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Cardiovascular Disease in Type 2 Diabetes: A Review of Sex-Related Differences in Predisposition and Prevention

  • Abdallah Al-Salameh
    Correspondence
    Correspondence: Address to Abdallah Al-Salameh, MD, Centre de Recherche Clinique Paris-Sud, Hôpital Bicêtre, 78 avenue du Général Leclerc, F-94275 Le Kremlin-Bicêtre, France.
    Affiliations
    Centre de recherche en Epidémiologie et Santé des Populations (CESP), Université Paris-Sud, Université Paris-Saclay, INSERM, Villejuif, France

    Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, France

    Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Centre de Recherche Clinique Paris-Sud, Le Kremlin-Bicêtre, France
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  • Philippe Chanson
    Affiliations
    Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, France

    Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

    INSERM U1185, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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  • Sophie Bucher
    Affiliations
    Centre de recherche en Epidémiologie et Santé des Populations (CESP), Université Paris-Sud, Université Paris-Saclay, INSERM, Villejuif, France

    General Practice Department, Paris-Sud Faculty of Medicine, Paris-Sud University, Le Kremlin-Bicêtre, France
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  • Virginie Ringa
    Affiliations
    Centre de recherche en Epidémiologie et Santé des Populations (CESP), Université Paris-Sud, Université Paris-Saclay, INSERM, Villejuif, France
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  • Laurent Becquemont
    Affiliations
    Centre de recherche en Epidémiologie et Santé des Populations (CESP), Université Paris-Sud, Université Paris-Saclay, INSERM, Villejuif, France

    Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Centre de Recherche Clinique Paris-Sud, Le Kremlin-Bicêtre, France

    Pharmacology Department, Paris-Sud Faculty of Medicine, Paris-Sud University, Le Kremlin-Bicêtre, France
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      Abstract

      Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled data suggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. In recent years, large meta-analyses have confirmed that women with type 2 diabetes have a higher relative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared with their male counterparts. The reasons for these disparities are not completely elucidated. A greater burden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, several studies suggest that women experience a larger deterioration in major cardiovascular risk factors and put on more weight than do men during their transition from normoglycemia to overt type 2 diabetes. This excess weight is associated with higher levels of biomarkers of endothelial dysfunction, inflammation, and procoagulant state. Moreover, sex differences in the prescription and use of some cardiovascular drugs may compound an “existing” disparity. We searched PubMed for articles published in English and French, by using the following terms: (“cardiovascular diseases”) AND (“diabetes mellitus”) AND (“sex disparity” OR “sex differences” OR “sex related differences” OR “sex-related differences” OR “sex disparities”). In this article, we review the available literature on the sex aspects of primary and secondary prevention of cardiovascular disease in people with type 2 diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes and associated cardiovascular risk factors.

      Abbreviations and Acronyms:

      ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Event Prevention Trial in Diabetes), ASCEND (A Study of Cardiovascular Events iN Diabetes), BMI (body mass index), BP (blood pressure), CHD (coronary heart disease), CRP (C-reactive protein), CVD (cardiovascular disease), CVRF (cardiovascular risk factor), HDL (high-density lipoprotein), HR (hazard ratio), IL-6 (interleukin 6), LDL (low-density lipoprotein), MACE (major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke)), T2DM (type 2 diabetes mellitus)
      Article Highlights
      • Women with type 2 diabetes have been underrepresented in most clinical trials that focused on the impact of drug interventions (stain therapy, newer antidiabetic drugs) on the occurrence of cardiovascular disease. This precludes firm conclusions about the effects of many drug treatments in women with type 2 diabetes.
      • Women with type 2 diabetes had higher levels of low-density lipoprotein cholesterol, and they are less likely to receive statin therapy when compared with their male counterparts.
      • Women with type 2 diabetes had to put on more weight to develop diabetes. This excess weight is associated with a greater deterioration in cardiovascular risk factors’ levels, endothelial dysfunction, low-grade inflammation, and hypercoagulability state in women as compared with men.
      • More research is needed to understand biological mechanisms underlying the sex differences in the risk of cardiovascular disease in people with type 2 diabetes.
      • More effort is needed to reduce the gap between the sexes in terms of the use of evidence-based treatment and participation in clinical trials.
      Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). Its prevalence is increasing worldwide, and this trend is projected to persist because of the demographic shift and the obesity pandemic. The global prevalence of diabetes was estimated at 8.8% in 2017, with a slightly higher prevalence among men (9.1%) than among women (8.4%).
      • Cho N.H.
      • Shaw J.E.
      • Karuranga S.
      • et al.
      IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045.
      However, despite large variations in the reported male-to-female ratio between studies in different countries and ethnicities, there is little evidence to support a sex difference in the prevalence of diabetes. Most people with diabetes have type 2 diabetes mellitus (T2DM). On the other hand, CVD is the leading cause of morbidity and mortality in people with diabetes. Modern studies show that CVD is responsible for 24% to 30% of hospitalizations
      American Diabetes Association
      Economic costs of diabetes in the U.S. in 2012.
      and around one-third of deaths
      • Rao Kondapally Seshasai S.
      • Kaptoge S.
      • Thompson A.
      • et al.
      Diabetes mellitus, fasting glucose, and risk of cause-specific death.
      • Harding J.L.
      • Shaw J.E.
      • Peeters A.
      • Guiver T.
      • Davidson S.
      • Magliano D.J.
      Mortality trends among people with type 1 and type 2 diabetes in Australia: 1997-2010.
      in people with diabetes. Despite improvements in CVD morbidity and mortality during recent decades, the population-attributable risk for diabetes as a cardiovascular risk factor continues to increase
      • Fox C.S.
      • Coady S.
      • Sorlie P.D.
      • et al.
      Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study.
      and the cardiovascular burden of diabetes remains important.
      Although women without diabetes have a lower risk of developing CVD compared with men without diabetes of the same age, this “female advantage” seems to diminish or disappear in the setting of T2DM. Indeed, the relative risk of CVD in people with T2DM compared with people without diabetes is greater in women than in men, whereas the absolute risk of CVD is either comparable between the sexes or the sex difference is much smaller in the presence of T2DM. This greater relative risk was confirmed by large meta-analyses and well-conducted studies (Figure 1; see Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org).
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
      • Shah A.D.
      • Langenberg C.
      • Rapsomaniki E.
      • et al.
      Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people.
      • Dong X.
      • Cai R.
      • Sun J.
      • et al.
      Diabetes as a risk factor for acute coronary syndrome in women compared with men: a meta-analysis, including 10 856 279 individuals and 106 703 acute coronary syndrome events.
      Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration
      Sex-specific relevance of diabetes to occlusive vascular and other mortality: a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies.
      Cardiovascular risk factors (CVRFs) clustering in women and a greater burden of novel (emergent) risk markers,
      • Lyon A.
      • Jackson E.A.
      • Kalyani R.R.
      • Vaidya D.
      • Kim C.
      Sex-specific differential in risk of diabetes-related macrovascular outcomes.
      as well as sex differences in the prescription and use of some cardiovascular drugs, were proposed to explain the higher relative risk of CVD in women with T2DM compared with their male counterparts. We therefore undertook this review of the literature concerning sex-related differences in the prevention of, and predisposition to, CVD in people with T2DM. References for this review were identified through searches of PubMed for articles published in English and French, by using the following terms: (“cardiovascular diseases”[MeSH] OR “cardiovascular diseases”[All Fields] OR “cardiovascular disease”[All Fields]) AND (“diabetes mellitus”[MeSH] OR “diabetes mellitus”[All Fields]) AND (“gender disparity”[All Fields] OR “gender differences”[All Fields] OR “sex disparity”[All Fields] OR “sex differences”[All Fields] OR “sex related differences”[All Fields] OR “sex-related differences”[All Fields] OR “gender related differences”[All Fields] OR “gender-related differences”[All Fields] OR “sex disparities”[All Fields] OR “gender disparities”[All Fields]) (see Supplemental Materials, available online at http://www.mayoclinicproceedings.org). Relevant articles based on the title and abstract were identified and retrieved. Additional articles were then added by searching references cited in the retrieved articles and by searching the authors’ personal files. There was no date limitation of our searches, but references published before 2000 were not included unless highly important or not reproduced in more recent research. It is worth mentioning that many studies refer to people with diabetes as a whole and do not distinguish between the different types of diabetes. Therefore, we use the term “diabetes” when the type of diabetes is not clearly noted. Otherwise, the term “T2DM” is used.
      Figure thumbnail gr1
      Figure 1Relative risks for major cardiovascular events in men and women with diabetes as compared with men and women without diabetes.

