Higher cardiovascular risk for women throughout the glycaemic spectrum: only a question of sex?

Key points This is an observational, cohort study, based on data from the UK Biobank and funded by Diabetes UK and British Heart Foundation, aimed at assessing sex-specific risk for cardiovascular disease (CVD) across the whole glycaemic spectrum and characterizing the contribution of clinical and lifestyle factors to sex-related differences. 1 From 2006 to 2010, a total number of 502 398 subjects aged 40-69 were recruited across England, Scotland, and Wales and followed through 2021.Every participant underwent baseline assessment for sociodemographic, clinical, and lifestyle characteristics and blood sampling for biomarker measurement.Based on glycated haemoglobin (HbA1c) levels, participants were categorized as (i) low-normal (<35 mmol/mol or <5.5%, including 47% of the entire population), (ii) normal (35-41 mmol/mol or 5.5%-5.9%,including 44% of the entire population), (iii) prediabetes (42-47 mmol/mol or 6.0%-6.4%,including 3% of the entire population), (iv) undiagnosed diabetes (48 mmol/mol or 6.5%, including 1% of the entire population), and (v) diagnosed diabetes (based on medical history and use of glucose-lowering medications, including 4% of the entire population). Outcomes included coronary artery disease (CAD), atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure, as well as a composite outcome of any CVD on its first occurrence.For the analysis of any CVD, individuals who had any CVD prior to baseline were excluded.Similarly, for the analysis of each outcome, individuals who had the respective event prior to baseline were excluded. Covariates were selected based on known determinants of HbA1c levels and CVD and included sociodemographic factors (i.e.age, sex, ethnicity, and index of multiple deprivation), mostly self-reported lifestyle i.e.smoking status, alcohol consumption, physical activity, body mass index (BMI), waist-hip ratio, and dietary intake, and clinical characteristics (i.e. total cholesterol, serum creatinine, C-reactive protein, diagnosed hypertension, use of antihypertensive drugs or statins, and family history of CVD). The final analysis included 427 435 participants, of whom 195 752 (45.8%) men and 231 683 (54.2%) women.Both men and women in higher HbA1c categories had higher BMI, poorer renal function, greater prevalence of hypertension, and use of antihypertensive medications or statins compared with their counterparts with low-normal or normal HbA1c levels.Over a median 12-year follow-up, age-standardized incidence rates for any CVD were 16.9 and 9.1 events/1000 person-years for men and women, respectively.Both men and women with pre-diabetes, undiagnosed diabetes, and, more markedly, diagnosed diabetes had higher CVD rates than those with normal HbA1c.In contrast, CVD rates were lower in those with low-normal HbA1c compared with normal HbA1c.The relative associations between diagnosed diabetes and any CVD were more pronounced in women than in men: age-adjusted hazard ratios (HRs) were 1.55 95% confidence interval (CI), 1.49-1.61 in men and 2.00 (95% CI, 1.89-2.12) in women (P for interaction <.0001).Compared with those with normal HbA1c, the risk of CVD was also higher in pre-diabetes and undiagnosed diabetes groups, with age-adjusted HRs ranging from 1.30 to 1.47, with relative increases higher for women.In addition, both women and men with low-normal HbA1c were at decreased risk of CVD (HR 0.86, 95% CI, 0.84-0.98 and 0.86, 0.84-0.88,respectively). These associations attenuated after additional adjustment for clinical and lifestyle factors, particularly BMI, waist-hip ratio, and antihypertensive or statin use.However, the increased risk of CVD remained higher in both sexes with diagnosed diabetes (fully adjusted HR: 1.06, 95% CI, 1.02-1.11for men and 1.17, 1.10-1.24for women; P for interaction = .0387).