Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

BACKGROUND: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. METHODS: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. RESULTS: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. CONCLUSIONS: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials.

BACKGROUND AND AIMS: Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD. METHODS: Randomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model. RESULTS: Ten studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60-0.92; I2 = 35), MI (RR 0.77, 95% CI 0.64-0.93; I2 = 0%), or stroke (RR 0.81, 95% CI 0.68-0.96; I2 = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81-1.08; I2 = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14-1.54). CONCLUSIONS: Pioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF.

Duration of diabetes and the risk of major cardiovascular events in women and men: A prospective cohort study of UK Biobank participants.

AIMS: Diabetes has been associated with a greater excess risk of cardiovascular disease (CVD) in women than men. We investigated whether there are also sex differences in the association of diabetes duration and the risk of CVD. METHODS: Data were used from 18,961 (40% women) individuals with type 2 diabetes, without a history of CVD, in the UK Biobank. Sex-specific incidence rates were calculated by diabetes duration. Cox proportional hazards analyses estimated multiple-adjusted sex-specific hazard ratios (HR) and women-to-men ratio of HRs (RHR). RESULTS: Over a median follow-up of 11 years, 1,506 (29% women) CVD events were documented. Compared with men, women had lower multiple-adjusted incidence rates of CVD per 10,000 person-years for all categories of diabetes duration. Duration of diabetes was associated with an increased risk of CVD in both sexes. A 5-year increase in diabetes duration was associated with an approximately similar excess risk of about 20% for each of the three endpoints, in both sexes. CONCLUSIONS/INTERPRETATION: The increased risk of CVD associated with longer duration of diabetes is similar in women and men, and thus cannot explain the higher excess risk from diabetes in women in this study population.

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.

Diabetes, Glycated Hemoglobin, and the Risk of Myocardial Infarction in Women and Men: A Prospective Cohort Study of the UK Biobank.

OBJECTIVE: Diabetes has shown to be a stronger risk factor for myocardial infarction (MI) in women than men. Whether sex differences exist across the glycemic spectrum is unknown. We investigated sex differences in the associations of diabetes status and glycated hemoglobin (HbA1c) with the risk of MI. RESEARCH DESIGN AND METHODS: Data were used from 471,399 (56% women) individuals without cardiovascular disease (CVD) included in the UK Biobank. Sex-specific incidence rates were calculated by diabetes status and across levels of HbA1c using Poisson regression. Cox proportional hazards analyses estimated sex-specific hazard ratios (HRs) and women-to-men ratios by diabetes status and HbA1c for MI during a mean follow-up of 9 years. RESULTS: Women had lower incidence rates of MI than men, regardless of diabetes status or HbA1c level. Compared with individuals without diabetes, prediabetes, undiagnosed diabetes, and previously diagnosed diabetes were associated with an increased risk of MI in both sexes. Previously diagnosed diabetes was more strongly associated with MI in women (HR 2.33 [95% CI 1.96; 2.78]) than men (1.81 [1.63; 2.02]), with a women-to-men ratio of HRs of 1.29 (1.05; 1.58). Each 1% higher HbA1c, independent of diabetes status, was associated with an 18% greater risk of MI in both women and men. CONCLUSIONS: Although the incidence of MI was higher in men than women, the presence of diabetes is associated with a greater excess relative risk of MI in women. However, each 1% higher HbA1c was associated with an 18% greater risk of MI in both women and men.

Sex differences in the risk of vascular disease associated with diabetes.

Diabetes is a strong risk factor for vascular disease. There is compelling evidence that the relative risk of vascular disease associated with diabetes is substantially higher in women than men. The mechanisms that explain the sex difference have not been identified. However, this excess risk could be due to certain underlying biological differences between women and men. In addition to other cardiometabolic pathways, sex differences in body anthropometry and patterns of storage of adipose tissue may be of particular importance in explaining the sex differences in the relative risk of diabetes-associated vascular diseases. Besides biological factors, differences in the uptake and provision of health care could also play a role in women's greater excess risk of diabetic vascular complications. In this review, we will discuss the current knowledge regarding sex differences in both biological factors, with a specific focus on sex differences adipose tissue, and in health care provided for the prevention, management, and treatment of diabetes and its vascular complications. While progress has been made towards understanding the underlying mechanisms of women's higher relative risk of diabetic vascular complications, many uncertainties remain. Future research to understanding these mechanisms could contribute to more awareness of the sex-specific risk factors and could eventually lead to more personalized diabetes care. This will ensure that women are not affected by diabetes to a greater extent and will help to diminish the burden in both women and men.

Sex differences in cardiometabolic risk factors, pharmacological treatment and risk factor control in type 2 diabetes: findings from the Dutch Diabetes Pearl cohort.

