Development and validation of a lifetime prediction model for incident type 2 diabetes in patients with established cardiovascular disease: the CVD2DM model.

AIMS: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD. METHODS AND RESULTS: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D. CONCLUSION: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

In this study, we developed and externally validated the CVD2DM model, which predicts the 10-year and lifetime risk of type 2 diabetes (T2D) in individuals who already have cardiovascular disease (CVD). The key findings are as follows: The CVD2DM model is the first model to estimate the risk of developing T2D applicable in all patients with atherosclerotic CVD. The model is based on several factors available in clinical practice, such as age, fasting plasma glucose, family history of diabetes, and body mass index. It was developed in 19 281 patients from the UK Biobank. The model performed well in 3481 patients from the UCC-SMART study.Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Sex differences in modifiable risk factors for stroke incidence and recurrence: the UCC-SMART study.

BACKGROUND AND PURPOSE: Risk factors for stroke differ between women and men in general populations. However, little is known about sex differences in secondary prevention. We investigated if sex interacted with modifiable risk factors for stroke in a large arterial disease cohort. METHODS: Within the prospective UCC-SMART study, 13,898 patients (35% women) with atherosclerotic disease or high-risk factor profile were followed up to 23 years for stroke incidence or recurrence. Hypertension, smoking, diabetes, overweight, dyslipidemia, high alcohol use, and physical inactivity were studied as risk factors. Association between these factors and ischemic and hemorrhagic stroke incidence or recurrence was studied in women and men using Cox proportional hazard models and Poisson regression models. Women-to-men relative hazard ratios (RHR) and rate differences (RD) were estimated for each risk factor. Left-truncated age was used as timescale. RESULTS: The age-adjusted stroke incidence rate was lower in women than men (3.9 vs 4.4 per 1000 person-years), as was the age-adjusted stroke recurrence rate (10.0 vs 11.7). Hypertension and smoking were associated with stroke risk in both sexes. HDL cholesterol was associated with lower stroke incidence in women but not in men (RHR 0.49; CI 0.27-0.88; and RD 1.39; CI - 1.31 to 4.10). Overweight was associated with a lower stroke recurrence in women but not in men (RHR 0.42; CI 0.23-0.80; and RD 9.05; CI 2.78-15.32). CONCLUSIONS: In high-risk population, sex modifies the association of HDL cholesterol on stroke incidence, and the association of overweight on stroke recurrence. Our findings highlight the importance of sex-specific secondary prevention.

Aligning organisational priorities and implementation science for cancer research.

BACKGROUND: The challenge of implementing evidence into routine clinical practice is well recognised and implementation science offers theories, models and frameworks to promote investigation into delivery of evidence-based care. Embedding implementation researchers into health systems is a novel approach to ensuring research is situated in day-to-day practice dilemmas. To optimise the value of embedded implementation researchers and resources, the aim of this study was to investigate stakeholders' views on opportunities for implementation science research in a cancer setting that holds potential to impact on care. The research objectives were to: 1) Establish stakeholder and theory informed organisation-level implementation science priorities and 2) Identify and prioritise a test case pilot implementation research project. METHODS: We undertook a qualitative study using semi-structured interviews. Participants held either a formal leadership role, were research active or a consumer advocate and affiliated with either a specialist cancer hospital or a cancer alliance of ten hospitals. Interview data were summarised and shared with participants prior to undertaking both thematic analysis, to identify priority areas for implementation research, and content analysis, to identify potential pilot implementation research projects. The selected pilot Implementation research project was prioritised using a synthesis of an organisational and implementation prioritisation framework - the organisational priority setting framework and APEASE framework. RESULTS: Thirty-one people participated between August 2022 and February 2023. Four themes were identified: 1) Integration of services to address organisational priorities e.g., tackling fragmented services; 2) Application of digital health interventions e.g., identifying the potential benefits of digital health interventions; 3) Identification of potential for implementation research, including deimplementation i.e., discontinuing ineffective or low value care and; 4) Focusing on direct patient engagement e.g., wider consumer awareness of the challenges in delivering cancer care. Six potential pilot implementation research projects were identified and the EMBED project, to support clinicians to refer appropriate patients with cancer for genetic testing, was selected using the synthesised prioritisation framework. CONCLUSIONS: Using a theory informed and structured approach the alignment between strategic organisational priorities and implementation research priorities can be identified. As a result, the implementation research focus can be placed on activities with the highest potential impact.