      Sex-Related Differences in the Association Between Obesity and T2DM and in the Impact of Lifestyle Intervention on CVD

      Obesity and T2DM

      Obesity is the most prominent risk factor for T2DM, and it is present in 37% to 61% of people with T2DM and another 26% to 42% are overweight.
      • Ridderstråle M.
      • Gudbjörnsdottir S.
      • Eliasson B.
      • Nilsson P.M.
      • Cederholm J.
      Steering Committee of the Swedish National Diabetes Register (NDR)
      Obesity and cardiovascular risk factors in type 2 diabetes: results from the Swedish National Diabetes Register.
      • Selvin E.
      • Parrinello C.M.
      • Sacks D.B.
      • Coresh J.
      Trends in prevalence and control of diabetes in the United States, 1988-1994 and 1999-2010.
      A significantly higher proportion of women with T2DM have obesity (estimated by body mass index [BMI]; calculated as the weight in kilograms divided by the height in meters squared) (P<.001) and central obesity (estimated by waist circumference; see Supplemental Table 1, available online at http://www.mayoclinicproceedings.org) (P=.0054) in comparison to their male counterparts.
      • Williams K.
      • Tchernof A.
      • Hunt K.J.
      • Wagenknecht L.E.
      • Haffner S.M.
      • Sniderman A.D.
      Diabetes, abdominal adiposity, and atherogenic dyslipoproteinemia in women compared with men.
      Moreover, women with T2DM have higher BMI values when compared with age-matched men with T2DM.
      • Awa W.L.
      • Fach E.
      • Krakow D.
      • et al.
      Type 2 diabetes from pediatric to geriatric age: analysis of gender and obesity among 120,183 patients from the German/Austrian DPV database.
      Obese people who have T2DM are characterized by higher rates of hypertension and dyslipidemia, which means an increased cardiovascular burden when compared with their nonobese counterparts, regardless of sex. However, even after adjusting for risk factors, obese individuals (with and without diabetes) still have an increased risk for CVD, meaning that obesity mediates CVD by other factors in addition to classical risk factors.
      • Lu Y.
      • Hajifathalian K.
      • et al.
      Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects)
      Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1.8 million participants.
      Interestingly, studies from Scotland and the United Kingdom showed that men develop T2DM at a lower BMI (≈2 kg/m2) than do women, presumably because of higher insulin resistance.
      • Logue J.
      • Walker J.J.
      • Colhoun H.M.
      • et al.
      Do men develop type 2 diabetes at lower body mass indices than women?.
      • Paul S.
      • Thomas G.
      • Majeed A.
      • Khunti K.
      • Klein K.
      Women develop type 2 diabetes at a higher body mass index than men.
      Also, differences in other measures of obesity (waist circumference and waist-to-hip ratio) between individuals with and without T2DM are greater in women than in men.
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Sex differences in body anthropometry and composition in individuals with and without diabetes in the UK Biobank.
      This means that women have to put on more weight (more adipose tissue) to become insulin resistant and develop T2DM. This excess weight is associated with a greater deterioration in the cardiometabolic risk. Supporting these conclusions, the mean differences in CVRF levels between individuals with T2DM and those without were greater for women than for men in a recent meta-analysis (Figure 2).
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
      Figure thumbnail gr2
      Figure 2Adjusted differences in cardiovascular risk factors between individuals with and without diabetes according to sex.
      Adapted from Lancet,
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes.
      with permission from Elsevier. Courtesy of Prof. Rachel R Huxley, MD, PhD. BMI = body mass index; BP = blood pressure; HDL = high-density lipoprotein.

