Sex Differences in the Burden and Complications of Diabetes

Purpose of the Review: To review the latest evidence on sex differences in the burden and complications of diabetes and discuss the potential explanations for the sex differences described. Recent Findings: Diabetes is a strong risk factor for vascular disease, with compelling evidence that the relative risks of vascular diseases conferred by diabetes are considerably greater in women than men. The mechanisms underpinning women’s excess relative risk of vascular disease from diabetes are unknown. Sex differences in the health care provided for the prevention, management, and treatment of diabetes and its complications could contribute to women’s greater excess relative risks of diabetes complications. However, since the excess risk of vascular disease is not seen for other major vascular risk factors, inherent biological factors may be more likely to be involved. In addition to other cardiometabolic pathways, the sex dimorphism in body composition and fat distribution may be particularly important in explaining women’s greater excess risk of the vascular complications of diabetes. Summary: There is strong evidence to suggest that diabetes is a stronger risk factor for vascular disease in women than men. Although several mechanisms may be involved, further research is needed to provide new and deeper insights into the mechanisms underpinning sex differences in the association between diabetes and vascular diseases. Such research will inform patients, health care professionals, and policy makers to ensure that women are not disproportionately affected by diabetes, and will help to reduce the burden in both sexes

Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events

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

Obesity as a risk factor for COVID-19 mortality in women and men in the UK Biobank: comparisons with influenza/pneumonia and coronary heart disease

Obesity is associated with severe COVID-19 outcomes, yet, it unclear whether the risk of COVID-19 mortality associated with obesity is similar between the sexes. We used data from the UK Biobank to assess the risk of COVID-19 mortality associated with various anthropometric measures in women and men. To put these results in context, we also compared these estimates with those for mortality from influenza/pneumonia and coronary heart disease (CHD). The analyses included 502,493 individuals (54% women), of whom 410 (36% women) died of COVID-19, 549 (36% women) died of influenza/pneumonia, and 3355 (19% women) died of CHD. A higher BMI, waist circumference, waist-to-hip ratio, and waist-to-height ratio were each associated with a greater risk of death from COVID-19, influenza/pneumonia, and CHD in both sexes, with the exception of the association between higher BMI and the risk of influenza/pneumonia death in men. A higher BMI was associated with a stronger risk of COVID-19 mortality in women than men; the women-to-men ratio of hazard ratios was 1.20 (95% confidence interval: 1.00; 1.43). This study demonstrates the role of obesity in COVID-19 mortality and shows that the relative effects of a higher BMI on COVID-19 mortality may be stronger in women than men. This article is protected by copyright. All rights reserved

Serum lipid traits and the risk of dementia: A cohort study of 254,575 women and 214,891 men in the UK Biobank

Background: Serum lipid traits are associated with cardiovascular disease, but uncertainty remains regarding their associations with dementia. Methods: From 2006 to 2010, 254,575 women and 214,891 men were included from the UK Biobank. Cox regression estimated overall and sex-specific hazard ratios (HRs) for apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL, LDL, total cholesterol, triglycerides, lipoprotein A, and various lipid ratios, by quarters and standard deviation (SD) higher, associated with all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD). Subgroup analyses by age and social deprivation were conducted. Findings: Over 11·8 years (median), 3734 all-cause dementia (1,716 women), 1231 AD and 929 VaD were recorded. Compared to respective lowest quarters, highest quarter of ApoA was associated with lower dementia risk (HR, [95% confidence interval (95% CI)]: 0·77 [0·69, 0·86]) while the highest quarter of ApoB was associated with greater risk (HR, 1·12 [1·01, 1·24]). Higher HDL/ApoA and ApoB/ApoA, were associated with greater risk of dementia (HR, 1·12 [1·00, 1·25], per standard deviation (SD), 1.23 [1·11, 1·37], per SD, respectively), LDL/ApoB was inversely associated (HR, 0·85 [0·76, 0·94], per SD. Higher triglycerides was associated with higher dementia risk in <60 years, but the inverse was observed for ≥60 years. Similar associations were observed for VaD and AD. Interpretation: Apolipoproteins, and their ratios, were associated with the risk of dementia. It may be prudent to consider apolipoproteins, along with circulating cholesterol, when assessing dementia risk. Funding: University of New South Wales, UK Medical Research Council, and the Australian National Health and Medical Research Council

Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals

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

The association of energy and macronutrient intake with all-cause mortality, cardiovascular disease and dementia: findings from 120 963 women and men in the UK Biobank

This study aimed to investigate the association between individual and combinations of macronutrients with premature death, CVD and dementia. Sex differences were investigated. Data were utilised from a prospective cohort of 120 963 individuals (57 % women) within the UK Biobank, who completed ≥ two 24-h diet recalls. The associations of macronutrients, as percentages of total energy intake, with outcomes were investigated. Combinations of macronutrients were defined using k-means cluster analysis, with clusters explored in association with outcomes. There was a higher risk of death with high carbohydrate intake (hazard ratios (HR), 95 % CI upper v. lowest third 1·13 (1·03, 1·23)), yet a lower risk with higher intakes of protein (upper v. lowest third 0·82 (0·76, 0·89)). There was a lower risk of CVD with moderate intakes (middle v. lowest third) of energy and protein (sub distribution HR (SHR), 0·87 (0·79, 0·97) and 0·87 (0·79, 0·96), respectively). There was a lower risk of dementia with moderate energy intake (SHR 0·71 (0·52, 0·96)). Sex differences were identified. The dietary cluster characterised by low carbohydrate, low fat and high protein was associated with a lower risk of death (HR 0·84 (0·76, 0·93)) compared with the reference cluster and a lower risk of CVD for men (SHR 0·83 (0·71, 0·97)). Given that associations were evident, both as single macronutrients and for combinations with other macronutrients for death, and for CVD in men, we suggest that the biggest benefit from diet-related policy and interventions will be when combinations of macronutrients are targeted

Serum lipid traits and the risk of dementia: A cohort study of 254,575 women and 214,891 men in the UK Biobank

Background Serum lipid traits are associated with cardiovascular disease, but uncertainty remains regarding their associations with dementia. Methods From 2006 to 2010, 254,575 women and 214,891 men were included from the UK Biobank. Cox regression estimated overall and sex-specific hazard ratios (HRs) for apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL, LDL, total cholesterol, triglycerides, lipoprotein A, and various lipid ratios, by quarters and standard deviation (SD) higher, associated with all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD). Subgroup analyses by age and social deprivation were conducted. Findings Over 11·8 years (median), 3734 all-cause dementia (1,716 women), 1231 AD and 929 VaD were recorded. Compared to respective lowest quarters, highest quarter of ApoA was associated with lower dementia risk (HR, [95% confidence interval (95% CI)]: 0·77 [0·69, 0·86]) while the highest quarter of ApoB was associated with greater risk (HR, 1·12 [1·01, 1·24]). Higher HDL/ApoA and ApoB/ApoA, were associated with greater risk of dementia (HR, 1·12 [1·00, 1·25], per standard deviation (SD), 1.23 [1·11, 1·37], per SD, respectively), LDL/ApoB was inversely associated (HR, 0·85 [0·76, 0·94], per SD. Higher triglycerides was associated with higher dementia risk in <60 years, but the inverse was observed for ≥60 years. Similar associations were observed for VaD and AD. Interpretation Apolipoproteins, and their ratios, were associated with the risk of dementia. It may be prudent to consider apolipoproteins, along with circulating cholesterol, when assessing dementia risk. Funding University of New South Wales, UK Medical Research Council, and the Australian National Health and Medical Research Council

Sex-specific associations of adiposity with cardiometabolic traits in the UK: A multi-life stage cohort study with repeat metabolomics

Background Sex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages. Methods and findings Data were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B-containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required. Conclusions The results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts