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Lancet. 2014 Mar 15;383(9921):970-83. doi: 10.1016/S0140-6736(13)61836-X. Epub 2013 Nov 22.

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.

Collaborators (275)

Selmer R, Strand BH, Fang X, Gu DF, Huxley R, Imai Y, Kim HC, Lam TH, Pan WH, Rodgers A, Suh I, Ueshima H, Woodward M, Maegawa H, Okayama A, Ueshima H, Aoki N, Nakamura M, Wu ZS, Wu ZS, Yao CH, Luszcz M, Welborn TA, Tang Z, Liu LS, Xie JX, Ameratunga S, MacMahon S, Norton R, Whitlock G, Knuiman MW, Divitini ML, Christensen H, Wu XG, Yu XH, Zhou J, Tamakoshi A, Pan WH, Chen LQ, Shan GL, Wu ZL, Sritara P, Duan XF, Gu DF, Jackson R, MacMahon S, Norton R, Whitlock G, Li YH, Jiang CQ, Lam TH, Arima H, Iida M, Kiyohara Y, Ho SC, Woo J, Hong Z, Huang MS, Zhou B, Fuh JL, Choudhury SR, Kita Y, Ueshima H, Jee SH, Kim IS, Suh I, Giles GG, Hashimoto T, Sakata K, Dobson A, Imai Y, Ohkubo T, Hozawa A, Jamrozik K, Hobbs M, Broadhurst R, Nakachi K, Fang XH, Li SC, Yang QD, Chen ZM, Tanaka H, Kita Y, Nozaki A, Ueshima H, Horibe H, Matsutani Y, Kagaya M, Hughes K, Lee J, Chew SK, Heng D, Zhang HY, Zhou BF, Shimamoto K, Saitoh S, Li ZZ, Zhang HY, Jamrozik K, Norman P, He Y, Lam TH, Yao SX, Parker ED, Pereira MA, Stevens J, Panagiotakos DB, Pitsavos C, Attia JR, D'Este CA, Zhang X, Clays E, De Bacquer DA, Van Herck K, Divitini ML, Knuiman MW, Morrison HI, Wang F, Chuang SY, Pan WH, Yeh WT, Chen Z, Smith MC, Zhou M, Wang W, Zhang XT, Zhao D, Selmer R, Strand BH, Vollset SE, Fuchs SC, Fuchs FD, Moreira LB, Dontas IA, Dontas CA, Kafatos AG, Moschandreas J, Lanti M, Menotti A, Kromhout D, Menotti A, Jensen MK, Overvad K, Tjonneland A, Klotsche J, Wittchen HU, Fischer S, Hanefeld M, Schwanebeck U, Simons LA, Simons J, Bender R, Matthies S, Nissinen A, Tolonen HK, Tuomilehto J, Nissinen A, Tuomilehto J, Chaturvedi N, Fuller JH, Soedamah-Muthu SS, De Bacquer DA, Kotseva K, Wood DA, Bots ML, Moons KG, Heliovaara M, Knekt PB, Rissanen H, Ferrie JE, Shipley MJ, Smith GD, Johansson S, Lappas G, Rosengren A, Sham A, Woo J, Yu RH, Hata J, Kiyohara Y, Ninomiya T, Hoshide S, Kario K, Rastenyte D, Tamosiunas A, de Simone G, Devereux RB, Gerdts E, Colquhoun DM, Keech AC, Kirby AC, Mizuno K, Nakamura H, Uchiyama S, Bassett JK, Giles GG, Hodge AM, Lappas G, Rosengren A, Wilhelmsen L, Dhaliwal SS, Welborn TA, Nakamura Y, Okayama A, Ueshima H, Kadota A, Okamura T, Ueshima H, Sandvei MS, Vatten LJ, Vik A, Morkedal B, Romundstad PR, Sandvei MS, Elkind MS, Gardener H, Sacco RL, Selmer R, Strand BH, Mignano A, Novo S, Rizzo M, Assmann G, Schulte H, Lissner L, Skoog I, Sundh V, Marin A, Medrano MJ, Hofman A, Kuningas M, Stricker BH, van der Graaf Y, Visseren FL, Lee JJ, Rastenyte D, Tamosiunas A, Bemelmans W, de Groot LC, de Hollander EL, Adachi H, Hirai Y, Azizi F, Hadaegh F, Khalili D, Mathiesen EB, Njolstad I, Wilsgaard T, Can G, Onat A, Arnlov J, Sundstrom J, Blackburn HW, Jacobs DR, Averna MR, Cefalu AB, Noto D, Concin H, Nagel G, Ulmer H, Krasnow RE, Swan G, Kivimaki M, Shipley MJ, Batty GD, Shipley MJ, Milic N, Ostojic MC, Parapid B, Geleijnse JM, Kromhout D, Waterham E, Feskens EJ, Kromhout D, Waterham E.



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.


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.


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.


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.


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.

[Indexed for MEDLINE]
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