      Lifestyle Interventions for the Prevention of CVD in People With T2DM

      Lifestyle interventions to improve dietary quality, increase physical activity, and obtain weight loss are indicated for people with T2DM because of their favorable effects on metabolic abnormalities and CVRFs. However, few studies have reported results of lifestyle interventions in people with T2DM in terms of the long-term occurrence and mortality of CVD. The Japan Diabetes Complications Study showed a significant reduction in the incidence of stroke among 2033 Japanese people with T2DM randomized to lifestyle intervention (P=.04), but the incidence of coronary heart disease (CHD) was not different between the intervention group and the control group. The intervention effect was not different between the sexes.
      • Sone H.
      • Tanaka S.
      • Iimuro S.
      • et al.
      Long-term lifestyle intervention lowers the incidence of stroke in Japanese patients with type 2 diabetes: a nationwide multicentre randomised controlled trial (the Japan Diabetes Complications Study).
      The Action for Health in Diabetes (Look AHEAD) study randomized 5145 individuals with T2DM from 16 centers in the United States (of whom 14% had CVD at baseline) to lifestyle intervention or usual care, and demonstrated no benefit on CVD
      • Wing R.R.
      • Bolin P.
      • et al.
      Look AHEAD Research Group
      Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
      ; the intervention effect was comparable between the sexes. Findings from a post hoc analysis of the Look AHEAD study suggest that individuals who lost 10% or more of their body weight in the first year of the study had a significant reduction (P=.034) in the occurrence of primary CVD outcomes (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for angina), with no interaction between weight loss and sex.
      • Gregg E.W.
      • Jakicic J.M.
      • et al.
      Look AHEAD Research Group
      Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial.
      The PREDIMED (Prevención con Dieta Mediterránea) study examined the effect of a Mediterranean diet supplemented with extra-virgin olive oil or with mixed nuts vs a control diet in the primary prevention of CVD. Among the 7447 randomized individuals, 4282 (57.5%) were female and 3614 (48.5%) had T2DM at baseline. The supplemented Mediterranean diet resulted in a relative risk reduction of approximately 30% in the occurrence of major adverse cardiovascular events (MACE) in the whole study population as well as in the diabetic subgroup. The effects of a supplemented Mediterranean diet were similar between the sexes regardless of diabetes status.
      • Estruch R.
      • Ros E.
      • Salas-Salvadó J.
      • et al.
      Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts.
      The impact of lifestyle intervention on CVD, especially on cardiovascular mortality, takes a long time to emerge. The Da Qing study randomized 577 Chinese individuals with impaired glucose tolerance into 1 of 4 groups: diet-only intervention, exercise-only intervention, diet plus exercise intervention, and usual care. The difference between the intervention group (composed of the 3 intervention subgroups) and the control group in terms of cardiovascular mortality became significant only after 23 years of follow-up (P=.033).
      • Li G.
      • Zhang P.
      • Wang J.
      • et al.
      Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study.
      Interestingly, in this study, the reduction in cardiovascular mortality occurred mainly in women (hazard ratio [HR]=0.28; 95% CI, 0.11-0.71; P=.01), but there was an imbalance between the sexes at baseline (men were older and more likely to be smokers).

      Sex-Related Differences in the Prevalence and Control of Classic Cardiovascular Risk Factors in People With T2DM

      Good control of classic CVRFs is of paramount importance in the primary and secondary prevention of CVD. We will consider each risk factor separately.

