【医脉通-指南】2015+AHA科学声明：糖尿病心血管结局的性别差异（英文版）.pdf

AHA Scientific Statement1The prevalence of diabetes mellitus(DM)is increasing at a rapid rate.In the United States in 2012,29.1 million Americans,or 9.3%of the population,had DM.1 Currently,1 in 13 people living in the United States has DM,and 90%to 95%of these individuals have type 2 DM(T2DM).2 Overall,the prevalence of T2DM is similar in women and men.In the United States,12.6 million women(10.8%)and 13 million men(11.8%)20 years of age are currently estimated to have T2DM.2Among individuals with T2DM,cardiovascular dis-ease(CVD)is the leading cause of morbidity and mortality and accounts for 75%of hospitalizations and 50%of all deaths.3 Although nondiabetic women have fewer cardio-vascular events than nondiabetic men of the same age,this advantage appears to be lost in the context of T2DM.4,5 The reasons for this advantage are not entirely clear but are likely multifactorial with contributions from inherent physiologi-cal differences,including the impact of the sex hormones,differences in cardiovascular risk factors,and differences between the sexes in the diagnosis and treatment of DM and CVD.6 In addition,there are racial and ethnic factors to con-sider because women of ethnic minority backgrounds have a higher prevalence of DM than non-Hispanic white(NHW)women.This scientific statement was designed to provide the cur-rent state of knowledge about sex differences in the cardiovas-cular consequences of DM,and it will identify areas that would benefit from further research because much is still unknown about sex differences in DM and CVD.Areas that are discussed include hormonal differences between the sexes and their pos-sible effects on the interaction between DM and CVD,sex dif-ferences in epidemiology,ethnic and racial differences and risk factors for CVD in DM across the life span,sex differences in various types of CVD and heart failure,and sex differences in the effects of treatments for DM,including both medications and lifestyle.In addition,there is discussion about risk factors that are specific to women,including gestational diabetes mel-litus(GDM)and polycystic ovarian syndrome(PCOS),which affect CVD risk.Table 1 focuses on sex differences in CVD risk factors and outcomes in DM,and Table 2 provides information about sex differences in CVD treatments and interventions in DM.Table 3 contains some of the important ideas for research in sex differences in the cardiovascular consequences of DM.(Circulation.2015;132:00-00.DOI:10.1161/CIR.0000000000000343.)2015 American Heart Association,Inc.Circulation is available at http:/circ.ahajournals.org DOI:10.1161/CIR.0000000000000343*The input provided by Dr.Fox is from her own perspective,and the opinions expressed in this article do not reflect the view of the National Institutes of Health,Department of Health and Human Services,or the US government.The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal,professional,or business interest of a member of the writing panel.Specifically,all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on July 31,2015,and the American Heart Association Executive Committee on September 5,2015.A copy of the document is available at http:/my.americanheart.org/statements by selecting either the“By Topic”link or the“By Publication Date”link.To purchase additional reprints,call 843-216-2533 or e-mail .The American Heart Association requests that this document be cited as follows:Regensteiner JG,Golden S,Huebschmann AG,Barrett-Connor E,Chang AY,Chyun D,Fox CS,Kim C,Mehta N,Reckelhoff JF,Reusch JEB,Rexrode KM,Sumner AE,Welty FK,Wenger NK,Anton B;on behalf of the American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health,Council on Epidemiology and Prevention,Council on Functional Genomics and Translational Biology,and Council on Hypertension.Sex differences in the cardiovascular consequences of diabetes mellitus:a scientific statement from the American Heart Association.Circulation.2015;132:XXXXXX.Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations.For more on AHA statements and guidelines development,visit http:/my.americanheart.org/statements and select the“Policies and Development”link.Permissions:Multiple copies,modification,alteration,enhancement,and/or distribution of this document are not permitted without the express permission of the American Heart Association.Instructions for obtaining permission are located at http:/www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp.A link to the“Copyright Permissions Request Form”appears on the right side of the page.Sex Differences in the Cardiovascular Consequences of Diabetes MellitusA Scientific Statement From the American Heart AssociationJudith G.Regensteiner,PhD,FAHA,Co-Chair;Sherita Golden,MD,MHS,FAHA,Co-Chair;Amy G.Huebschmann,MD,MSc;Elizabeth