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

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.

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).

Figure 1

Age-specific and sex-specific relevance of diabetes at study recruitment to occlusive vascular mortality Analyses are stratified by study and adjusted for age at risk, BMI, systolic and diastolic blood pressure, total cholesterol, and smoking status. Each diamond is the inverse-variance weighted average of the two estimates for men and women. The size of the blocks reflects the amount of statistical information (ie, the inverse-variance of the log death RR). RR=rate ratio.

Figure 2

Sex-specific relevance of diabetes at study recruitment to occlusive vascular mortality at ages 35–89 years, by baseline BMI (A), total cholesterol (B), systolic blood pressure (C), and smoking status (D) Each risk factor was split into three strata; approximate thirds for the range of values for BMI, total cholesterol, and systolic blood pressure, and three categories for smoking status. Analyses are stratified by study and adjusted for age at risk, BMI, systolic and diastolic blood pressure, total cholesterol, and smoking status (apart from the analyses stratified by smoking status). Each diamond is the inverse-variance weighted average of the two estimates for men and women. The size of the block reflects the amount of statistical information (ie, the inverse-variance of the log death RR). RR=rate ratio. *Includes ex-smokers of any type of tobacco, current smokers of other types of tobacco, or smoking status not known.

Figure 3

Relevance of total cholesterol (A), systolic blood pressure (B), and BMI (C) to RR of occlusive vascular mortality at ages 35–89 years, by diabetes status at study recruitment Analyses are stratified by study and sex, and adjusted for age at risk, smoking status, and, if appropriate, total cholesterol, systolic and diastolic blood pressure, and BMI. Usual total cholesterol and systolic blood pressure are the long-term average level of that risk factor. Regression dilution ratios of 0·65 for total cholesterol and 0·67 for systolic blood pressure were calculated by regressing serial measurements from 175 000 participants with at least one re-measurement, on average, 3 years later, on baseline levels of these risk factors. No such adjustment was applied for BMI, since one single measurement at baseline was highly correlated with long-term BMI. The vertical lines through the plotted boxes are 95% CIs that reflect only the variance of the log risk in that group (and are therefore shown for every group including the reference group), and the size of each box reflects the amount of statistical information. RR=rate ratio.

Figure 4

Sex-specific relevance of diabetes at study recruitment to cause-specific and all-cause mortality at ages 35–89 years Analyses are stratified by study and adjusted for age at risk, BMI, systolic and diastolic blood pressure, total cholesterol, and smoking status. Each diamond is the inverse-variance weighted average of the two estimates for men and women. The size of the block reflects the amount of statistical information (ie, the inverse-variance of the log death RR). RR=rate ratio. *Except for deaths attributed directly to diabetes, including acute diabetic crises (ICD-9 code 250), which occurred among 107 of the participants with diabetes at recruitment and 35 of the participants without diabetes at recruitment.