      Hypertension

      Hypertension is the most important risk factor. Its prevalence in people with T2DM is double that in the general population (59.4% vs 29.6% in the United States).
      • Low Wang C.C.
      • Hess C.N.
      • Hiatt W.R.
      • Goldfine A.B.
      Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus—mechanisms, management, and clinical considerations.
      Although hypertension is more common in men with diabetes before the age of 60 years, it becomes more common in women with diabetes after the age of 60 to 65 years.
      • Awa W.L.
      • Fach E.
      • Krakow D.
      • et al.
      Type 2 diabetes from pediatric to geriatric age: analysis of gender and obesity among 120,183 patients from the German/Austrian DPV database.
      This is related, at least partially, to declines in estrogens’ levels and signaling after menopause. Elevated blood pressure (BP) in the presence of T2DM is associated with an incremental increase in the cardiovascular risk, in a continuous fashion, in both sexes. Each 10-mm Hg lower BP step in people with T2DM is associated with a considerable reduction in CVD until a target systolic BP toward 130 mm Hg. Targeting systolic BP of less than 130 mm Hg is associated with fewer strokes but no further reduction in other major CVDs is observed.
      • Emdin C.A.
      • Rahimi K.
      • Neal B.
      • Callender T.
      • Perkovic V.
      • Patel A.
      Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
      So, the BP targets to be achieved are still debated (<140/90 or <130/80 mm Hg). The cardiovascular benefit seems to be dependent more on the achieved BP levels than on the drug used to achieve this target. Regardless of BP targets, many cross-sectional studies that looked at the sex aspect in the control of hypertension in people with T2DM found that hypertension is less well controlled in women than in their male counterparts (Table 1).
      • Collier A.
      • Ghosh S.
      • Hair M.
      • Waugh N.
      Gender differences and patterns of cardiovascular risk factors in type 1 and type 2 diabetes: a population-based analysis from a Scottish region.
      • Franch-Nadal J.
      • Mata-Cases M.
      • Vinagre I.
      • et al.
      Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
      • Sekerija M.
      • Poljicanin T.
      • Erjavec K.
      • Liberati-Cizmek A.-M.
      • Prašek M.
      • Metelko Z.
      Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
      • Göbl C.S.
      • Brannath W.
      • Bozkurt L.
      • et al.
      Sex-specific differences in glycemic control and cardiovascular risk factors in older patients with insulin-treated type 2 diabetes mellitus.
      • Ferrara A.
      • Mangione C.M.
      • Kim C.
      • et al.
      Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) study.
      • Gouni-Berthold I.
      • Berthold H.K.
      • Mantzoros C.S.
      • Böhm M.
      • Krone W.
      Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      • Nilsson P.M.
      • Theobald H.
      • Journath G.
      • Fritz T.
      Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
      Few studies have examined the difference in antihypertensive classes between sexes. Women with T2DM are more likely to be prescribed diuretics and beta blockers
      • Ljungman C.
      • Kahan T.
      • Schiöler L.
      • et al.
      Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD).
      and less likely to receive angiotensin-converting enzyme inhibitors
      • Norhammar A.
      • Stenestrand U.
      • Lindbäck J.
      • Wallentin L.
      Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA)
      Women younger than 65 years with diabetes mellitus are a high-risk group after myocardial infarction: a report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA).
      • Butalia S.
      • Lewin A.M.
      • Simpson S.H.
      • et al.
      Sex-based disparities in cardioprotective medication use in adults with diabetes.
      • Wallentin F.
      • Wettermark B.
      • Kahan T.
      Drug treatment of hypertension in Sweden in relation to sex, age, and comorbidity.
      and calcium channel blockers than are men with T2DM.
      • Ljungman C.
      • Kahan T.
      • Schiöler L.
      • et al.
      Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD).
      • Krämer H.U.
      • Raum E.
      • Rüter G.
      • et al.
      Gender disparities in diabetes and coronary heart disease medication among patients with type 2 diabetes: results from the DIANA study.
      Table 1Summary of Studies That Analyzed the Association Between Sex and the Control of Hypertension in People With Type 2 Diabetes Mellitus
      ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CHD = coronary heart disease; CVD = cardiovascular disease; DBP = diastolic blood pressure; NR = not reported; NS = not significant, SBP = systolic blood pressure; ↔ = no difference.
      SBP and DBP were deemed controlled if <140 mm Hg and <90 mm Hg, respectively, unless otherwise indicated.
      Reference, yearSettingsNo. of participantsWomen: mean SBP ± (% controlled)Men: mean SBP ± (% controlled)DBPDifferences in drug treatmentRemarks
      Al-Salameh et al,
      • Al-Salameh A.
      • Bucher S.
      • Bauduceau B.
      • et al.
      Gender-related differences in the control of cardiovascular risk factors in primary care for elderly patients with type 2 diabetes: a cohort study.
      2017
      Prospective cohort, primary care, France517 Men

      466 Women
      134.7 mm Hg133.8 mm Hg75.7 vs 75.4 mm Hg for women and men, respectivelyNS
      Billimek et al,
      • Billimek J.
      • Malik S.
      • Sorkin D.H.
      • et al.
      Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification.
      2015
      Cross-sectional study, USA555 Men

      814 Women
      67.7% Controlled71.8% ControlledNRNS
      Schroeder et al,
      • Schroeder E.B.
      • Bayliss E.A.
      • Daugherty S.L.
      • Steiner J.F.
      Gender differences in cardiovascular risk factors in incident diabetes.
      2014
      Retrospective cohort study, USA3509 Men

