Aims/hypothesis
A previous pooled analysis suggested that women with diabetes are at substantially increased risk of fatal CHD compared with affected men. Additional findings from several larger and ...more contemporary studies have since been published on the sex-specific associations between diabetes and incident CHD. We performed an updated systematic review with meta-analysis to provide the most reliable evidence of any sex difference in the effect of diabetes on subsequent risk of CHD.
Methods
PubMed MEDLINE was systematically searched for prospective population-based cohort studies published between 1 January 1966 and 13 February 2013. Eligible studies had to have reported sex-specific RR estimates for incident CHD associated with diabetes and its associated variability that had been adjusted at least for age. Random-effects meta-analyses with inverse variance weighting were used to obtain sex-specific RRs and the RR ratio (RRR) (women:men) for incident CHD associated with diabetes.
Results
Data from 64 cohorts, including 858,507 individuals and 28,203 incident CHD events, were included. The RR for incident CHD associated with diabetes compared with no diabetes was 2.82 (95% CI 2.35, 3.38) in women and 2.16 (95% CI 1.82, 2.56) in men. The multiple-adjusted RRR for incident CHD was 44% greater in women with diabetes than in men with diabetes (RRR 1.44 95% CI 1.27, 1.63) with no significant heterogeneity between studies (
I
2
= 20%).
Conclusions/interpretation
Women with diabetes have more than a 40% greater risk of incident CHD compared with men with diabetes. Sex disparities in pharmacotherapy are unlikely to explain much of the excess risk in women, but future studies are warranted to more clearly elucidate the mechanisms responsible for the substantial sex difference in diabetes-related risk of CHD.
Obesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, ...it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death. We constructed sex-specific genetic risk scores (GRS) for three obesity traits; body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI, including 565, 324, and 337 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality in the UK Biobank using Mendelian randomization. We also investigated associations with potential mediators, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran's Q-test (Phet). A Mendelian randomization analysis of 228,466 women and 195,041 men showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. Higher BMI led to higher risk of type 2 diabetes in women than in men (Phet = 1.4×10-5). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet = 3.7×10-6) and higher risk of chronic renal failure (Phet = 1.0×10-4) in men than women. Obesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have downstream implications for public health.
Women's reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated ...with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank.
A total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche <12 years and 1.19 (1.07, 1.34) (p = 0.024) for menarche >14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth <21 compared to 25 to 26 years; 0.82 (0.71, 0.94) (p = 0.006) for each abortion; 1.32 (1.15, 1.51) (p = 0.008) for natural menopause at <47 compared to 50 years; 1.12 (1.01, 1.25) (p = 0.039) for hysterectomy; 2.35 (1.06, 5.23) (p = 0.037) for hysterectomy with previous oophorectomy; and 0.80 (0.72, 0.88) (p < 0.001) for oral contraceptive pills use. The U-shaped associations between the number of children and the risk of dementia were similar for both sexes: Compared with those with 2 children, for those without children, the multiple adjusted HR ((95% CIs), p-value) was 1.18 (1.04, 1.33) (p = 0.027) for women and 1.10 (0.98, 1.23) (p = 0.164) for men, and the women-to-men ratio of HRs was 1.09 (0.92, 1.28) (p = 0.403); for those with 4 or more children, the HR was 1.14 (0.98, 1.33) (p = 0.132) for women and 1.26 (1.10, 1.45) (p = 0.003) for men, and the women-to-men ratio of HRs was 0.93 (0.76, 1.14) (p = 0.530). There was evidence that hysterectomy (HR, 1.31 (1.09, 1.59), p = 0.013) and oophorectomy (HR, 1.39 (1.08, 1.78), p = 0.002) were associated with a higher risk of dementia among women of relatively lower SES only. Limitations of the study include potential residual confounding and self-reported measures of reproductive factors, as well as the limited representativeness of the UK Biobank population.
In this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men.
Aims/hypothesis
The prevalence of diabetes and heart failure is increasing, and diabetes has been associated with an increased risk of heart failure. However, whether diabetes confers the same excess ...risk of heart failure in women and men is unknown. The aim of this study was to conduct a comprehensive systematic review with meta-analysis of possible sex differences in the excess risk of heart failure consequent to diabetes. Our null hypothesis was that there is no such sex difference.
Methods
A systematic search was conducted in PubMed for population-based cohort studies published between January 1966 and November 2018. Studies were selected if they reported sex-specific estimates of RRs for heart failure associated with diabetes, and its associated variability, which were adjusted at least for age. Random-effects meta-analyses with inverse variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratio of RRs (RRRs) for heart failure associated with diabetes.
Results
Data from 47 cohorts, involving 12,142,998 individuals and 253,260 heart failure events, were included. The pooled multiple-adjusted RR for heart failure associated with type 1 diabetes was 5.15 (95% CI 3.43, 7.74) in women and 3.47 (2.57, 4.69) in men, leading to an RRR of 1.47 (1.44, 1.90). Corresponding pooled RRs for heart failure associated with type 2 diabetes were 1.95 (1.70, 2.22) in women and 1.74 (1.55, 1.95) in men, with a pooled RRR of 1.09 (1.05, 1.13).