Sex differences in risk factors for incident peripheral artery disease hospitalisation or death: Cohort study of UK Biobank participants.

BACKGROUND: Women with peripheral artery disease (PAD) often have atypical symptoms, late hospital presentations, and worse prognosis. Risk factor identification and management are important. We assessed sex differences in associations of risk factors with PAD. METHODS: 500,207 UK Biobank participants (54.5% women, mean age 56.5 years) without prior hospitalisation of PAD at baseline were included. Examined risk factors included blood pressure, smoking, diabetes, lipids, adiposity, history of stroke or myocardial infarction (MI), socioeconomic status, kidney function, C-reactive protein, and alcohol consumption. Poisson and Cox regressions were used to estimate sex-specific incidence of PAD hospitalisation or death, hazard ratios (HRs), and women-to-men ratios of HRs (RHR) with confidence intervals (CIs). RESULTS: Over a median of 12.6 years, 2658 women and 5002 men had a documented PAD. Age-adjusted incidence rates were higher in men. Most risk factors were associated with a higher risk of PAD in both sexes. Compared with men, women who were smokers or had a history of stroke or MI had a greater excess risk of PAD (relative to those who never smoked or had no history of stroke or MI): RHR 1.18 (95%CI 1.04, 1.34), 1.26 (1.02, 1.55), and 1.50 (1.25, 1.81), respectively. Higher high-density lipoprotein cholesterol (HDL-C) was more strongly associated with a lower risk of PAD in women than men, RHR 0.81 (0.68, 0.96). Compared to HDL-C at 40 to 60 mg/dL, the lowest level of HDL-C (≤40 mg/dL) was related to greater excess risk in women, RHR 1.20 (1.02, 1.41), whereas the highest level of HDL-C (>80 mg/dL) was associated with lower risk of PAD in women, but higher risk in men, RHR 0.50 (0.38, 0.65). CONCLUSIONS: While the incidence of PAD was higher in men, smoking and a history of stroke or MI were more strongly associated with a higher risk of PAD in women than men. HDL-C was more strongly associated with a lower risk of PAD in women than men.

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Sex hormones and the risk of myocardial infarction in women and men: a prospective cohort study in the UK Biobank.

OBJECTIVES: There is conflicting evidence around the role of sex hormones with cardiovascular outcomes. The aim of this study was to examine the association of sex hormones with the risk of myocardial infarction (MI) in pre- and post-menopausal women, and men in the UK Biobank. METHODS: The UK Biobank is a prospective population-based cohort study, that recruited over 500,000 (aged 40-69 years) women and men between 2006 and 2010. Sex specific cox regression models, estimating hazard ratios (HRs) and women to men ratio of HRs (RHR) with respective 95% confidence intervals (CI), were used to model the association of sex hormones [oestrogen, testosterone, oestrogen: testosterone (O/T) ratio, sex hormone-binding globulin (SHBG) and the free androgen index (FAI)], measured at study baseline, with incident MI for women and men. RESULTS: Data were from 479,797 participants [264,282 (55.1%) women] without a history of MI at study baseline. Over 12.5 years of follow-up, there were 4,908 MI events in women and 10,517 in men. Neither oestrogen nor testosterone were associated with MI in women and men after multiple adjustment. For men, but not women, a unit higher log-transformed O/T ratio was associated with a lower risk of MI 0.79 (0.65, 0.95) after adjustment for traditional CVD risk factors. The corresponding women to men RHR (95% CI) was 1.24 (0.99, 1.56). Higher SHBG (per unit) was also associated with a lower risk of MI in men 0.94 (0.89, 0.99), and not in women 1.02 (0.95, 1.09) after multiple adjustment, the corresponding women to men RHR (95% CI) was 1.09 (1.00, 1.18). Higher FAI was associated with a higher risk of MI in men 1.09 (1.02, 1.15), though not in women 0.97 (0.92, 1.02), the corresponding women to men RHR was 0.89 (0.82, 0.97). Finally, there were differential effects in the association of SHBG and FAI between pre- and post-menopausal women. CONCLUSIONS: A higher O/T ratio was associated with a lower risk of MI, and a higher FAI with a higher risk of MI after adjustment for CVD risk factors in men, but not in women. Thus, hormone ratios, rather than each alone, may play an important role in modulating the effect of MI.