      3038 Women all with incident diabetes
      129.8 mm Hg128.9 mm Hg77 vs 77.6 mm Hg for women and men, respectivelyWomen more likely to be on combination antihypertensive therapy, but less likely to be on ACE inhibitor or ARBWomen more likely to be at target (<130/80 or <140/80 mm Hg) compared with men in multivariate analysis
      Collier et al,
      • Collier A.
      • Ghosh S.
      • Hair M.
      • Waugh N.
      Gender differences and patterns of cardiovascular risk factors in type 1 and type 2 diabetes: a population-based analysis from a Scottish region.
      2015
      Cross-sectional study, Scotland7422 Men

      6067 Women
      134.7 mm Hg133.6 mm Hg74.9 vs 75.8 mm Hg for women and men, respectivelyNRSBP was better controlled in men but DBP better controlled in women
      Franch-Nadal et al,
      • Franch-Nadal J.
      • Mata-Cases M.
      • Vinagre I.
      • et al.
      Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
      2014
      Cross-sectional study, Spain153,987 Men

      132,804 Women
      137.5 mm Hg136.9 mm Hg76.2 vs 76.6 mm Hg for women and men, respectively73.2% of women vs 65.8% were taking antihypertensive drugsBetter control of BP in men with CVD and worse control in men without CVD compared with female counterparts
      Vimalananda et al,
      • Vimalananda V.G.
      • Miller D.R.
      • Hofer T.P.
      • Holleman R.G.
      • Klamerus M.L.
      • Kerr E.A.
      Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
      2013
      Retrospective cohort study, USA646,429 Men

      21,780 Women all were veterans
      132 mm Hg132 mm Hg74 vs 75 mm Hg for women and men, respectivelyNRNS
      Penno et al,
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      2013
      Cross-sectional study, diabetes clinics, Italy8960 Men

      6813 Women
      140 mm Hg (64.6% Controlled)136 mm Hg (68.1% Controlled)47.6% vs 41.3% of women and men were taking combination therapy
      Franzini et al,
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
      2013
      Cross-sectional study, diabetes clinics, Italy1297 Men

      1168 Women
      28% Controlled (<130 mm Hg)31.2% Controlled (<130 mm Hg)Controlled (<80 mm Hg) in 47.6% vs 42% of women and men, respectively66.1% vs 54% of women and men were taking antihypertensive drugs, respectivelyDifference in SBP was evident only in subjects aged <65 y
      Rossi et al,
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative.
      2013

      Russo et al,
      • Russo G.
      • Pintaudi B.
      • Giorda C.
      • et al.
      Age- and gender-related differences in LDL-cholesterol management in outpatients with type 2 diabetes mellitus.
      2015
      Cross-sectional study, diabetes clinics, Italy227,169 Men

      188,125 Women
      139.9 mm Hg138.6 mm Hg78.9 vs 79.3 mm Hg for women and men, respectively35.9% vs 27.6% of women and men were taking diuretics, respectivelyWomen more likely to be at target (<130/80 mm Hg) compared with men in adjusted analysis
      Sekerija et al,
      • Sekerija M.
      • Poljicanin T.
      • Erjavec K.
      • Liberati-Cizmek A.-M.
      • Prašek M.
      • Metelko Z.
      Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
      2012
      Cross-sectional study, diabetes clinic, Croatia4578 Men

      4197 Women
      144.7 mm Hg141.9 mm HgNR
      Göbl et al,
      • Göbl C.S.
      • Brannath W.
      • Bozkurt L.
      • et al.
      Sex-specific differences in glycemic control and cardiovascular risk factors in older patients with insulin-treated type 2 diabetes mellitus.
      2010
      Cross-sectional study, Austria171 Men

      145 Women all receiving insulin and aged ≥60 y
      156.8 mm Hg146.1 mm Hg83 vs 78.6 mm Hg for women and men, respectively
      Ferrara et al,
      • Ferrara A.
      • Mangione C.M.
      • Kim C.
      • et al.
      Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) study.
      2008
      Cross-sectional study, USA3876 Men

      4544 Women
      55.9% Controlled60% ControlledNRDifference in SBP was evident only in subjects with CVD
      Gouni-Berthold et al,
      • Gouni-Berthold I.
      • Berthold H.K.
      • Mantzoros C.S.
      • Böhm M.
      • Krone W.
      Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
      2008
      Cross-sectional study, Germany21,938 Men

      22,955 Women
      33.6% and 36.9% of women with and without CVD were controlled37.7% and 38.6% of men with and without CVD were controlledDifference in SBP was evident only in subjects with CVD
      Wexler et al,
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      2005
      Cross-sectional study, USA1896 Men

