The Effect of Sex Hormones on Cardiometabolic Outcomes in Men and Women with Diabetes: The Look AHEAD (Action for Health in Diabetes) Study

性激素对男性和女性糖尿病患者心脏代谢结果的影响：展望未来（糖尿病健康行动）研究

• 批准号: 10474585
• 负责人: Wendy Lynet Bennett
• 金额: $ 64.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474585
• 关键词: Address; Age; Albumins; Biological; Blood Pressure; Body Composition; Body Weight decreased; Body mass index; Cardiovascular Diseases; Chronic Disease; Chronic Kidney Failure; Clinical; Control Groups; Coronary heart disease; Data; Diabetes Mellitus; Diet; Disparity; Eating; Education; Estradiol; Etiology; Event; Exercise; Female; General Population; Glycosylated hemoglobin A; Gonadal Steroid Hormones; Health; Hormonal Change; Individual; Life Style; Life Style Modification; Lipids; Longitudinal Studies; Measurement; Morbidity - disease rate; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Participant; Persons; Physical activity; Prevalence; Preventive measure; Preventive treatment; Randomized, Controlled Trials; Recommendation; Relative Risks; Research; Risk; Risk Factors; Role; Sex Differences; Sex Hormone-Binding Globulin; Stroke; Testing; Testosterone; Time; United States National Institutes of Health; Vascular Dementia; Weight; Woman; adjudication; adverse outcome; cardiometabolic risk; cardiometabolism; cardiovascular disorder prevention; cardiovascular disorder risk; clinically significant; comparison intervention; design; diabetes management; disadvantaged women; follow-up; healthy lifestyle; improved; kidney vascular structure; lifestyle intervention; men; mortality; primary outcome; response; sex; treatment arm; waist circumference

Although women and men have about an equal prevalence of type 2 diabetes (DM), DM imposes a clinically significant excess relative risk of coronary heart disease (44% higher), stroke (27% higher) and vascular dementia (19% higher) in women compared to men. Understanding these sex differences could inform research to improve DM outcomes for both women and men. Postulated reasons for the “female disadvantage” include an adverse cardiometabolic profile (particularly greater obesity) and disparities in aggressiveness of CV preventive treatments (e.g. use of statins). In addition, differences in endogenous sex hormones, including estradiol (E2), testosterone (T) and sex hormone binding globulin (SHBG), may contribute to the excess risk for women conferred by DM. Although lifestyle changes (diet, exercise and weight loss) are the cornerstone of diabetes management, it is not known if weight loss and healthier lifestyle can modulate the trajectory of sex hormones over time, and the role of these hormonal changes on cardiometabolic risk factors. The Action for Health In Diabetes (Look AHEAD) Study was a randomized controlled trial among 5,145 overweight individuals with obesity and type 2 diabetes designed to evaluate the effect of an Intensive Lifestyle Intervention (ILI) compared to a control group on incident CVD events. A major strength of Look AHEAD is its capacity to address questions of causation, because study participants were followed over 8 years (~3000 with longitudinal biospecimens for sex hormone measurements), with significant and well-characterized alterations in weight and with adjudicated clinical outcomes. In this proposal, we will first analyze the stored biospecimens for sex hormones (E2, T), SHBG and albumin. We will then 1) Test whether the ILI improves endogenous sex hormones over time and whether the effect of ILI is moderated by sex; 2) Evaluate the longitudinal associations between endogenous sex hormones and cardiometabolic risk factors (HbA1c, lipid levels, body mass index and weight, waist circumference, body composition, blood pressure) (primary outcomes); 3) Test the effect of the time-trajectory of endogenous sex hormones on improving cardio-metabolic risk factors and long term DM outcomes (i.e. CVD, stroke, chronic kidney disease and vascular dementia) over 8 years of followup, and whether differences exist by sex. Our overall hypothesis is that ILI improves the sex hormone profile, and that an unfavorable sex hormone profile, i.e. high free T in women and low free T in men, is associated with an adverse cardiometabolic risk profile. Ultimately, understanding the biological role of sex hormones in DM could target treatments, particularly lifestyle modification, and inform the prevention of CVD and other DM complications, to reduce DM-related morbidity and mortality for both women and men.

尽管女性和男性的2型糖尿病（DM）患病率大致相同，但糖尿病在临床上施加了很大的压力