There are conflicting findings surrounding the association of sex hormones and myocardial infarction (MI) (heart disease). In particular, high oestradiol levels in women are often thought to be protective and explain why the rates of heart disease are lower in women than men. For men, those with low levels of testosterone are often thought to be more prone to develop heart disease in their lifetimes.Our study presents a comprehensive analysis of the association of sex hormones (in isolation and also together via their ratios), in women and men using the large-scale UK Biobank.We found that neither oestrogen nor testosterone alone were associated with heart disease in women and men after accounting for cardiovascular risk factors, but the ratio of testosterone and oestrogen was associated with a lower risk of heart disease in men, though not in women. We also saw the association of sex hormone­binding globulin (SHBG), and free androgen index (FAI) (calculated by the ratio of total testosterone level to SHBG) with heart disease was different between women and men, and between pre- and post-menopausal women.This paper highlights the complex interplay between sex hormones with heart disease in the presence of age and cardiovascular risk factors. In particular the balance (ratio) of sex hormones maybe more important, rather than each in isolation, when exploring their association with heart disease.

Psychosocial Well-Being of Older Spouses During End-of-Life Caregiving for Their Partners With Cancer: A Phenomenological Study.

Specific burdens of older spousal caregivers often remain invisible, and spousal caregivers rarely receive the support they need to perform their role. To provide suitable support for spousal caregivers, it is crucial to develop a comprehensive understanding of their well-being, particularly during end-of-life caregiving. The aim of the current study was to gain more insight into the psychosocial well-being of older spouses engaged in end-of-life caregiving for their partners with cancer. This qualitative study uses a phenomenological approach with in-depth interviews conducted with older (aged ≥65 years) spousal caregivers of individuals who died of cancer. Eleven spouses participated in the study. Strains on psychosocial well-being during end-of-life caregiving fell into four major themes: The Disease Itself, The Caregiving Process, The Partner Relationship, and Support From Others. Results suggest that older spousal caregivers are experiencing issues that might be more pronounced due to their older age, for example, physical and emotional exhaustion and loneliness. Providing care is time-consuming and often leads to a reduced social network, which enhances loneliness. Moreover, as relationships with ailing partners changed and communication deteriorated, participants reported feeling more like a caregiver rather than a partner. [Journal of Gerontological Nursing, 48(6), 33-39.].

Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Breastfeeding Is Associated With a Reduced Maternal Cardiovascular Risk: Systematic Review and Meta-Analysis Involving Data From 8 Studies and 1 192 700 Parous Women.

Background Breastfeeding has been robustly linked to reduced maternal risk of breast cancer, ovarian cancer, and type 2 diabetes. We herein systematically reviewed the published evidence on the association of breastfeeding with maternal risk of cardiovascular disease (CVD) outcomes. Methods and Results Our systematic search of PubMed and Web of Science of articles published up to April 16, 2021, identified 8 relevant prospective studies involving 1 192 700 parous women (weighted mean age: 51.3 years at study entry, 24.6 years at first birth; weighted mean number of births: 2.3). A total of 982 566 women (82%) reported having ever breastfed (weighted mean lifetime duration of breastfeeding: 15.6 months). During a weighted median follow-up of 10.3 years, 54 226 CVD, 26 913 coronary heart disease, 30 843 stroke, and 10 766 fatal CVD events were recorded. In a random-effects meta-analysis, the pooled multivariable-adjusted hazard ratios comparing parous women who ever breastfed to those who never breastfed were 0.89 for CVD (95% CI, 0.83-0.95; I2=79.4%), 0.86 for coronary heart disease (95% CI, 0.78-0.95; I2=79.7%), 0.88 for stroke (95% CI, 0.79-0.99; I2=79.6%), and 0.83 for fatal CVD (95% CI, 0.76-0.92; I2=47.7%). The quality of the evidence assessed with the Grading of Recommendations Assessment, Development, and Evaluation tool ranged from very low to moderate, which was mainly driven by high between-studies heterogeneity. Strengths of associations did not differ by mean age at study entry, median follow-up duration, mean parity, level of adjustment, study quality, or geographical region. A progressive risk reduction of all CVD outcomes with lifetime durations of breastfeeding from 0 up to 12 months was found, with some uncertainty about shapes of associations for longer durations. Conclusions Breastfeeding was associated with reduced maternal risk of CVD outcomes.

