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. Results: Individual participant-level data were analysed from 980 793 adults. During 9·8 million person-years of follow-up, among participants aged between 35 and 89 years, 19 686 (25·6%) of 76 965 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] 2·10, 95% CI 1·97–2·24) and tripled risk among women (3·00, 2·71–3·33; χ2 test for heterogeneity p<0·0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35–59 years: 2·60, 2·30–2·94) than in older individuals (aged 70–89 years: 2·01, 1·85–2·19; p=0·0001 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 (5·55, 4·15–7·44). 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 0·05% (95% CI 0·03–0·07) per year in women compared with 0·08% (0·05–0·10) per year in men; the corresponding excess at ages 70–89 years was 1·08% (0·84–1·32) per year in women and 0·91% (0·77–1·05) 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. Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Union BIOMED programme, and National Institute on Aging (US National Institutes of Health).
Bibliographical noteFunding Information:
In this analysis of individual participant-level data from nearly 1 million adults with no previous vascular disease who were followed up prospectively to monitor mortality, we determined that having diabetes at recruitment was associated with a doubling in death rates from ischaemic heart disease and ischaemic stroke among men, but a tripling of these death rates among women. For both men and women, the death RRs for occlusive vascular mortality were greater in early middle-aged (ie, 35–59 years) than in older patients, so that diabetes was associated with an almost six times higher occlusive vascular death rate among women aged 35–59 years, even after controlling for other established major vascular risk factors. At any given age, the underlying confounder-adjusted occlusive vascular death rates were higher for men than for women, so despite higher death RRs among women than among men, we estimate that the absolute excess risk of occlusive vascular mortality associated with diabetes was similar in men and women. The adjusted occlusive vascular mortality rates among women with diabetes aged 35–59 or 60–69 years were similar to those among men without diabetes of a similar age ( table ). Sex differences in the relative excess of occlusive vascular risk associated with diabetes have been reported in several studies, 3,4,15,16 but most have not considered how this relative excess risk translates to absolute excess risk. By contrast with these studies, the main strength of our analysis is the inclusion of studies with complete availability of baseline information on systolic and diastolic blood pressure, total cholesterol, BMI, and smoking status in a large number of apparently healthy people (ie, without occlusive vascular disease) followed up prospectively. Underprescription of cardiovascular-risk-modifying therapy among women has been described, 17 but since many of the cohort studies included in our meta-analysis were completed before the introduction of statin therapy and widespread screening for high blood pressure for primary prevention, our findings suggest that underprescription among women is unlikely to account for the differences between the sexes in our calculated diabetes death RRs. Indeed, our findings remain relevant, since results from a study of 1·9 million patients in an English primary-care database who were identified and followed up between 1998 and 2010 showed that relative risks for non-fatal ischaemic heart disease were somewhat higher among women than among men, even after adjustment for disease management via antihypertensive medication and statin use 16 (which are similarly efficacious in both sexes 18,19 ). However, sex differences in the management of cardiac disease during and after treatment in hospital might, to some extent, help to account for the higher diabetes death RRs among women than among men. 20 Several hypotheses that could account for sex differences in diabetes-associated vascular risk remain unexplored. Hormone-replacement therapy has been shown to increase cardiovascular risk, 21 and both oestrogens and androgens can affect lipid metabolism; 22 therefore, future analyses considering sex-hormone concentrations and subclasses of lipids would be of interest. 23–25 Sex differences in inflammation might also exist, 26 and since targeting interleukin-1β can reduce occlusive vascular risk, 27 inflammation should be a focus of future research aimed at devising novel therapeutic approaches. The main limitation of this study was the absence of phenotypic information on diabetes and its complications, which have been shown to affect risk (eg, type of diabetes, glycaemic control, 3 duration of diabetes, 28 and the presence of complications such as renal disease 29 ). Other studies have considered these factors, but rarely are all factors comprehensively measured, and whether sex differences in diabetes phenotype could account for sex differences in the relation of diabetes with occlusive vascular mortality risk is unclear. For example, type 1 diabetes might be associated with high cardiovascular risk, 30 but among adults with diabetes the proportion who have type 1 diabetes is usually low in most populations (3–15%) and, if anything, this proportion is higher in men than in women. 31 Differences in glycaemic control are also not a clear explanation for sex differences observed in the English primary care study of 1·9 million patients, 16 since diabetes was associated with a somewhat higher risk of ischaemic heart disease in women than in men despite similar prescription of diabetes treatments, and glycaemic control being, if anything, slightly better in women than in men. 16 However, in a prospective study of 150 000 Hispanic adults from Mexico City, Mexico, 5 no difference was seen between men and women in the diabetes death RR for vascular causes (or for all causes combined). Notably, both men and women in that study had a similar duration of diabetes and similarly poor glycaemic control. Additionally, our meta-analysis does not take into account the effects of undiagnosed diabetes at baseline or the development of new diabetes during follow-up. However, among participants with glucose measurements, only 2% of those not reporting a diagnosis at baseline had measurements that indicated the presence of undiagnosed diabetes, and, therefore, if a similarly small percentage of participants developed diabetes during follow-up then the reported death RRs would not be greatly affected since these people would contribute only a very small proportion of those classified as not having diabetes at baseline. Another limitation of this study is that the cohorts were recruited some years ago, with baseline data ranging from 1949 to 1997. Although this aspect of the study also has some advantages (primarily that the participants were recruited before widespread treatment with statins or blood-pressure-lowering medication), we must recognise that treatment of both diabetes and vascular risk factors have changed substantially over the past few decades and these changes might affect the current vascular risks associated with a diagnosis of diabetes. Hence, analysis of recently established and future prospective cohorts is needed to assess whether developments in the treatment of both diabetes and vascular risk factors over the past few decades are having any effect on contemporary diabetes-associated risks and on the age and sex differences in these associations. Our analyses showed that the strength of the association of total cholesterol and BMI with occlusive vascular mortality risk was similar irrespective of the presence of diabetes, and that at any level of these risk factors, diabetes carries a substantially increased risk ( figure 3 ). Hence, the absolute relevance of these risk factors to occlusive vascular disease would be greater for people with diabetes than those without. Although the association between systolic blood pressure and occlusive vascular mortality risk was slightly weaker among participants with diabetes, the absolute relevance to risk would again be greater among those with diabetes than those without diabetes. In the WHO 2013–20 non-communicable disease global plan targets, 32 one of the main priorities is a 25% reduction in the risk of premature mortality from cardiovascular diseases and diabetes by 2025 relative to 2013. The continuous nature of the associations of conventional risk factors with vascular events among people with diabetes in our analyses supports data from randomised trials 33,34 that suggest that the vascular benefits of intensive versus recommended standard