@article{e3eedd9b11844242ad7a055ba400733f,
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",
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.",
author = "{The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects)} and Yuan Lu and Kaveh Hajifathalian and Majid Ezzati and Mark Woodward and Rimm, {Eric B.} and Goodarz Danaei and Randi Selmer and Strand, {Bjorn H.} and A. Dobson and A. Hozawa and A. Nozaki and Akira Okayama and A. Rodgers and A. Tamakoshi and Zhou, {B. F.} and B. Zhou and Yao, {C. H.} and Jiang, {C. Q.} and Gu, {D. F.} and D. Heng and Giles, {Graham G.} and Shan, {G. L.} and G. Whitlock and H. Arima and Kim, {H. C.} and H. Christensen and H. Horibe and H. Maegawa and H. Tanaka and Hirotsugu Ueshima and Zhang, {H. Y.} and Kim, {I. S.} and I. Suh and Fuh, {J. L.} and J. Lee and Jean Woo and Xie, {J. X.} and J. Zhou and K. Hughes and K. Jamrozik and K. Nakachi and K. Sakata and K. Shimamoto and Chen, {L. Q.} and Liu, {L. S.} and M. Hobbs and M. Iida and M. Kagaya and Divitini, {Mark L.} and M. Luszcz and M. Nakamura and Huang, {M. S.} and Knuiman, {Matthew W.} and N. Aoki and P. Norman and P. Sritara and Yang, {Q. D.} and R. Broadhurst and R. Huxley and R. Jackson and R. Norton and S. Ameratunga and Ho, {S. C.} and Li, {S. C.} and Jee, {S. H.} and Chew, {S. K.} and S. Macmahon and Choudhury, {S. R.} and S. Saitoh and Yao, {S. X.} and Welborn, {Timothy A.} and Lam, {T. H.} and T. Hashimoto and T. Ohkubo and Pan, {Wen Harn} and Duan, {X. F.} and X. Fang and Wu, {X. G.} and Fang, {X. H.} and Yu, {X. H.} and Li, {Y. H.} and Y. He and Y. Imai and Y. Kita and Yutaka Kiyohara and Y. Matsutani and Z. Hong and Wu, {Z. L.} and Chen, {Z. M.} and Wu, {Z. S.} and Z. Tang and Li, {Z. Z.} and Parker, {Emily D.} and Pereira, {Mark A.} and June Stevens and Panagiotakos, {Demosthenes B.} and Christos Pitsavos and Attia, {John R.} and D{\^a}€{\texttrademark}este, {Catherine A.} and Xiaofei Zhang and Els Clays and {De Bacquer}, {Dirk A.O.} and {Van Herck}, Koen and Morrison, {Howard I.} and Feng Wang and Chuang, {Shao Yuan} and Yeh, {Wen Ting} and Zhengming Chen and Smith, {Margaret C.} and Maigeng Zhou and Wei Wang and Zhang, {Xiao Ting} and Dong Zhao and Vollset, {Stein Emil} and Fuchs, {Sandra C.} and Fuchs, {Flavio D.} and Moreira, {Leila B.} and Dontas, {Ismene A.} and Dontas, {Cleo A.} and Kafatos, {Anthony G.} and Joanna Moschandreas and Mariapaola Lanti and Alessandro Menotti and Daan Kromhout and Jensen, {Majken K.} and Kim Overvad and Anne Tjonneland and Jens Klotsche and Wittchen, {Hans Ulrich} and Sabine Fischer and Markolf Hanefeld and Uta Schwanebeck and Simons, {Leon A.} and Judith Simons and Ralf Bender and Silke Matthies and Aulikki Nissinen and Tolonen, {Hanna K.} and Jaakko Tuomilehto and Nish Chaturvedi and Fuller, {John H.} and Soedamah-Muthu, {Sabita S.} and Kornelia Kotseva and Wood, {David A.} and Bots, {Michiel L.} and Moons, {Karel G.M.} and Markku Heliovaara and Knekt, {Paul B.} and Harri Rissanen and Ferrie, {Jane E.} and Shipley, {Martin J.} and Smith, {George Davey} and Saga Johansson and Georgios Lappas and Annika Rosengren and Aprille Sham and Yu, {Ruby H.Y.} and Jun Hata and Toshiharu Ninomiya and Satoshi Hoshide and Kazuomi Kario and Daiva Rastenyte and Abdonas Tamosiunas and {de Simone}, Giovanni and Devereux, {Richard B.} and Eva Gerdts and Colquhoun, {David M.} and Keech, {Anthony C.} and Kirby, {Adrienne C.} and Kyoichi Mizuno and Haruo Nakamura and Shinichiro Uchiyama and Bassett, {Julie K.} and Hodge, {Allison M.} and Lars Wilhelmsen and Dhaliwal, {Satvinder S.} and Yasuyuki Nakamura and Aya Kadota and Tomonori Okamura and Sandvei, {Marie S.} and Vatten, {Lars J.} and Anne Vik and Bjorn Morkedal and Romundstad, {Pal R.} and Elkind, {Mitchell S.V.} and Hannah Gardener and Sacco, {Ralph L.} and Antonino Mignano and Salvatore Novo and Manfredi Rizzo and Gerd Assmann and Helmut Schulte and Lauren Lissner and Ingmar Skoog and Valter Sundh and Alejandro Marin and Medrano, {Maria Jose} and Albert Hofman and Maris Kuningas and Stricker, {Bruno H.} and {van der Graaf}, Yolanda and Visseren, {Frank L.J.} and Lee, {Jeannette J.M.} and Wanda Bemelmans and {de Groot}, {Lisette C.P.G.M.} and {de Hollander}, {Ellen L.} and Hisashi Adachi and Yuji Hirai and Fereidoun Azizi and Farzad Hadaegh and Davood Khalili and Mathiesen, {Ellisiv B.} and Inger Njolstad and Tom Wilsgaard and Gunay Can and Altan Onat and Johan Arnlov and Johan Sundstrom and Blackburn, {Henry W.} and Jacobs, {David R.} and Averna, {Maurizio R.} and Cefalu, {Angelo B.} and Davide Noto and Hans Concin and Gabriele Nagel and Hanno Ulmer and Krasnow, {Ruth E.} and Swan, {Gary E.} and Mika Kivimaki and {David Batty}, G. and Natasa Milic and Ostojic, {Miodrag C.} and Biljana Parapid and Geleijnse, {Johanna M.} and Eveline Waterham and Feskens, {Edith J.}",
year = "2014",
doi = "10.1016/S0140-6736(13)61836-X",
language = "English",
volume = "383",
pages = "970--983",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier B.V.",
number = "9921",
}