@article{3110854,
    title = "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",
    author = "Lu, Y. and Hajifathalian, K. and Ezzati, M. and Woodward, M. and Rimm, E.B. and Danaei, G. and Selmer, R. and Strand, B.H. and Dobson, A. and Hozawa, A. and Nozaki, A. and Okayama, A. and Rodgers, A. and Tamakoshi, A. and Zhou, B.F. and Zhou, B. and Yao, C.H. and Jiang, C.Q. and Gu, D.F. and Heng, D. and Giles, G.G. and Shan, G.L. and Whitlock, G. and Arima, H. and Kim, H.C. and Christensen, H. and Horibe, H. and Maegawa, H. and Tanaka, H. and Ueshima, H. and Zhang, H.Y. and Kim, I.S. and Suh, I. and Fuh, J.L. and Lee, J. and Woo, J. and Xie, J.X. and Zhou, J. and Hughes, K. and Jamrozik, K. and Nakachi, K. and Sakata, K. and Shimamoto, K. and Chen, L.Q. and Liu, L.S. and Hobbs, M. and Iida, M. and Kagaya, M. and Divitini, M.L. and Luszcz, M. and Nakamura, M. and Huang, M.S. and Knuiman, M.W. and Aoki, N. and Norman, P. and Sritara, P. and Yang, Q.D. and Broadhurst, R. and Huxley, R. and Jackson, R. and Norton, R. and Ameratunga, S. and Ho, S.C. and Li, S.C. and Jee, S.H. and Chew, S.K. and Macmahon, S. and Choudhury, S.R. and Saitoh, S. and Yao, S.X. and Welborn, T.A. and Lam, T.H. and Hashimoto, T. and Ohkubo, T. and Pan, W.-H. and Duan, X.F. and Fang, X. and Wu, X.G. and Fang, X.H. and Yu, X.H. and Li, Y.H. and He, Y. and Imai, Y. and Kita, Y. and Kiyohara, Y. and Matsutani, Y. and Hong, Z. and Wu, Z.L. and Chen, Z.M. and Wu, Z.S. and Tang, Z. and Li, Z.Z. and Parker, E.D. and Pereira, M.A. and Stevens, J. and Panagiotakos, D.B. and Pitsavos, C. and Attia, J.R. and D’este, C.A. and Zhang, X. and Clays, E. and De Bacquer, D.A.O. and Van Herck, K. and Morrison, H.I. and Wang, F. and Chuang, S.-Y. and Yeh, W.-T. and Chen, Z. and Smith, M.C. and Zhou, M. and Wang, W. and Zhang, X.-T. and Zhao, D. and Vollset, S.E. and Fuchs, S.C. and Fuchs, F.D. and Moreira, L.B. and Dontas, I.A. and Dontas, C.A. and Kafatos, A.G. and Moschandreas, J. and Lanti, M. and Menotti, A. and Kromhout, D. and Jensen, M.K. and Overvad, K. and Tjonneland, A. and Klotsche, J. and Wittchen, H.-U. and Fischer, S. and Hanefeld, M. and Schwanebeck, U. and Simons, L.A. and Simons, J. and Bender, R. and Matthies, S. and Nissinen, A. and Tolonen, H.K. and Tuomilehto, J. and Chaturvedi, N. and Fuller, J.H. and Soedamah-Muthu, S.S. and Kotseva, K. and Wood, D.A. and Bots, M.L. and Moons, K.G.M. and Heliovaara, M. and Knekt, P.B. and Rissanen, H. and Ferrie, J.E. and Shipley, M.J. and Smith, G.D. and Johansson, S. and Lappas, G. and Rosengren, A. and Sham, A. and Yu, R.H.Y. and Hata, J. and Ninomiya, T. and Hoshide, S. and Kario, K. and Rastenyte, D. and Tamosiunas, A. and de Simone, G. and Devereux, R.B. and Gerdts, E. and Colquhoun, D.M. and Keech, A.C. and Kirby, A.C. and Mizuno, K. and Nakamura, H. and Uchiyama, S. and Bassett, J.K. and Hodge, A.M. and Wilhelmsen, L. and Dhaliwal, S.S. and Nakamura, Y. and Kadota, A. and Okamura, T. and Sandvei, M.S. and Vatten, L.J. and Vik, A. and Morkedal, B. and Romundstad, P.R. and Elkind, M.S.V. and Gardener, H. and Sacco, R.L. and Mignano, A. and Novo, S. and Rizzo, M. and Assmann, G. and Schulte, H. and Lissner, L. and Skoog, I. and Sundh, V. and Marin, A. and Medrano, M.J. and Hofman, A. and Kuningas, M. and Stricker, B.H. and van der Graaf, Y. and Visseren, F.L.J. and Lee, J.J.M. and Bemelmans, W. and de Groot, L.C.P.G.M. and de Hollander, E.L. and Adachi, H. and Hirai, Y. and Azizi, F. and Hadaegh, F. and Khalili, D. and Mathiesen, E.B. and Njolstad, I. and Wilsgaard, T. and Can, G. and Onat, A. and Arnlov, J. and Sundstrom, J. and Blackburn, H.W. and Jacobs, D.R. and Averna, M.R. and Cefalu, A.B. and Noto, D. and Concin, H. and Nagel, G. and Ulmer, H. and Krasnow, R.E. and Swan, G.E. and Kivimaki, M. and David Batty, G. and Milic, N. and Ostojic, M.C. and Parapid, B. and Geleijnse, J.M. and Waterham, E. and Feskens, E.J. and The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects)",
    journal = "The Lancet Neurology",
    year = "2014",
    volume = "383",
    number = "9921",
    pages = "970-983",
    publisher = "Elsevier B.V.",
    doi = "10.1016/S0140-6736(13)61836-X",
    keywords = "cholesterol;  glucose;  hemoglobin A1c;  high density lipoprotein;  low density lipoprotein cholesterol, article;  Asian;  Australia;  blood pressure;  body mass;  cerebrovascular accident;  cholesterol blood level;  cohort analysis;  geographic distribution;  glucose blood level;  human;  hypertension;  ischemic heart disease;  North America;  obesity;  priority journal;  risk assessment;  risk reduction;  Western Europe;  adult;  age distribution;  Article;  blood pressure;  blood pressure monitoring;  body mass;  cardiovascular risk;  cause of death;  cholesterol blood level;  diabetes mellitus;  disease association;  follow up;  glucose blood level;  hypercholesterolemia;  major clinical study;  obesity;  outcome assessment;  prevalence;  prospective study;  risk factor;  sex difference;  systematic review (topic);  systolic blood pressure;  waist circumference;  waist hip ratio, Biological Markers;  Blood Glucose;  Blood Pressure;  Body Mass Index;  Cholesterol;  Coronary Disease;  Humans;  Obesity;  Overweight;  Risk Factors;  Stroke",
    abstract = "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/m2, 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/m2 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/m2) and obesity (BMI ≥30 kg/m2) were associated with a significantly increased risk of coronary heart disease 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 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."
}