Sex-specific risks for cardiovascular disease across the glycaemic spectrum: a population-based cohort study using the UK Biobank

Background We sought to examine sex-specific risks for incident cardiovascular disease (CVD) across the full glycaemic spectrum. Methods Using data from UK Biobank, we categorised participants’ glycosylated haemoglobin (HbA1c) at baseline as low-normal (<35 mmol/mol), normal (35-41 mmol/mol), pre-diabetes (42-47 mmol/mol), undiagnosed diabetes (≥48 mmol/mol), or diagnosed diabetes. Our outcomes were coronary artery disease (CAD), atrial fibrillation, deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, heart failure, and a composite outcome of any CVD. Cox regression estimated sex-specific associations between HbA1c and each outcome, sequentially adjusting for socio-demographic, lifestyle, and clinical characteristics. Findings Among 427,435 people, CVD rates 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 were at higher risks of CVD than those with normal HbA1c, with relative increases more pronounced in women than men. Age-adjusted HRs for pre-diabetes and undiagnosed diabetes ranged from 1.30 to 1.47; HRs for diagnosed diabetes were 1.55 (1.49-1.61) in men and 2.00 (1.89-2.12) in women (p-interaction<0.0001). Excess risks attenuated and were more similar between men and women after adjusting for clinical and lifestyle factors particularly obesity and antihypertensive or statin use (fully adjusted HRs for diabetes: 1.06 [1.02-1.11] and 1.17 [1.10-1.24], respectively). Interpretation Excess risks in men and women were largely explained by modifiable factors, and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications. Addressing these risk factors could reduce sex disparities in glycaemia-related risks of CVD. Funding Diabetes UK (#15/0005250) and British Heart Foundation (SP/16/6/32726) Evidence before this study It has long been asserted that men and women with diabetes have differential risks of cardiovascular disease (CVD), but it is unclear which risk factors drive these sex differences, and whether men or women with moderately elevated glycosylated haemoglobin (HbA1c) below the threshold for diabetes are also at increased risk of CVD. We searched MEDLINE and PubMed on 15 March 2023 for studies evaluating sex differences in the risk of CVD across the glycaemic spectrum. The keywords “ (sex difference* OR sex disparit* OR sex-strat* OR sex-specific) AND (glycaemia OR glycemia OR glycosylated OR hemoglobin OR haemoglobin) AND (non-diabetes OR non-diabetic) AND (cardiovascular) AND (rate OR hazard OR odds OR risk)” were used and results were filtered to articles with an abstract available in English. 33 papers were identified and all 33 were eligible for screening; none reported sex-stratified associations of CVD risk across the full glycaemic spectrum. Previous studies have suggested a J-shaped curve in the relationship between HbA1c and outcomes including CVD and all-cause mortality, with individuals with low-normal HbA1c at excess risk compared to normal HbA1c. However, these studies were limited in sample size, combined people with controlled diabetes with those without diabetes, and did not analyse individual CVD outcomes. The present study leveraged UK Biobank data, which measured HbA1c on ∼500,000 men and women, regardless of diabetes status, presenting a unique opportunity to study sex disparities in the risk of CVD across the glycaemic spectrum. Added value of this study We uncovered novel insights around sex disparities in CVD risk across the glycaemic spectrum. Absolute CVD rates were higher in men than women at all levels of HbA1c. Both men and women with pre-diabetes, undiagnosed diabetes, and, more markedly, diagnosed diabetes were at higher risks of CVD than those with normal HbA1c, with relative increases in risk more pronounced in women than men. Both men and women with low-normal HbA1c had lower absolute rates of CVD than those with normal HbA1c. We extended previous evidence by showing most excess risk, and thereby differential relative risks between men and women, disappeared after accounting for lifestyle and clinical characteristics, namely measures of obesity and use of antihypertensive or lipid-lowering medications. Implications of all the available evidence This is the largest study to date to investigate sex differences in the risk of CVD across the glycaemic spectrum. While those with diagnosed diabetes carried the highest risk compared to those with normal HbA1c, men and women with pre-diabetes and undiagnosed diabetes were also at higher risk and those with low-normal HbA1c were at lower risk of CVD outcomes, highlighting the need for strategies to reduce risk of CVD across the glycaemic spectrum. Our findings suggest that excess risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications. Addressing these risk factors could reduce sex disparities in glycaemia-related risks of CVD. ### Competing Interest Statement NC receives compensation from AstraZeneca for participation on data safety and monitoring boards of clinical trials. RM receives salary contributions for her work on the Genes & Health programme, by a Life Sciences Consortium that includes Astra Zeneca PLC, Bristol-Myers Squibb Company, GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc, Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc, Takeda Development Centre Americas Inc. All other authors declare no potential conflicts of interest. ### Funding Statement This work was jointly funded by Diabetes UK and British Heart Foundation grant 15/0005250. VG is supported by the Diabetes Research and Wellness Foundation Professor David Matthews Non-Clinical Fellowship (SCA/01/NCF/22). RM is supported by Barts Charity (MGU0504). KB holds a Senior Research Fellowship funded by the Wellcome Trust (220283/Z/20/Z). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study had local approval from the UK Biobank (#21893) and institutional approval from the London School of Hygiene & Tropical Medicine (#14387). All participants provided informed consent at the time of recruitment to the UK Biobank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UK Biobank data are available to any bona fide researcher to conduct health-related research that is in the public interest at .