Conclusions/interpretation
The excess risk of heart failure associated with diabetes is significantly greater in women with diabetes than in men with diabetes.
PROSPERO registration: CRD42019135246
Aims/hypothesis
Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown.
Methods
A ...systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers.
Results
Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer.
Conclusions/interpretation
Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer.
Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men ...remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia.
A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses.
Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 95% CI 1.45-1.80; men: pooled RR 1.58 95% CI 1.38-1.81). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 95% CI 1.08-1.30; P < 0.001).
Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.
Summary Background Diabetes mellitus is a major cause of death and disability worldwide and is a strong risk factor for stroke. Whether and to what extent the excess risk of stroke conferred by ...diabetes differs between the sexes is unknown. We did a systematic review and meta-analysis to estimate the relative effect of diabetes on stroke risk in women compared with men. Methods We systematically searched PubMed for reports of prospective, population-based cohort studies published between Jan 1, 1966, and Dec 16, 2013. Studies were selected if they reported sex-specific estimates of the relative risk (RR) for stroke associated with diabetes, and its associated variability. We pooled the sex-specific RRs and their ratio comparing women with men using random-effects meta-analysis with inverse-variance weighting. Findings Data from 64 cohort studies, representing 775 385 individuals and 12 539 fatal and non-fatal strokes, were included in the analysis. The pooled maximum-adjusted RR of stroke associated with diabetes was 2·28 (95% CI 1·93–2·69) in women and 1·83 (1·60–2·08) in men. Compared with men with diabetes, women with diabetes therefore had a greater risk of stroke—the pooled ratio of RRs was 1·27 (1·10–1·46; I2 =0%), with no evidence of publication bias. This sex differential was seen consistently across major predefined stroke, participant, and study subtypes. Interpretation The excess risk of stroke associated with diabetes is significantly higher in women than men, independent of sex differences in other major cardiovascular risk factors. These data add to the existing evidence that men and women experience diabetes-related diseases differently and suggest the need for further work to clarify the biological, behavioural, or social mechanisms involved. Funding None.
To investigate sex differences in risk factors for incident myocardial infarction (MI) and whether they vary with age.
Prospective population based study.
UK Biobank.
471 998 participants (56% women; ...mean age 56.2) with no history of cardiovascular disease.
Incident (fatal and non-fatal) MI.
5081 participants (1463 (28.8%) of whom were women) had MI over seven years' mean follow-up, resulting in an incidence per 10 000 person years of 7.76 (95% confidence interval 7.37 to 8.16) for women and 24.35 (23.57 to 25.16) for men. Higher blood pressure indices, smoking intensity, body mass index, and the presence of diabetes were associated with an increased risk of MI in men and women, but associations were attenuated with age. In women, systolic blood pressure and hypertension, smoking status and intensity, and diabetes were associated with higher hazard ratios for MI compared with men: ratio of hazard ratios 1.09 (95% confidence interval 1.02 to 1.16) for systolic blood pressure, 1.55 (1.32 to 1.83) for current smoking, 2.91 (1.56 to 5.45) for type 1 diabetes, and 1.47 (1.16 to 1.87) for type 2 diabetes. There was no evidence that any of these ratios of hazard ratios decreased with age (P>0.2). With the exception of type 1 diabetes, the incidence of MI was higher in men than in women for all risk factors.
Although the incidence of MI was higher in men than in women, several risk factors were more strongly associated with MI in women compared with men. Sex specific associations between risk factors and MI declined with age, but, where it occurred, the higher relative risk in women remained. As the population ages and the prevalence of lifestyle associated risk factors increase, the incidence of MI in women will likely become more similar to that in men.
Studies have suggested that women's reproductive factors are associated with the risk of cardiovascular disease (CVD); however, findings are mixed. We assessed the relationship between reproductive ...factors and incident CVD in the UK Biobank.
Between 2006 and 2010, the UK Biobank recruited over 500 000 participants aged 40-69 years across the UK. During 7 years of follow-up, 9054 incident cases of CVD (34% women), 5782 cases of coronary heart disease (CHD) (28% women), and 3489 cases of stroke (43% women) were recorded among 267 440 women and 215 088 men without a history of CVD at baseline. Cox regression models yielded adjusted hazard ratios (HRs) for CVD, CHD and stroke associated with reproductive factors.
Adjusted HRs (95% CI) for CVD were 1.10 (1.01 to 1.30) for early menarche (<12 years), 0.97 (0.96 to 0.98) for each year increase in age at first birth, 1.04 (1.00 to 1.09) for each miscarriage, 1.14 (1.02 to 1.28) for each stillbirth, and 1.33 (1.19 to 1.49) for early menopause (<47 years). Hysterectomy without oophorectomy or with previous oophorectomy had adjusted HRs of 1.16 (1.06 to 1.28) and 2.30 (1.20 to 4.43) for CVD. Each additional child was associated with a HR for CVD of 1.03 (1.00 to 1.06) in women and 1.03 (1.02 to 1.05) in men.
Early menarche, early menopause, earlier age at first birth, and a history of miscarriage, stillbirth or hysterectomy were each independently associated with a higher risk of CVD in later life. The relationship between the number of children and incident CVD was similar for men and women.
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