Sex differences in the association between diabetes and risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality: a systematic review and meta-analysis of 5,162,654 participants

According to the Global Burden of Disease Study (GBD), non-communicable diseases (NCDs) are the main cause of premature deaths amongst the world’s population [1]. As one of four main NCDs, diabetes affected an estimated 387 million people throughout the world and caused around 1.3 million deaths worldwide in 2010 alone [2‐4]. With the increasing prevalence of physical inactivity and obesity, the burden of diabetes is predicted to increase to 592 million by 2035, making it a major contributor to the global burden of disease [5].

Type 2 diabetes mellitus is associated with an approximate twofold increase in the risk of all-cause mortality as well as death from cardiovascular disease (CVD), kidney disease, infectious disease, respiratory disease, and several specific forms of cancer [6]. Previous meta-analyses, through internal, within-study comparisons of female and male participants, have observed that women with diabetes are at substantially higher risk of coronary heart disease (CHD), stroke, and gastric cancer compared to affected men. On the other hand, no sex differences were found between diabetes and the risk of esophageal cancer, colorectal cancer, and pancreatic cancer [7‐9]. However, the magnitude of the excess risk of these and other cause-specific outcomes that are conferred by diabetes for men and women is unknown. Furthermore, it is unclear whether important confounders (e.g., age) and methodological heterogeneity (duration of follow-up, method of diabetes classification or assessment) would modify any such sex differential in the association between diabetes and mortality. It is also unclear whether such a difference might be more pronounced in recent years with the growing obesity epidemic (e.g., year of publication).

Accordingly, we sought to conduct a meta-analysis of prospective cohort studies in order to (i) calculate any sex differential in the association between diabetes and risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality for the general population and (ii) to determine whether these associations are modified by demographics, setting, length of follow-up, diabetes measurement, and recency of publication.

Of the 24,303 references identified through the systematic search, 375 were examined in the full-text review (Fig. 1). In addition, 6 articles were retrieved from the reference lists of relevant articles and reviews. Subsequently, individual participant data from NHIS were added to these published results. Finally, 49 studies with 86 prospective cohorts met the inclusion criteria and [17‐63] were eligible for analysis (Table 1).

The characteristics of the included studies are described in Table 1. Baseline surveys were conducted between 1950 and 2014, and the number of participants ranged from 379 to 1,298,358. The mean/median duration of follow-up ranged from 6.0 to 21.4 years, while the average baseline age was between 33.3 and 80.0 years. The quality of all included studies based on NOS was high (Additional file 1: Table S2). All studies adjusted for age and most of the studies also controlled for smoking (n = 77), hypertension (n = 71), and body mass index (n = 68).

Twenty-eight studies with 3,887,585 participants were included to assess the sex-specific association between diabetes and all-cause mortality. For cause-specific mortality, 14 studies with 4,482,501 reported on cancer mortality, 23 studies with 2,067,486 reported on CVD mortality, 23 studies with 2,050,929 reported on CHD mortality, 15 studies with 2,292,387 reported on stroke mortality, 4 studies with 1,633,520 reported on respiratory disease mortality, and 3 studies with 1,638,651 reported on infectious disease mortality.

This systematic review and meta-analysis of 49 studies with 86 prospective cohorts found that diabetes conferred a greater risk for almost all outcomes of interest. Diabetes appears to be a stronger risk factor for CHD, CVD, and all-cause mortality in women than in men. Of note, compared to men with diabetes, women with the same condition had 57% excess risk for CHD. Although diabetes was associated with a higher risk of cancer mortality, infectious disease, and respiratory disease mortality, we did not observe a sex difference between diabetes and mortality. Interestingly, however, these results were only upheld in studies that used self-reporting measures to identify diabetes cases.

Diabetologists and epidemiologists have long been aware that diabetes has pronounced cardiovascular consequences for women, irrespective of diabetes type [10, 28, 64]. Indeed, CVD is the leading cause of morbidity and mortality for individuals with diabetes, which accounts for > 50% of all deaths [65]. We found that for women, diabetes confers a 54% excess risk of CHD death. While such sex-specific differences are of increasing interest in cardiology and medical fields, the underpinning mechanisms driving this association are not entirely clear. The pathogenesis seems to be multifactorial with contributions from sex differences in genetic and biological factors, gender disparities from cultural and environmental factors, and the well-documented differences in the diagnosis, management, and treatment of DM and CVD of women and men [66‐68].