      1943 Women
      66% and 65% of women with and without CHD were controlled71% and 66% of men with and without CHD were controlledAs for systolic BPDifferences in BP were evident only in subjects with CHD
      Nilsson et al,
      • Nilsson P.M.
      • Theobald H.
      • Journath G.
      • Fritz T.
      Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
      2004
      Cross-sectional study, primary care, Sweden5082 Men

      4293 Women
      139.1, 147, and 151.7 mm Hg for women aged <59, 60-75, and >76 y, respectively138.2, 145.5, and 145.4 mm Hg for men aged <59, 60-75, and >76 y, respectively79.8 vs 81 mm Hg for women and men in the age group 60-75 y, no difference between women and men in other groups26.7% vs 33.2% of women and men were taking ACE inhibitorsDifferences in BP were evident only in subjects aged ≥60 y
      a ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CHD = coronary heart disease; CVD = cardiovascular disease; DBP = diastolic blood pressure; NR = not reported; NS = not significant, SBP = systolic blood pressure; ↔ = no difference.
      b SBP and DBP were deemed controlled if <140 mm Hg and <90 mm Hg, respectively, unless otherwise indicated.

      Dyslipidemia

      Type 2 diabetes mellitus is associated with a cluster of lipid abnormalities (diabetic dyslipidemia) that include elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol levels, and an increase in small, dense low-density lipoprotein (LDL) particles. Dyslipidemia is present in most people with T2DM.
      • Ali M.K.
      • Bullard K.M.
      • Saydah S.
      • Imperatore G.
      • Gregg E.W.
      Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988-2014.
      It appears to be more frequent in women with T2DM after the age of 60 years than in men with T2DM of the same age group.
      • Awa W.L.
      • Fach E.
      • Krakow D.
      • et al.
      Type 2 diabetes from pediatric to geriatric age: analysis of gender and obesity among 120,183 patients from the German/Austrian DPV database.
      Again, this may be due to declines in estrogens’ levels and signaling after menopause. In a large sample of people with T2DM from Sweden, women had significantly higher levels of total, LDL, and HDL cholesterol (P<.001 for all) when compared with men. Triglyceride levels were lower in women in the youngest age group (40-54 years) but higher in elderly women (≥70 years) when compared with age-matched men.
      • Eriksson M.
      • Zethelius B.
      • Eeg-Olofsson K.
      • et al.
      Blood lipids in 75,048 type 2 diabetic patients: a population-based survey from the Swedish National Diabetes Register.
      Nowadays, statins represent the mainstay of dyslipidemia treatment and are indicated for primary prevention in most people with diabetes as well as for secondary prevention.
      • In primary prevention, the Cholesterol Treatment Trialists’ Collaboration analyzed individual participant data from 14 trials of statin therapy and found a considerable 27% relative risk reduction per 1 mmol/L reduction in LDL cholesterol in major vascular events in people with diabetes without known CVD. However, most of the evidence concerns men, because they represented more than 67% of participants in this analysis.
        • Kearney P.M.
        • Blackwell L.
        • et al.
        Cholesterol Treatment Trialists’ (CTT) Collaborators
        Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
        Indeed, women are underrepresented in primary prevention trials of statin therapy (in both diabetic and nondiabetic populations), a fact that hampers evidence-based conclusions concerning the effect of statin therapy for primary prevention in women. In a recent meta-analysis, women (with and without diabetes) allocated to statin therapy for primary prevention had a lower relative risk reduction for major vascular events when compared with men (15% vs 28% per 1 mmol/L reduction in LDL cholesterol; P=.023 for heterogeneity), but the authors did not present stratified results for the diabetic subgroup.
        • Fulcher J.
        • O’Connell R.
        • et al.
        Cholesterol Treatment Trialists’ (CTT) Collaboration
        Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
        However, the difference may be related to the lower cardiovascular risk in women. In the same meta-analysis, allocation to statin therapy (primary and secondary prevention) was associated with an absolute reduction of 1.1 mmol/L at 1 year in men and 1 mmol/L in women (P=.01 for heterogeneity). No stratified results were presented for the diabetic subgroup. So, statin therapy for primary prevention seems to be as effective in women as it is in men provided that they are at equivalent risk of CVD.
      • In secondary prevention, the efficacy of statin therapy is similar in the 2 sexes in randomized trials.