blood-pressure-lowering medications and targets are similar among those with and without diabetes, and support the existing guideline recommendation 35 favouring treatment of absolute risk of disease rather than threshold concentrations of cholesterol. Since the relevance of blood pressure, blood cholesterol, and BMI to occlusive vascular mortality risk was broadly similar among people with and without diabetes, the absolute benefits of strategies to achieve effective lowering of these multiple risk factors in both women and men with diabetes will help to achieve global health priorities. However, the use of only these strategies would not be expected to reduce all the relative excess of diabetes-associated vascular risk seen among women, since this excess risk does not seem to be explained by these traditional major vascular risk factors. Correspondence to: Dr Sarah Lewington, MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK firstname.lastname@example.org Contributors Louisa Gnatiuc, William G Herrington, Jonathan R Emberson, Mark Woodward, and Sarah Lewington specified the analyses. Jim Halsey, Paul Sherliker, and Sarah Lewington analysed the data. Louisa Gnatiuc, William G Herrington, and Sarah Lewington wrote the first draft of the report. All members of the writing committee contributed to the revision of the report. All collaborators had an opportunity to contribute to the interpretation of the results and to redrafting of the report. The writing committee accepts full responsibility for the content of this report. Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration Writing committee: Louisa Gnatiuc* (University of Oxford, Oxford, UK), William G Herrington* (University of Oxford, Oxford, UK), Jim Halsey (University of Oxford, Oxford, UK), Prof Jaakko Tuomilehto (Dasman Diabetes Institute, Dasman, Kuwait; National Institute for Health and Welfare, Helsinki, Finland; and King Abdulaziz University, Jeddah, Saudi Arabia), Prof Xianghau Fang (Xuanwu Hospital, Capital Medical University, Beijing, China), Prof Hyeon C Kim (Yonsei University College of Medicine, Seoul, South Korea), Prof Dirk DeBacquer (Ghent University, Ghent, Belgium), Prof Annette J Dobson (University of Queensland, Brisbane, QLD, Australia), Prof Michael H Criqui (University of California San Diego, La Jolla, CA, USA), Prof David R Jacobs Jr (University of Minnesota, Minneapolis, MN, USA), Prof David A Leon (London School of Hygiene & Tropical Medicine, London, UK; and UiT The Arctic University of Norway, Tromsø, Norway), Sanne A E Peters (University of Oxford, Oxford, UK), Prof Hirotsugu Ueshima (Shiga University of Medical Science, Shiga, Japan), Paul Sherliker (University of Oxford, Oxford, UK), Prof Richard Peto (University of Oxford, Oxford, UK), Prof Rory Collins (University of Oxford, Oxford, UK), Prof Rachel R Huxley (La Trobe University, Melbourne, VIC, Australia), Jonathan R Emberson* (University of Oxford, Oxford, UK), Prof Mark Woodward* (University of Oxford, Oxford, UK; UNSW, Sydney, NSW, Australia; and Johns Hopkins University, Baltimore, MA, USA), Sarah Lewington* (University of Oxford, Oxford, UK). *Contributed equally. Principal collaborators: Europe and the Middle East : BIRNH (Belgian Inter-university Research on Nutrition and Health) G De Backer, D De Bacquer, M Kornitzer; BRHS (British Regional Heart Study) R Morris, S G Wannamethee, P Whincup; BUPA (British United Provident Association) M Law, J Morris, N Wald; (CB Project) D Kromhout; IPC (Centre d'Investigations Preventives et Cliniques Paris) A Benetos, L Guize; (Copenhagen City Heart Study) G Jensen, P Schnohr; (Finrisk) P Jousilahti, P Puska, J Tuomilehto, E Vartiainen; FMCS (Finnish Mobile Clinic Survey) A Aromaa, P Knekt, A Reunanen; (Glostrup Population Studies, Research Centre for Prevention and Health) N Borup Johansen, T Thomsen; (Gothenburg Prospective Study of Women) C Bengtsson, C Björkelund, L Lissner; (Israeli Ischaemic Heart Disease Study) U Goldbourt; (Norwegian Counties Study) R Selmer, A Tverdal; NPHS (Norwich Park Heart Study) T Meade; (Oslo Study) L Haheim, I Hjermann, I Holme, P Leren; (Paris Prospective Study) P Ducimetiere, J Empana; PROCAM (Prospective Cardiovascular Munster Study) G Assmann, H Schulte; (Renfrew/Paisley Study) G Davey Smith, C Hart, D Hole; SHHS (Scottish Heart Health Study) H Tunstall-Pedoe; (Caerphilly and Speedwell Study) G Davey Smith, P Sweetnam, J Yarnell; (Tromso Study) E Arnesen, K Bonaa; UKHDPP (United Kingdom Heart Disease Prevention Project) H Tunstall-Pedoe; (Whitehall Study) D A Leon, M Marmot, M Shipley; (West of Scotland Study) G Davey Smith, C Gillis, C Hart, D Hole. North America and Australasia: ARIC (Atherosclerosis Risk in Communities) L Chambless; (Australian Longitudinal Study of Aging) M Luszcz; (Australian National Heart Foundation) S S Dhaliwal, T A Welborn; (Busselton Health Study) H Bartholomew, M W Knuiman; (Cardiovascular Health Study) R Kronmal; (Charleston Study) P J Nietert, S E Sutherland, D L Bachman, P Gazes, E Boyle; (Fletcher Challenge) R Jackson, S MacMahon, R Norton, G Whitlock (deceased); NHLBI FHS (National Heart, Lung, and Blood Institute Framingham Heart Study) R D'Agostino, D Levy, H Silbershatz; (Honolulu Heart Program) J D Curb, D Sharp; (Melbourne Collaborative Cohort) G G Giles; (The Miyama study) S Hashimoto, K Sakata; (Minnesota Heart Survey) H Blackburn, D Jacobs, R Luepker; (Newcastle study) A Dobson; NHEFS (The First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study) C Cox; (Perth study) R Broadhurst, M Hobbs, K Jamrozik; (Puerto Rico Health Heart Program) M Garcia-Palmieri, P Sorlie; (The Tecumseh Community Health Study) J Keller; (US Health Professionals Follow-up Study) M Guasch-Ferre, F Hu; and (US Nurses' Health Study II) W Willett, H Eliassen. Southeast Asia: (Aito Town study) H Maegawa, A Okayama, H Ueshima; (Akabane study) N Aoki, M Nakamura; (Anzhen 2 study) Z L Wu; (Beijing Ageing) X Shifu; (Civil Service Workers) A Tamakoshi; EGAT (Electricity Generating Authority of Thailand) P Sritara; (Fangshan Cohorts) X F Duan, D F Gu; (Guangzhou Occupational Cohort) C Q Jiang, T H Lam; (Hong Kong study) S C Ho, J Woo; (Ikawa study) H Iso, A Kitamura, Y Naito, S Sato; (Japan Railways) T Murayama, Y Nishimoto, M Tomita; KMIC (Korean Medical Insurance Cohort) S H Jee, I S Kim, I Suh; (Kounan study) H Ueshima, Y Kita, I Niki; (Kyowa Studies) H Iso, A Kitamura, Y Naito, S Sato; (The Miyama Study) T Hashimoto; (Noichi Studies) H Iso, A Kitamura, Y Naito, S Sato; (The Ohasama Study): A Hozawa, Y Imai, T Ohkubo; (Saitama Cohort Study) K Imai, K Nakachi; (The Shibata Study) C Date, T Nakayama, T Yokoyama, N Yoshiike, H Tanaka; (The Shigaraki Town Study) Y Kita, A Nozaki, H Ueshima; (The Shirakawa Study) H Horibe, M Kagaya, Y Matsutani; (Singapore Heart & Thyroid) K Hughes, J Lee; NHS92 (Singapore National Health Survey 1992) S K Chew, D Heng; (Tanno and Soubetsu Studies) S Saitoh, K Shimamoto; CVDFACTS (Two Township Study in Taiwan) W H Pan; and (Yunnan Tin Miner Study) S X Yao. Prospective Studies Collaboration Steering Committee: S Lewington (coordinator), S MacMahon (chairman), R Peto, A Aromaa, C Baigent, J Carstensen, Z Chen, R Clarke, R Collins, S Duffy, D Kromhout, J Neaton, N Qizilbash, A Rodgers, S Tominaga, S Törnberg, H Tunstall-Pedoe, G Whitlock (deceased). Asia Pacific Cohort Studies Collaboration Executive Committee: D Bennett, D Gu, H Horibe, R Huxley, S MacMahon, WH Pan, A Rodgers, I Suh, H Ueshima, M Woodward, Z L Wu, X H Zhang. Declaration of interests William G Herrington has received grant support from Boehringer Ingelheim. Rory Collins has received grant support from British United Provident Association (BUPA), Abbott Solvay, Bayer, AstraZeneca, GlaxoSmithKline, Merck, Liposcience, Novartis, and Pfizer. All other writing committee members declare no competing interests. Acknowledgments The Prospective Studies Collaboration has been supported by the UK Medical Research Council (MRC), British Heart Foundation, Cancer Research UK, European Union BIOMED programme, National Institute on Aging (US National Institutes of Health) grant P01 AG17625–01, and Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) overheads. Merck helped to support the 1996 meeting of collaborators. Sarah Lewington had a British Heart Foundation Fellowship to coordinate this project. Sanne A E Peters is supported by an MRC Skills Development Fellowship (MR/P014550/1). William G Herrington is supported by an MRC and Kidney Research UK Prof David Kerr Clinician Scientist Award. The University of Oxford MRC Population Health Research Unit is funded through a strategic partnership between the MRC and the University of Oxford.
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license