Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease
Open accessAbstract
Objectives The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD).Background LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified.Methods We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin.Results All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)).Conclusions Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.
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Genetic variants reflect the effect of lifelong changes in ApoB-containing lipoproteins on cardiovascular disease risk, which appear to be cumulative over time.
“Second, genetic variants reflect the effect of lifelong changes in ApoB-containing lipoproteins on the risk of cardiovascular disease, which appear to be cumulative over time.5,34”
From Association of Triglyceride-Lowering <i>LPL</i> Variants and LDL-C–Lowering <i>LDLR</i> Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [34]
The Discussion (page not provided) says genetically mediated differences in LDL-C reflect the cumulative effect of lifelong exposure, and the study links those differences to coronary heart disease risk. It does not establish the same claim for ApoB-containing lipoproteins as a whole or for cardiovascular disease beyond coronary heart disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNumerous epidemiological studies, Mendelian randomization studies, and randomized controlled trials consistently show a log-linear relationship between absolute changes in plasma LDL-C and atherosclerotic cardiovascular disease risk.
“Numerous epidemiological studies, Mendelian randomization studies, and RCTs have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD [34,45-50].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [47]
The duration of exposure to low LDL-C levels may be as important as the magnitude of LDL-C lowering.
“Additionally, increasing evidence also suggests that the duration of exposure to low LDL-C levels may be as important as the magnitude of LDL-C lowering [11][12][13][14][15][16].”
Prolonged exposure to lower LDL-C levels beginning at a young age is associated with a substantially greater reduction in CVD risk than lowering LDL-C levels later in life.
“A large meta-analysis by Ference et al. has demonstrated that prolonged exposure to lower LDL-C levels beginning at a young age is associated with a substantially greater reduction in the risk of CVD than the current practice of lowering LDL-C levels later in life [13].”
Lifelong exposure to low LDL-C levels as a result of gene polymorphisms is associated with a three-fold greater reduction in the risk of CVD per unit lower LDL-C level than that observed during treatment with a statin started later in life.
“It was found that lifelong exposure to low LDL-C levels as a result of these gene polymorphisms was associated with three-fold greater reduction in the risk of CVD per unit lower LDL-C level than that observed during treatment with a statin started later in life.”
Early initiation of LDL-C-lowering therapy regardless of the plasma LDL-C level was useful for the long-term prevention of cardiovascular events and all-cause mortality in high-risk patients.
“The long-term follow-up of large clinical trials of statins that were conducted in the 1990s, such as the West of Scotland Coronary Prevention Study (WOSCOPS) and the Heart Protection Study (HPS)628, 629) confirmed that early initiation of LDLC-lowering therapy regardless of the plasma LDL-C level was useful for the long-term prevention of cardiovascular events and all-cause mortality in high-risk”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [628]
No increases in new-incidence cancer or non-CVD deaths were observed with long-term LDL-C-lowering therapy using statins.
“No increases in new-incidence cancer or non-CVD deaths were observed, which reconfirms the safety of long-term LDL-C-lowering therapy using statins.”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [628]
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- Authors
- Ference, B. A., Yoo, W., Alesh, I., Mahajan, N., Mirowska, K. K., Mewada, A., Kahn, J., Afonso, L., Williams, K. A., & Flack, J. M.
- Affiliations
- Wayne State University (US)
- University of Tennessee Health Science Center (US)
- Detroit Medical Center (US)
- Corresponding author
- Ference, Brian A.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 60
- Issue
- 25
- Pages
- 2631-2639
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W72392028
- Cited by
- 898
- References
- 44
- Citations by year
- 2026: 69 · 2025: 61 · 2024: 65 · 2023: 80 · 2022: 64 · 2021: 69 · 2020: 81 · 2019: 74 · 2018: 55 · 2017: 48 · 2016: 82 · 2015: 67 · 2014: 41 · 2013: 37 · 2012: 2
- FWCI
- 47.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis
- Medtronic
- NIH
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- LDL cholesterol, coronary heart disease risk, genetic polymorphism, Mendelian randomization, statin therapy, LDL cholesterol lowering, cardiovascular risk reduction
- MeSH terms
- Coronary Artery Disease, Follow-Up Studies, Genetic Markers, Humans, Cholesterol, LDL, Polymorphism, Genetic, Risk Factors, Time Factors, Global Health, Incidence, Risk Assessment, Genetic Predisposition to Disease, Mendelian Randomization Analysis
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