Better COVID-19 Intensive Care Unit survival in females, independent of age, disease severity, comorbidities, and treatment.

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.

Sex differences in the association between major cardiovascular risk factors in midlife and dementia: a cohort study using data from the UK Biobank.

BACKGROUND: Sex differences in major cardiovascular risk factors for incident (fatal or non-fatal) all-cause dementia were assessed in the UK Biobank. The effects of these risk factors on all-cause dementia were explored by age and socioeconomic status (SES). METHODS: Cox proportional hazards models were used to estimate hazard ratios (HRs) and women-to-men ratio of HRs (RHR) with 95% confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP), smoking, diabetes, adiposity, stroke, SES and lipids with dementia. Poisson regression was used to estimate the sex-specific incidence rate of dementia for these risk factors. RESULTS: 502,226 individuals in midlife (54.4% women, mean age 56.5 years) with no prevalent dementia were included in the analyses. Over 11.8 years (median), 4068 participants (45.9% women) developed dementia. The crude incidence rates were 5.88 [95% CI 5.62-6.16] for women and 8.42 [8.07-8.78] for men, per 10,000 person-years. Sex was associated with the risk of dementia, where the risk was lower in women than men (HR = 0.83 [0.77-0.89]). Current smoking, diabetes, high adiposity, prior stroke and low SES were associated with a greater risk of dementia, similarly in women and men. The relationship between blood pressure (BP) and dementia was U-shaped in men but had a dose-response relationship in women: the HR for SBP per 20 mmHg was 1.08 [1.02-1.13] in women and 0.98 [0.93-1.03] in men. This sex difference was not affected by the use of antihypertensive medication at baseline. The sex difference in the effect of raised BP was consistent for dementia subtypes (vascular dementia and Alzheimer's disease). CONCLUSIONS: Several mid-life cardiovascular risk factors were associated with dementia similarly in women and men, but not raised BP. Future bespoke BP-lowering trials are necessary to understand its role in restricting cognitive decline and to clarify any sex difference.

Sex Disparities in Cardiovascular Risk Factor Assessment and Screening for Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review.

Background: Insight in sex disparities in the detection of cardiovascular risk factors and diabetes-related complications may improve diabetes care. The aim of this systematic review is to study whether sex disparities exist in the assessment of cardiovascular risk factors and screening for diabetes-related complications. Methods: PubMed was systematically searched up to April 2020, followed by manual reference screening and citations checks (snowballing) using Google Scholar. Observational studies were included if they reported on the assessment of cardiovascular risk factors (HbA1c, lipids, blood pressure, smoking status, or BMI) and/or screening for nephropathy, retinopathy, or performance of feet examinations, in men and women with diabetes separately. Studies adjusting their analyses for at least age, or when age was considered as a covariable but left out from the final analyses for various reasons (i.e. backward selection), were included for qualitative analyses. No meta-analyses were planned because substantial heterogeneity between studies was expected. A modified Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess risk of bias. Results: Overall, 81 studies were included. The majority of the included studies were from Europe or North America (84%).The number of individuals per study ranged from 200 to 3,135,019 and data were extracted from various data sources in a variety of settings. Screening rates varied considerably across studies. For example, screening rates for retinopathy ranged from 13% to 90%, with half the studies reporting screening rates less than 50%. Mixed findings were found regarding the presence, magnitude, and direction of sex disparities with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, with some evidence suggesting that women, compared with men, may be more likely to receive retinopathy screening and less likely to receive foot exams. Conclusion: Overall, no consistent pattern favoring men or women was found with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, and screening rates can be improved for both sexes.