Barrett-Connor,MD,FAHA;Alice Y.Chang,MD,MSc;Deborah Chyun,PhD,RN,FAHA;Caroline S.Fox,*MD,FAHA;Catherine Kim,MD,MPH;Nehal Mehta,MD,MSCE;Jane F.Reckelhoff,PhD,FAHA;Jane E.B.Reusch,MD;Kathryn M.Rexrode,MD,MPH;Anne E.Sumner,MD,FAHA;Francine K.Welty,MD,FAHA;Nanette K.Wenger,MD,FAHA;Blair Anton,MLIS,MS,AHIP;on behalf of the American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health,Council on Epidemiology and Prevention,Council on Functional Genomics and Translational Biology,and Council on Hypertension by guest on December 9,2015http:/circ.ahajournals.org/Downloaded from 2 Circulation December 22/29,2015Sex Differences in the Hormonal Milieu Between Women and Men:Could They Differentially Influence Coronary Risk in DM?For years,it has been recognized that the incidence of coro-nary heart disease(CHD)in women lags behind that of men by 10 years,7 thus generating hypotheses that differences in endogenous sex steroid levels contribute to sex differences in CHD.It also has been recognized for years that DM confers greater risk for CHD death in women compared with men.8Early Rancho Bernardo Study publications noted that men with DM by history or by fasting plasma glucose had a 2.4-fold excess risk of ischemic heart disease death compared with men without DM,whereas women who had DM had a 3.5-fold excess risk compared with women without DM that was inde-pendent of multiple covariates(P=0.048 for effect modification by sex).9 As they age,women with DM eventually have a risk of CHD death similar to that of men with DM.8 Therefore,is it possible that differences in endogenous sex steroids contribute to the sex differences in the association between DM and CHD death?Testosterone and estrogens may play a significant role in the development of CHD in both women and men.Early studies,including those from Rancho Bernardo,noted that sex steroid lev-els were frequently undetectable among older adults.10 However,low levels of total testosterone in men predicted incident coronary events,and extremes of bioavailable or unbound testosterone in women predicted coronary events.10 These data suggest that high bioavailable testosterone may be harmful for women because of its association with obesity,DM,and metabolic syndrome com-ponents,1113 whereas low total testosterone effects in men may be enacted through different mechanisms.Whether testosterone levels are associated with the greater degree of CVD risk factor clustering observed with DM in women14 needs to be addressed.Therefore,the answer to the question of whether sex ste-roids influence the different risk factor levels and clustering of CVD risk factors in women and men remains uncertain.The conflicting results of exogenous estrogen trials compared with endogenous estrogen studies and exogenous testosterone trials compared with endogenous testosterone observations highlight the possibility that randomized sex steroid trials may not reflect naturally occurring mechanisms.15 Our traditional approach to manipulating the hormonal milieu to understand how it influences CHD risk needs to be supplemented with other approaches.Assessing trajectories or repeated mea-sures of risk factors,including sex steroids,before the onset of obesity and DM helps to elucidate the pathophysiology of hormonal sex differences and how they contribute to CHD in both sexes.Table 1.Sex Differences in CVD Risk Factors and Outcomes in DMSex DifferencesRisk factor Sex hormones:testosteroneHigh bioavailable or unbound testosterone predicts incident coronary eventsLow levels of total testosterone predict incident coronary events Generalized obesityHigher prevalence of obesity in women,particularly postmenopausal women,than men HDL-CWomen have higher HDL-C compared with men HypertensionWomen with DM have more hypertension at 60 y of age(ie,postmenopausal)Men with DM and hypertension are at greater risk for renal injury than women(perhaps because of sex hormone differences)Cardiovascular risk profileMore adverse in women with DM:impaired endothelium-dependent vasodilation,worse atherogenic dyslipidemia,prothrombotic coagulation profile,higher metabolic syndrome prevalenceCompared with men,women have worse HbA1c and blood pressure controlCHD predictors in T1DM(Pittsburgh Epidemiology of Diabetes Complications Study)Women only:abdominal adiposity,insulin resistance,HbA1cMen and women:inflammatory markers(fibrinogen,white blood cell count),microalbuminuria AdiposityAbdominal adiposity was more strongly associated with cardiovascular mortality in women compared with men with DM in a Finnish populationOutcome CHDWomen with DM have a 2-fold excess CHD risk compared with men Myocardial infarction occurs earlier and has higher mortality in women with DM compared with menRevascularization rates(angioplasty,coronary artery bypass grafting)are lower in women with DM compared with