matthijs
Hovingh, G. Kees
Mora, Samia
Amarenco, Pierre
Pedersen, Terje R.
Waters, David D.
DeMicco, David A.
Simes, R. John
Hitman, Graham A.
Colhoun, Helen M.
Gotto, Antonio M.
Ridker, Paul M.
Grundy, Scott M.
Kastelein, John J.P.
Venue: Journal of the American College of Cardiology
Publisher: Elsevier BV
Published: 2014-08
Volume: 64
Issue: 5
Pages: 485-494
ISSN: 0735-1097 (ISSN-L)
DOI: 10.1016/j.jacc.2014.02.615
PMC: PMC4443441
OpenAlex: W199262836
Cited by: 581
References: 50
Citations by year: 2026: 16 · 2025: 23 · 2024: 33 · 2023: 40 · 2022: 36 · 2021: 55 · 2020: 48 · 2019: 68 · 2018: 57 · 2017: 67 · 2016: 75 · 2015: 49 · 2014: 12 · 2013: 1
FWCI: 67.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
Locations: Journal of the American College of Cardiology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders: Netherlands Organisation for Scientific Research
Atherotech Diagnostics
AstraZeneca Pharma U.S., Inc.
National Heart, Lung, and Blood Institute
AstraZeneca
Boehringer Ingelheim Ltd. U.K.
Eli Lilly and Co., Ltd.
JRDF
Pfizer Inc.
Roche Products Ltd.
Sanofi-Aventis
Topics: Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords: statin therapy, LDL cholesterol, non-HDL cholesterol, apolipoprotein B, atherogenic lipoproteins, interindividual variability, LDL-C goal attainment, cardiovascular events, high-intensity statin therapy, lipid-lowering therapy, cardiovascular risk, statin trials
MeSH terms: Cardiovascular Diseases, Humans, Lipoproteins, Risk Factors, Global Health, Biomarkers, Incidence, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atherosclerosis

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Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events

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