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

Study Questions:

How much of the effects of body mass index (BMI) on coronary heart disease (CHD) and stroke are mediated through blood pressure, cholesterol, and glucose?


Cohorts were identified through a review of published articles and through the National Heart, Lung, and Blood Institute (NHLBI; Bethesda, MD, USA), and through personal communication with researchers. Data were pooled from 97 prospective cohort studies that collectively enrolled 1.8 million participants. For each cohort, participants who were younger than age 8 years, had a BMI of lower than 20 kg/m2, or had a history of CHD or stroke were excluded. The hazard ratio (HR) of BMI on CHD and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose was estimated. HRs were then pooled with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators.


Of the 97 prospective cohorts included in the analysis, participants were enrolled between 1948 and 2005. Follow-up periods ranged between 2.7 and 57.5 years (median time across all cohorts was 13.3 years). A total of 57,161 CHD and 31,093 stroke events were reported. Western European cohorts (32 cohorts) had the largest number of CHD and stroke events, contributing 31,289 (55%) of CHD and 13,591 (44%) of stroke events. Cohorts from East and Southeast Asia (33 cohorts) contributed 10,163 (33%) of stroke events, but only 3,763 (7%) of CHD events, showing the importance of stroke in Asia compared with CHD. The HR for each 5 kg/m2 higher BMI was 1.27 (95% confidence interval [CI], 1.23-1.31) for CHD and 1.18 (1.14-.22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors (blood pressure, cholesterol, and glucose) reduced the HRs to 1.15 (1.12-1.18) for CHD and 1.04 (1.01-1.08) for stroke, suggesting that 46% (95% CI, 42-50) of the excess risk of BMI for CHD 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 CHD 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/m2) and obesity (BMI ≥30 kg/m2) were associated with a significantly increased risk of CHD and stroke, compared with normal weight (BMI ≥20 to <25 kg/m2), with 50% (44-58) of the excess risk of overweight and 44% (41-48) of the excess risk of obesity for CHD mediated by the selected three mediators. The percentages for stroke were 98% (69-155) for overweight and 69% (64-77) for obesity.


The investigators concluded that interventions that reduce high blood pressure, cholesterol, and glucose might address about one-half of excess risk of CHD and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.


Pooling cohorts together allows for examination of the effect of multiple factors such as blood pressure, cholesterol, and glucose, together with BMI on cardiovascular events. These results suggest that interventions which improve these factors are important to reduce cardiovascular disease risk; however, normalizing BMI can add further risk reduction.

Clinical Topics: Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Hypertension

Keywords: New Zealand, North America, Stroke, National Heart, Lung, and Blood Institute (U.S.), Overweight, Risk Reduction Behavior, Coronary Disease, Europe, Glucose, Cholesterol, Body Mass Index, Australia, Obesity, Hypertension

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