men Heart failureRisk of incident heart failure is greater in women than men StrokeMale stroke patients have a higher prevalence of DM than female stroke patientsDM is a stronger risk factor for stroke in women compared with men PADDM is a more significant risk factor for the development of claudication in women compared with menWomen with PAD and DM respond less well to exercise training compared with women without DM and men with and without DMDecreased long-term survival in women undergoing revascularization and increased postsurgical mortality are seen in women but not men with DMCHD indicates coronary heart disease;CVD,cardiovascular disease;DM,diabetes mellitus;HbA1c,hemoglobin A1c;HDL-C,high-density lipoprotein cholesterol;PAD,peripheral arterial disease;and T1DM,type 1 diabetes mellitus.by guest on December 9,2015http:/circ.ahajournals.org/Downloaded from Regensteiner et al Sex Differences in the Cardiovascular Consequences of DM 3Epidemiology,Ethnic and Racial Differences,and Risk Factors for CVD in DM Across the Life SpanEpidemiologyIntroduction to Sex Differences in Cardiovascular Outcomes Within Racial/Ethnic GroupsSex differences in cardiovascular consequences of DM are mod-ified in distinct racial/ethnic subgroups for 2 reasons(Figures 1 and 2).First,patients from a specific racial/ethnic subgroup with DM show sex differences in biological and social/cultural factors,which may modify key cardiovascular consequences of DM.16 Second,understanding the cardiovascular consequences of DM within racial/ethnic subgroups with DM is important to guide prevention targets to reduce cardiovascular health dis-parities.16 In this section,we use the Williams17 definition of race/ethnicity as“a complex multidimensional construct”that includes biological,geographic,and socioeconomic factors.Table 2.Sex Differences in CVD Treatments and Interventions in DMCVD Treatment/InterventionSex DifferencesPrescription of pharmacotherapyCompared with men,women have lower frequency of lipid-lowering(statin)therapy,lower aspirin use,and lower ACE inhibitor and-blocker useLower medication adherence in women compared with men in some but not all studiesStatin therapy*Equally effective for secondary CVD prevention in both men and womenNo prospective evidence for primary CVD with statins in women;however,on the basis of expert opinion and cholesterol theory of atheroma progression,statins are recommended for primary prevention in womenAtheroma regression and LDL lowering greater with statins in women than in men in the Study of Coronary Atheroma by Intravascular UltrasoundStatin therapy side effects:Women may have a greater likelihood of developing DM on statins Myalgia may be more frequent in women Increase in creatinine phosphokinase or abnormal liver function may be more frequent in menFenofibrateGreater lipid-lowering impact and greater reduction in CVD end point in women compared with men,although sex interaction for the latter was not significant(from the FIELD study)ACE inhibitors,-blockers,spironolactone*Guidelines support use for the treatment of heart failure for both men and womenAspirin therapyPrimary prevention:Consider low-dose aspirin(75162 mg/d)for individuals with 10-y CVD risk of at least 10%who do not have an increased risk of bleeding and have at least 1 additional CVD risk factor Men 50 y of age Women 60 y of ageNot recommended for adults with DM at low risk with no additional CVD risk factors Men 50 y of age Women 60 y of ageLifestyle treatmentCardiovascular events and mortality:Da Qing Diabetes Prevention Study of Chinese adults with prediabetes demonstrated a sex difference in cardiovascular mortality of the lifestyle intervention that favored women(although smoking prevalence was higher in men than women)No sex differences in cardiovascular outcomes in individuals with DM in the Japanese Diabetes Complications Study(stroke)or the Look AHEAD Study(cardiovascular mortality/major cardiovascular events)Observational studies suggest that women with DM may require greater frequency/intensity of physical activity than men to reduce cardiovascular eventsFitness:Look AHEAD showed greater improvements in cardiorespiratory fitness in men compared with women Diabetes Aerobic and Resistance Exercise trial and a meta-analysis showed similar improvements in fitness in response to exercise trainingGlycemic control/DM prevention:Women with T1DM may have greater improvement in HbA1c with exercise than men Data on the effect of exercise on HbA1c in men and women with T2DM are inconclusive Men and women with prediabetes had similar weight loss and DM prevention rates in the US Diabetes Prevention Program and the Finnish National Diabetes Prevention StudyACE indicates angiotensin-converting enzyme;CVD,cardiovascular disease;DM,diabetes mellitus;FIELD,Fenofibrate Intervention a