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Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies

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Abstract
Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Findings: Individual participant-level data were analysed from 980793 adults. During 9 center dot 8 million person-years of follow-up, among participants aged between 35 and 89 years, 19686 (25 center dot 6%) of 76965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2 center dot 10, 95% CI 1 center dot 97-2 center dot 24) and tripled risk among women (3 center dot 00, 2 center dot 71-3 center dot 33; x(2) test for heterogeneity p<0 center dot 0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35-59 years: 2 center dot 60, 2 center dot 30-2 center dot 94) than in older individuals (aged 70-89 years: 2 center dot 01, 1 center dot 85-2 center dot 19; p=0 center dot 0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35-59 years had the highest death RR across all age and sex groups (5 center dot 55, 4 center dot 15-7 center dot 44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35-59 years, the excess absolute risk was 0 center dot 05% (95% CI 0 center dot 03-0 center dot 07) per year in women compared with 0 center dot 08% (0 center dot 05-0 center dot 10) per year in men; the corresponding excess at ages 70-89 years was 1 center dot 08% (0 center dot 84-1 center dot 3 2) per year in women and 0 center dot 91% (0 center dot 77-1 center dot 05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained.
Keywords
BLOOD-PRESSURE, RANDOMIZED-TRIALS, RISK-FACTORS, WOMEN, MELLITUS, MEN, HEALTH, ASSOCIATION, COHORT

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Chicago
Gnatiuc, L, WG Herrington, J Halsey, J Tuomilehto, X Fang, HC Kim, Dirk De Bacquer, et al. 2018. “Sex-specific Relevance of Diabetes to Occlusive Vascular and Other Mortality : a Collaborative Meta-analysis of Individual Data from 980 793 Adults from 68 Prospective Studies.” Lancet Diabetes & Endocrinology 6 (7): 538–546.
APA
Gnatiuc, L., Herrington, W., Halsey, J., Tuomilehto, J., Fang, X., Kim, H., De Bacquer, D., et al. (2018). Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies. LANCET DIABETES & ENDOCRINOLOGY, 6(7), 538–546.
Vancouver
1.
Gnatiuc L, Herrington W, Halsey J, Tuomilehto J, Fang X, Kim H, et al. Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies. LANCET DIABETES & ENDOCRINOLOGY. 2018;6(7):538–46.
MLA
Gnatiuc, L, WG Herrington, J Halsey, et al. “Sex-specific Relevance of Diabetes to Occlusive Vascular and Other Mortality : a Collaborative Meta-analysis of Individual Data from 980 793 Adults from 68 Prospective Studies.” LANCET DIABETES & ENDOCRINOLOGY 6.7 (2018): 538–546. Print.
@article{8561415,
  abstract     = {Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. 
Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. 
Findings: Individual participant-level data were analysed from 980793 adults. During 9 center dot 8 million person-years of follow-up, among participants aged between 35 and 89 years, 19686 (25 center dot 6\%) of 76965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2 center dot 10, 95\% CI 1 center dot 97-2 center dot 24) and tripled risk among women (3 center dot 00, 2 center dot 71-3 center dot 33; x(2) test for heterogeneity p{\textlangle}0 center dot 0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35-59 years: 2 center dot 60, 2 center dot 30-2 center dot 94) than in older individuals (aged 70-89 years: 2 center dot 01, 1 center dot 85-2 center dot 19; p=0 center dot 0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35-59 years had the highest death RR across all age and sex groups (5 center dot 55, 4 center dot 15-7 center dot 44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35-59 years, the excess absolute risk was 0 center dot 05\% (95\% CI 0 center dot 03-0 center dot 07) per year in women compared with 0 center dot 08\% (0 center dot 05-0 center dot 10) per year in men; the corresponding excess at ages 70-89 years was 1 center dot 08\% (0 center dot 84-1 center dot 3 2) per year in women and 0 center dot 91\% (0 center dot 77-1 center dot 05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. 
Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained.},
  author       = {Gnatiuc, L and Herrington, WG and Halsey, J and Tuomilehto, J and Fang, X and Kim, HC and De Bacquer, Dirk and Dobson, AJ and Criqui, MH and Jacobs, DR and Leon, DA and Peters, SAE and Ueshima, H and Sherliker, P and Peto, R and Collins, R and Huxley, RR and Emberson, JR and Woodward, M and Lewington, S and Aoki, N and Arima, H and Arnesen, E and Aromaa, A and Assmann, G and Bachman, DL and Baigent, C and Bartholomew, H and Benetos, A and Bengtsson, C and Bennett, D and Bj{\"o}rkelund, C and Blackburn, H and Bonaa, K and Boyle, E and Broadhurst, R and Carstensen, J and Chambless, L and Chen, Z and Chew, SK and Clarke, R and Cox, C and Curb, JD and D'Agostino, R and Date, C and Davey Smith, G and De Backer, Gui and Dhaliwal, SS and Duan, XF and Ducimetiere, P and Duffy, S and Eliassen, H and Elwood, P and Empana, J and Garcia-Palmieri, MH and Gazes, P and Giles, GG and Gillis, C and Goldbourt, U and Gu, DF and Guasch-Ferre, M and Guize, L and Haheim, L and Hart, C and Hashimoto, S and Hashimoto, T and Heng, D and Hjermann, I and Ho, SC and Hobbs, M and Hole, D and Holme, I and Horibe, H and Hozawa, A and Hu, F and Hughes, K and Iida, M and Imai, K and Imai, Y and Iso, H and Jackson, R and Jamrozik, K and Jee, SH and Jensen, G and Jiang, CQ and Johansen, NB and Jorgensen, T and Jousilahti, P and Kagaya, M and Keil, J and Keller, J and Kim, IS and Kita, Y and Kitamura, A and Kiyohara, Y and Knekt, P and Knuiman, M and Kornitzer, M and Kromhout, D and Kronmal, R and Lam, TH and Law, M and Lee, J and Leren, P and Levy, D and Li, YH and Lissner, L and Luepker, R and Luszcz, M and MacMahon, S and Maegawa, H and Marmot, M and Matsutani, Y and Meade, T and Morris, J and Morris, R and Murayama, T and Naito, Y and Nakachi, K and Nakamura, M and Nakayama, T and Neaton, J and Nietert, PJ and Nishimoto, Y and Norton, R and Nozaki, A and Ohkubo, T and Okayama, A and Pan, WH and Puska, P and Qizilbash, N and Reunanen, A and Rimm, E and Rodgers, A and Saitoh, S and Sakata, K and Sato, S and Schnohr, P and Schulte, H and Selmer, R and Sharp, D and Shifu, X and Shimamoto, K and Shipley, M and Silbershatz, H and Sorlie, p and Sritara, P and Suh, I and Sutherland, SE and Sweetnam, P and Tamakoshi, A and Tanaka, H and Thomsen, T and Tominaga, S and Tomita, M and T{\"o}rnberg, S and Tunstall-Pedoe, H and Tverdal, A and Ueshima, H and Vartiainen, E and Wald, N and Wannamethee, SG and Welborn, TA and Whincup, P and Whitlock, G and Willett, W and Woo, J and Wu, ZL and Yao, SX and Yarnell, J and Yokoyama, T and Yoshiike, N and Zhang, XH},
  issn         = {2213-8587},
  journal      = {LANCET DIABETES \& ENDOCRINOLOGY},
  language     = {eng},
  number       = {7},
  pages        = {538--546},
  title        = {Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980\phantom{,}793 adults from 68 prospective studies},
  url          = {http://dx.doi.org/10.1016/s2213-8587(18)30079-2},
  volume       = {6},
  year         = {2018},
}

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