Female reproductive factors and risk of cardiovascular disease and mortality among women with diabetes

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People with diabetes are at increased risk of developing life-threatening vascular comorbidities such as coronary heart disease (CHD), stroke, and other macrovascular and microvascular complications of diabetes. Although men are at a higher absolute risk of cardiovascular disease, the relative risk of CHD, stroke, and heart failure is higher in women with diabetes than in men with diabetes. The underlying mechanisms behind these sex-specific risks are still largely unknown. In recent years, women-specific risk factors such as adverse pregnancy outcome (preeclampsia, gestational hypertension, gestational diabetes, preterm birth) and fertility complications have been linked with cardiometabolic risk. In addition, the association between gestational diabetes and long-term risk of hypertension and other cardiovascular diseases is well established and holds true even for women with a history of gestational diabetes who do not progress to overt diabetes. However, the associations between female reproductive risk factors and cardiovascular disease in women with type 2 diabetes and/or gestational diabetes have not been explored yet. The aim of this research project is to investigate the relationships between female reproductive factors and risk of cardiovascular disease and mortality in women with type 2 diabetes and/or gestational diabetes. I hypothesize the following: There is an association between female reproductive factors (early menarche and early menopause, infertility, nulliparity, and others) and cardiovascular and mortality risks in women with diabetes. Furthermore, these relationships are mediated by alterations in metabolic pathways and metabolic intermediates (metabolites). To test these hypotheses, I will use the prospective data from approximately 14 000 women with type 2 diabetes and 5 000 women with a history of gestational diabetes from the two Nurses' Health Studies. The Nurses' Health Studies have been ongoing for more than 40 years at the Harvard School of Public Health and are among the largest and longest prospective investigations into risk factors for chronic diseases in women. Exposures (reproductive and lifestyle factors, diet, and others) and newly diagnosed diseases, including diabetes, CHD, and stroke, are updated every two years. Metabolites and metabolomic signatures associated with female reproductive factors such as breastfeeding, oral contraceptive use, and early menarche will be identified using machine learning approaches. The research findings from this proposal will provide an evidence base for primordial, primary, secondary, and tertiary prevention in women with diabetes and a predisposition to diabetes-related cardiovascular disease.