Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants
Open accessAbstract
Background Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors.Methods We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57,161 coronary heart disease and 31,093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m(2), or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators.Findings The HR for each 5 kg/m(2) higher BMI was 1·27 (95% CI 1·23-1·31) for coronary heart disease and 1·18 (1·14-1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12-1·18) for coronary heart disease and 1·04 (1·01-1·08) for stroke, suggesting that 46% (95% CI 42-50) of the excess risk of BMI for coronary heart disease and 76% (65-91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28-35) of the excess risk for coronary heart disease and 65% (56-75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) were associated with a significantly increased risk of coronary heart disease and stroke, compared with normal weight (BMI ≥20 to <25 kg/m(2)), with 50% (44-58) of the excess risk of overweight and 44% (41-48) of the excess risk of obesity for coronary heart disease mediated by the selected three mediators. The percentages for stroke were 98% (69-155) for overweight and 69% (64-77) for obesity.Interpretation Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of excess risk of coronary heart disease and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.Funding US National Institute of Health, UK Medical Research Council, National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust, Lown Scholars in Residence Program on cardiovascular disease prevention, and Harvard Global Health Institute Doctoral Research Grant.
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Overweight and obesity are independently associated with an increased risk of cardiovascular events, even after accounting for metabolic cardiovascular risk factors linked to excess weight.
“Overweight and obesity are independently associated with an increased risk of cardiovascular events, even after the influence of metabolic cardiovascular risk factors linked to excess weight has been accounted for. 3-6”
From Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (2023) · cites this paper as [5]
The Results (table 3) show that, after adjustment for blood pressure, cholesterol, and glucose, overweight and obesity remained associated with increased coronary heart disease risk, and obesity remained associated with increased stroke risk. Overweight was not associated with increased stroke risk after that adjustment (HR 1.00, 95% CI 0.96–1.05), so the claim is too broad if cardiovascular events includes stroke. (LLM, conf=0.90)
Experimental — accuracy not yet measuredObesity was associated with an increased risk of AD, DM, CHD, stroke and liver and bowel cancer by between 33% and 588%.
“Obesity was associated with an increased risk of AD, DM, CHD, stroke and liver and bowel cancer by between 33% and 588%.11,77,81,85”
From Common risk factors for major noncommunicable disease, a systematic overview of reviews and commentary: the implied potential for targeted risk reduction (2019) · cites this paper as [81]
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Obesity and anxiety symptoms: a systematic review and meta-analysis
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Obesity and subtypes of incident cardiovascular disease
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Glyoxalase 1 Modulation in Obesity and Diabetes
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- Authors
- *
- Corresponding author
- *
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 383
- Issue
- 9921
- Pages
- 970-983
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3959199
- OpenAlex
- W2029465266
- Cited by
- 1,121
- References
- 61
- Citations by year
- 2026: 62 · 2025: 76 · 2024: 83 · 2023: 108 · 2022: 83 · 2021: 97 · 2020: 104 · 2019: 103 · 2018: 107 · 2017: 96 · 2016: 77 · 2015: 70 · 2014: 50 · 2013: 2
- FWCI
- 52.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Lancet (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- NHRI Institutional Repository (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Lume (Universidade Federal do Rio Grande do Sul) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institute of Health (RO1 DK090435)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Keywords
- body mass index, obesity, overweight, coronary artery disease, stroke, mediation analysis, blood pressure, cholesterol, glucose, metabolic risk factors, excess risk, Asian populations, hypertension, hyperlipidemia, hyperglycemia, cardiovascular risk factors
- MeSH terms
- Blood Glucose, Blood Pressure, Cholesterol, Coronary Disease, Humans, Obesity, Risk Factors, Biomarkers, Body Mass Index, Stroke, Overweight
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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