Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events
Open accessAbstract
Importance: Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk. Objective: To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life. Design, Setting, and Participants: This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021. Exposures: Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years. Main Outcomes and Measures: Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF). Results: A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF. Conclusions and Relevance: This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.
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There is a strong, dose-dependent relationship between LDL-C levels and ASCVD incidence.
“Evidence from prospective longitudinal cohort studies and Mendelian randomization support a strong, dose-dependent relationship between LDL-C levels and ASCVD incidence [2, 3].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [3]
The Discussion reports a dose-response association between cumulative LDL-C exposure and coronary heart disease (CHD) risk, and the Results show higher CHD risk across LDL-C exposure quartiles. The claim is broader than this paper’s finding: the Results report no association between the LDL-C measures and ischemic stroke, another ASCVD outcome. (LLM, conf=0.86)
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- Authors
- Zhang, Y., Pletcher, M. J., Vittinghoff, E., Clemons, A. M., Jacobs, D. R., Allen, N. B., Alonso, A., Bellows, B. K., Oelsner, E. C., Zeki Al Hazzouri, A., Kazi, D. S., de Ferranti, S. D., & Moran, A. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- University of California, San Francisco (US)
- Columbia University (US)
- University of Minnesota (US)
- Northwestern University (US)
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
- Beth Israel Deaconess Medical Center (US)
- Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts
- Corresponding author
- Zhang, Yiyi
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-12-01
- Volume
- 6
- Issue
- 12
- Pages
- 1406
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC8459309
- OpenAlex
- W3200269653
- Cited by
- 257
- References
- 24
- Citations by year
- 2026: 77 · 2025: 67 · 2024: 47 · 2023: 40 · 2022: 21 · 2021: 4
- FWCI
- 26.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Cardiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (K24HL148521, R01HL107475, K23HL130627, R01HL141823, R21HL129924)
- National Institute of Environmental Health Sciences (T32ES007322)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- LDL cholesterol, early adulthood, middle age (human life stage), cardiovascular risk, coronary artery disease, ischemic stroke, heart failure, incident cardiovascular events, atherosclerosis, dyslipidemia, cardiovascular risk factors, sex differences, LDL-C lowering therapy, statins, PCSK9
- MeSH terms
- Adolescent, Adult, Hypolipidemic Agents, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Cholesterol, LDL, Male, Middle Aged, Primary Prevention, Prognosis, Prospective Studies, Risk Factors, Time Factors, United States, Incidence, Risk Assessment, Young Adult
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