INTRODUCTION: Sex differences in cardiometabolic risk factors and their management in type 2 diabetes (T2D) have not been fully identified. Therefore, we aimed to examine differences in cardiometabolic risk factor levels, pharmacological treatment and achievement of risk factor control between women and men with T2D. RESEARCH DESIGN AND METHODS: Cross-sectional data from the Dutch Diabetes Pearl cohort were used (n=6637, 40% women). Linear and Poisson regression analyses were used to examine sex differences in cardiometabolic risk factor levels, treatment, and control. RESULTS: Compared with men, women had a significantly higher body mass index (BMI) (mean difference 1.79 kg/m2 (95% CI 1.49 to 2.08)), while no differences were found in hemoglobin A1c (HbA1c) and systolic blood pressure (SBP). Women had lower diastolic blood pressure (-1.94 mm Hg (95% CI -2.44 to -1.43)), higher total cholesterol (TC) (0.44 mmol/L (95% CI 0.38 to 0.51)), low-density lipoprotein cholesterol (LDL-c) (0.26 mmol/L (95% CI 0.22 to 0.31)), and high-density lipoprotein cholesterol (HDL-c) sex-standardized (0.02 mmol/L (95% CI 0.00 to 0.04)), and lower TC:HDL ratio (-0.29 (95% CI -0.36 to -0.23)) and triglycerides (geometric mean ratio 0.91 (95% CI 0.85 to 0.98)). Women had a 16% higher probability of being treated with antihypertensive medication in the presence of high cardiovascular disease (CVD) risk and elevated SBP than men (relative risk 0.84 (95% CI 0.73 to 0.98)), whereas no sex differences were found for glucose-lowering medication and lipid-modifying medication. Among those treated, women were less likely to achieve treatment targets of HbA1c (0.92 (95% CI 0.87 to 0.98)) and LDL-c (0.89 (95% CI 0.85 to 0.92)) than men, while no differences for SBP were found. CONCLUSIONS: In this Dutch T2D population, women had a slightly different cardiometabolic risk profile compared with men and a substantially higher BMI. Women had a higher probability of being treated with antihypertensive medication in the presence of high CVD risk and elevated SBP than men, and were less likely than men to achieve treatment targets for HbA1c and LDL levels.

Sex differences in cardiovascular risk management for people with diabetes in primary care: a cross-sectional study.

BACKGROUND: Diabetes is a stronger risk factor for cardiovascular complications in women than men. AIM: To evaluate whether there are sex differences in cardiovascular risk management in patients with diabetes in primary care. DESIGN & SETTING: A cross-sectional study was undertaken using data from 12 512 individuals with diabetes within the Dutch Julius General Practitioners Network (JGPN) from 2013. METHOD: Linear and Poisson regression analyses were used to assess sex differences in risk factor levels, assessment, treatment, and control. RESULTS: No sex differences were found in HbA1c levels and control, while small differences were found for cardiovascular risk management. Blood pressure levels were higher (mean difference [MD] 1.09 mmHg; 95% confidence intervals [CI] = 0.41 to 1.77), while cholesterol levels (MD -0.38 mmol/l; 95% CI = -0.42 to -0.34) and body mass index ([BMI] MD -1.79 kg/m2; 95% CI = -2.03 to 1.56) were lower in men than women. Risk factor assessment was similar between sexes, apart from high-density lipoprotein cholesterol (HDL-c), which was more commonly assessed in women (risk ratio [RR] 1.16; 95% CI = 1.13 to 1.20). Among those with a treatment indication for prevention, women with cardiovascular disease (CVD) were less likely to receive lipid-lowering drugs (RR 0.84; 95% CI = 0.76 to 0.93) than men, while women without CVD were more likely to receive lipid-lowering drugs (RR 1.16; 95% CI = 1.04 to 1.2). Among those treated, women were more likely to achieve systolic blood pressure (SBP) control (RR 1.06; 95% CI = 1.02 to 1.10) and less likely to achieve low-density lipoprotein cholesterol (LDL-c) control (RR 0.88; 95% CI = 0.85 to 0.91) than men. CONCLUSION: In this Dutch primary care setting, sex differences in risk factor assessment and treatment of people with diabetes were small. However, women with diabetes were less likely to achieve control for LDL-c and more likely to achieve blood pressure control than men with diabetes.

Adverse differences in cardiometabolic risk factor levels between individuals with pre-diabetes and normal glucose metabolism are more pronounced in women than in men: the Maastricht Study.

Objective: To investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing individuals with and without diabetes, are also present before type 2 diabetes onset. Research design and methods: In a population-based cohort study of individuals aged 40-75 years (n=3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated associations with cardiometabolic and lifestyle risk factors of (1) pre-diabetes and type 2 diabetes (reference category: normal glucose metabolism) and (2) among non-diabetic individuals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms. Results: In pre-diabetes, adverse differences in cardiometabolic risk factors were greater in women than men for systolic blood pressure (difference, 3.02 mm Hg; 95% CI:-0.26 to 6.30), high-density lipoprotein (HDL) cholesterol (difference, -0.10 mmol/L; 95% CI: -0.18 to -0.02), total-to-HDL cholesterol ratio (difference, 0.22; 95% CI: -0.01 to 0.44), triglycerides (ratio: 1.11; 95% CI: 1.01 to 1.22), and inflammation markers Z-score (ratio: 1.18; 95% CI: 0.98 to 1.41). In type 2 diabetes, these sex differences were similar in direction, and of greater magnitude. Additionally, HbA1c among non-diabetic individuals was more strongly associated with several cardiometabolic risk factors in women than men: per one per cent point increase, systolic blood pressure (difference, 3.58 mm Hg; 95% CI: -0.03 to 7.19), diastolic blood pressure (difference, 2.10 mm Hg; 95% CI: -0.02 to 4.23), HDL cholesterol (difference, -0.09 mmol/L; 95% CI: -0.19 to 0.00), and low-density lipoprotein cholesterol (difference, 0.26 mmol/L; 95% CI: 0.05 to 0.47). With regard to lifestyle risk factors, no consistent pattern was observed. Conclusion: Our results are consistent with the concept that the more adverse changes in cardiometabolic risk factors in women (than men) arise as a continuous process before the onset of type 2 diabetes.