Oestradiol and the risk of myocardial infarction in women: a cohort study of UK Biobank participants.

BACKGROUND: It is commonly assumed that high oestradiol levels in women are cardioprotective. We assessed the association between oestradiol and the risk of incident myocardial infarction (MI) in women. METHODS: We used data from 263 295 female UK Biobank participants [mean age 56.2; standard deviation (SD) 8.0 years] without previous cardiovascular disease (CVD). Associations of oestradiol with age and other cardiovascular risk factors were assessed. Cox proportional hazards models estimated crude, ag- and multiple-adjusted hazard ratios (HR) for MI associated with oestradiol levels. RESULTS: After a mean follow-up of 9 years, 2206 incident cases of MI had been recorded, including 230 events among the 57 204 women (mean age 48) with detectable oestradiol levels. In the unadjusted analyses, a unit higher in log-transformed oestradiol was associated with an HR [95% confidence interval (CI) for MI of 0.73 (0.58; 0.92)]. After adjusting for age, this HR became 0.94 (0.75; 1.17), and after further adjusting for classical CVD risk factors, it was 1.05 (0.83; 1.31. Results were similar in subgroup analyses defined by age, menopausal status, socioeconomic status, contraceptive pill use and the use of hormone replacement therapy. The multivariable-adjusted HR for the 171 431 women (mean age 59) with undetectable levels of oestradiol, compared with those with detectable levels, was 0.97 (0.92; 1.02). CONCLUSIONS: Higher levels of oestradiol were not associated with a decreased risk of MI. The presumed cardioprotective effects of oestradiol seem to be largely confounded by age and further confounded by other cardiovascular risk factors.

Risk Factor Clusters and Cardiovascular Disease in High-Risk Patients: The UCC-SMART Study.

Background: Clustering of vascular risk factors, i.e., the co-existence of two or more risk factors, has been associated with a higher risk of cardiovascular disease (CVD) in the general population. This study aims to firstly, examine patterns of clustering of major cardiovascular risk factors in high-risk patients and their relation with the risk of recurrent cardiovascular disease and all-cause mortality. Secondly, to assess which combinations are associated with the highest risk of CVD and all-cause mortality and to study population attributable fractions. Methods: A total of 12,616 patients from the Utrecht Cardiovascular Cohort - Second Manifestations of ARTerial diseases (UCC-SMART) study consisting of patients with or a high risk to develop cardiovascular disease were studied. We constructed sixteen clusters based on four individual modifiable risk factors (hypertension, dyslipidemia, current smoking, overweight). Patients were followed from September 1997 to March 2017. Cox proportional hazard models were used to compute adjusted hazard ratios for CVD risk and all-cause mortality and 95% confidence intervals for clusters, with patients without any risk factor as reference group. The population attributable fractions (PAFs) were calculated. Subgroup analyses were conducted by age and sex. Results: During a mean follow-up period of 8.0 years, 1836 CVD events were registered. The prevalence of patients with zero, one, two, three, and four risk factors was 1.4, 11.4, 32.0, 44.8 and 10.4%. The corresponding hazard ratios (HR) for CVD risk and all-cause mortality were 1.65 (95% CI 0.77; 3.54) for one risk factor, 2.61 (1.24; 5.50) for two, 3.25 (1.55; 6.84) for three, and 3.74 (1.77; 7.93) for four risk factors, with patients without any risk factor as reference group. The PAFs were 6.9, 34.0, 50.1 and 22.2%, respectively. The smoking-hypertension-dyslipidemia combination was associated with the highest HR: 4.06 (1.91; 8.63) and the hypertension-dyslipidemia combination with the highest PAF: 37.1%. Conclusion: Clusters including smoking and hypertension contributed to the highest risk of CVD and all-cause mortality. This study confirms that risk factor clustering is common among patients at high-risk for CVD and is associated with an increased risk of CVD and all-cause mortality.