The putative biological mechanisms have centered on the effects of estrogen which can deplete during menopause to elevate women’s CHD risk [69]. Testosterone may be involved in different mechanisms attributed to sex differential in CHD risk [70‐72]. In men, higher total testosterone levels are associated with reduced risk of future CHD and ischemic stroke. Testosterone has anabolic effects, promoting muscle mass and strength [73]. The recent prospective cohort study of half a million UK Biobank participants showed that higher grip strength was associated with a lower risk of incidence of and mortality from CVD [74]. Compared with men, women with lower testosterone levels have low mass and strength of muscle, which also partially explain greater risk for CHD death conferred by diabetes in women compared with men.

Women with diabetes are more likely to have poor risk factor profiles and suffer greater disease risk owing to the effects of individual risk factors. A recent meta-analysis showed that smoking conferred 25% excess risk for CHD in women than in men [7]. In addition, women with diabetes remain less likely to achieve high-density lipoprotein cholesterol targets and have a higher prevalence of obesity than men [75‐77]. Whether existing sex differences in diabetic heart disease are magnified by sex differences in traditional and modifiable cardiac risk factors requires consideration. Recently, a meta-analysis of individual data from 68 prospective studies showed that body mass index, blood pressure, and total cholesterol each had continuous log-linear associations with CHD or stroke mortality that were similar in strength among those with and those without diabetes, irrespective of sex [78]. Our other study found that compared with men with metabolic syndrome, women with metabolic syndrome had a significant 16% higher risk of CHD incidence (RRR 1.16, 95% CI 1.01 to 1.34; P = 0.04), and the significant sex difference disappeared in non-diabetes population (RRR 0.92, 95% CI 0.73 to 1.17; P = 0.50). This partly supported the hypothesis that the stronger detrimental effects of diabetes for women than for men in CVD could not be explained by the different levels of established major CVD risk factors and their clusters. Differences in the clinical manifestation of diabetes warrants further consideration. Prediabetes is associated with an increased risk of cardiovascular disease [79], and the sex differences in the non-physiological effects can be partly accounted for the diabetes-related excess risk of CVD in women. In the prediabetic state, impaired glucose tolerance may be more serious in women than in men [80, 81].

Biases embedded within health service need to be considered. There is evidence that women, compared to their male counterparts, are less likely to have their risk factors assessed by physicians when they present in primary care. Compared to older women at high risk of CVD, younger women at high risk were less likely to receive preventative treatment [82]. Indeed, women with diabetes or CVD are diagnosed later and have a lower frequency of statin therapy, aspirin use, and ACE inhibitor and β-blocker use than men [83]. Some studies observed lower medication adherence in women than in men [84, 85]. Where medication is adhered to, women do not always benefit to the same extent as men given the well-documented issues with under-representation of women in clinical trials [66]. What is more, younger women’s symptoms often present differently to those of men of the same age. There may be less myocardial ischemic preconditioning in women, and subsequently greater susceptibility to ischemia. Therefore, sex and gender disparities in treatment may exacerbate the sex differences in CVD owing to diabetes [86, 87].

Some studies show that the proportion of undiagnosed diabetes to total diabetes in men is higher than that in women [88, 89]. In studies that used self-reported measures to identify diabetes, there was a greater proportion of undiagnosed diabetes in men. It is possible that this concealed the true excess risk of mortality conferred by diabetes in men and subsequent sex-specific relative risk estimates that were calculated for women and men.

Our finding that diabetes elevates the risk of all-cancer mortality is in general agreement with previous reviews [90]. However, most have looked at site-specific cancers; sex-specific associations from which results have been inconsistent. One meta-analysis indicated that diabetes conferred a stronger positive relationship with kidney cancer mortality and gastric cancer risk in women than in men [91, 92]. Others have found that diabetes increased the risk of esophageal cancer and leukemia in men, but not in women [93, 94]. Prospective studies showed that HRs for non-cancer, non-vascular deaths among participants with diabetes, as compared to those without diabetes, were also significantly higher among women (women: HR 2.20, 95% CI 1.91 to 2.52; men: HR 1.58, 95% CI 1.41 to 1.76; P_interaction < 0.001). The absence of sex disparities for infectious disease and respiratory disease mortality did not contribute to the sex difference for non-cancer, non-vascular deaths [95]. Therefore, future research is needed to distinguish whether and to what extent the excess risk of cause-specific mortality from non-cancer, non-vascular deaths conferred by diabetes differs between the sexes, such as kidney disease mortality.

Our study demonstrated that women with diabetes have a greater risk of all-cause mortality, particularly from CHD, compared with men with the same condition. An increased understanding and appreciation of sex differences in the relationship between diabetes and risk of all-cause and CHD mortality is required given the substantial global and regional burden of NCDs. Women with diabetes should be treated and managed throughout their life course with the view to reduce the burden of other diseases related to diabetes. In the future, in-depth sex-specific analyses from randomized trials and other studies using approaches like Mendelian randomization are needed to clarify the biological, behavioral, or social mechanisms involved.