Sex differences in the association between major risk factors and the risk of stroke in the UK Biobank cohort study.

OBJECTIVE: To determine whether there are sex differences in the association between risk factors and incident stroke, including stroke subtypes. METHODS: A total of 471,971 (56% women) UK Biobank participants without a history of cardiovascular disease were included. During 9 years of follow-up, 4,662 (44% women) cases of stroke were recorded. Cox models yielded adjusted hazard ratios (HRs) and women-to-men ratios of HRs (RHRs) for stroke associated with 7 risk factors. RESULTS: The incidence rate per 10,000 person-years was 8.66 (8.29-9.04) in women and 13.96 (13.44-14.50) in men for any stroke, 6.06 (5.75-6.38) in women and 11.35 (10.88; 11.84) in men for ischemic stroke, and 1.56 (1.41-1.73) in women and 2.23 (2.02-2.45) in men for hemorrhagic stroke. The association between increases in blood pressure, body anthropometry, and lipids, diabetes, and atrial fibrillation and any stroke was similar between men and women. Hypertension, smoking, and a low socioeconomic status were associated with a greater HR of any stroke in women than men; the RHRs were 1.36 (1.26-1.47), 1.18 (1.02-1.36), and 1.17 (1.03-1.33), respectively. Diabetes was associated with a higher HR of ischemic stroke in women than men (RHR 1.25 [1.00-1.56]). Atrial fibrillation was associated with a higher HR of hemorrhagic stroke in women than men (RHR 2.80 [1.07-7.36]). CONCLUSION: Several risk factors are more strongly associated with the risk of any stroke or stroke subtypes in women compared with men. Despite this, the incidence of stroke remains higher among men than women.

Sex differences in prevalence, treatment and control of cardiovascular risk factors in England.

OBJECTIVE: To investigate sex differences in prevalence, treatment and control of major cardiovascular risk factors in England. METHODS: Data from the Health Survey for England 2012-2017 on non-institutionalised English adults (aged ≥16 years) were used to investigate sex differences in prevalence, treatment and control of major cardiovascular risk factors: body mass index, smoking, systolic blood pressure and hypertension, diabetes, and cholesterol and dyslipidaemia. Physical activity and diet were not assessed in this study. RESULTS: Overall, 49 415 adults (51% women) were included. Sex differences persisted in prevalence of cardiovascular risk factors, with smoking, hypertension, overweight and dyslipidaemia remaining more common in men than in women in 2017. The proportion of individuals with neither hypertension, dyslipidaemia, diabetes nor smoking increased from 32% to 36% in women and from 28% to 29% in men between 2012 and 2017. Treatment and control of hypertension and diabetes improved over time and were comparable in both sexes in 2017 (66% and 51% for treatment and control of hypertension and 73% and 20% for treatment and control of diabetes). However, women were less likely than men to have treated and controlled dyslipidaemia (21% vs 28% for treatment and 15% vs 24% for control, for women versus men in 2017). CONCLUSIONS: Important sex differences persist in cardiovascular risk factors in England, with an overall higher number of risk factors in men than in women. A combination of public health policy and individually tailored interventions is required to further reduce the burden of cardiovascular disease in England.

Sex-specific associations between cardiovascular risk factors and myocardial infarction in patients with type 2 diabetes: The ADVANCE-ON study.

AIM: To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large-scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. MATERIALS AND METHODS: Eleven thousand and sixty-five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non-fatal) by sex, and the women-to-men ratio of HRs (RHR). RESULTS: Over a median of 9.6 years of follow-up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05-2.91) for current smoking, 1.53 (1.00-2.32) for former smoking, 1.18 (1.02-1.37) for SBP, and 1.13 (95% CI, 1.003-1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person-years) compared with women (5.8 per 1000 person-years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. CONCLUSIONS: In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex-specific approaches and early interventions in women with diabetes.

Causal relationships between obesity and the leading causes of death in women and men.

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.