        • Kearney P.M.
        • Blackwell L.
        • et al.
        Cholesterol Treatment Trialists’ (CTT) Collaborators
        Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
        Nevertheless, some studies found that women with T2DM were less likely to be prescribed statin (or lipid-lowering treatment) when compared with male counterparts.
        • Wexler D.J.
        • Grant R.W.
        • Meigs J.B.
        • Nathan D.M.
        • Cagliero E.
        Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
        • Butalia S.
        • Lewin A.M.
        • Simpson S.H.
        • et al.
        Sex-based disparities in cardioprotective medication use in adults with diabetes.
        • Yu M.K.
        • Lyles C.R.
        • Bent-Shaw L.A.
        • Young B.A.
        Sex disparities in diabetes process of care measures and self-care in high-risk patients.
        • Baviera M.
        • Santalucia P.
        • Cortesi L.
        • et al.
        Sex differences in cardiovascular outcomes, pharmacological treatments and indicators of care in patients with newly diagnosed diabetes: analyses on administrative database.
        • Gamboa C.M.
        • Colantonio L.D.
        • Brown T.M.
        • Carson A.P.
        • Safford M.M.
        Race-sex differences in statin use and low-density lipoprotein cholesterol control among people with diabetes mellitus in the reasons for geographic and racial differences in stroke study.
        Moreover, numerous observational and cross-sectional studies had shown that a lower proportion of women with T2DM were on target regarding LDL cholesterol when compared with men (Table 2).
        • Al-Salameh A.
        • Bucher S.
        • Bauduceau B.
        • et al.
        Gender-related differences in the control of cardiovascular risk factors in primary care for elderly patients with type 2 diabetes: a cohort study.
        • Billimek J.
        • Malik S.
        • Sorkin D.H.
        • et al.
        Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification.
        • Schroeder E.B.
        • Bayliss E.A.
        • Daugherty S.L.
        • Steiner J.F.
        Gender differences in cardiovascular risk factors in incident diabetes.
        • Franch-Nadal J.
        • Mata-Cases M.
        • Vinagre I.
        • et al.
        Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
        • Vimalananda V.G.
        • Miller D.R.
        • Hofer T.P.
        • Holleman R.G.
        • Klamerus M.L.
        • Kerr E.A.
        Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
        • Penno G.
        • Solini A.
        • Bonora E.
        • et al.
        Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
        • Franzini L.
        • Ardigò D.
        • Cavalot F.
        • et al.
        Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
        • Rossi M.C.
        • Cristofaro M.R.
        • Gentile S.
        • et al.
        Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative.
        • Russo G.
        • Pintaudi B.
        • Giorda C.
        • et al.
        Age- and gender-related differences in LDL-cholesterol management in outpatients with type 2 diabetes mellitus.
        • Sekerija M.
        • Poljicanin T.
        • Erjavec K.
        • Liberati-Cizmek A.-M.
        • Prašek M.
        • Metelko Z.
        Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
        • Göbl C.S.
        • Brannath W.
        • Bozkurt L.
        • et al.
        Sex-specific differences in glycemic control and cardiovascular risk factors in older patients with insulin-treated type 2 diabetes mellitus.
        • Ferrara A.
        • Mangione C.M.
        • Kim C.
        • et al.
        Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) study.
        • Gouni-Berthold I.
        • Berthold H.K.
        • Mantzoros C.S.
        • Böhm M.
        • Krone W.
        Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
        • Wexler D.J.
        • Grant R.W.
        • Meigs J.B.
        • Nathan D.M.
        • Cagliero E.
        Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
        • Nilsson P.M.
        • Theobald H.
        • Journath G.
        • Fritz T.
        Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
        • Yu M.K.
        • Lyles C.R.
        • Bent-Shaw L.A.
        • Young B.A.
        Sex disparities in diabetes process of care measures and self-care in high-risk patients.
        • Vimalananda V.G.
        • Miller D.R.
        • Palnati M.
        • Christiansen C.L.
        • Fincke B.G.
        Gender disparities in lipid-lowering therapy among veterans with diabetes.
        • Chou A.F.
        • Scholle S.H.
        • Weisman C.S.
        • Bierman A.S.
        • Correa-de-Araujo R.
        • Mosca L.
        Gender disparities in the quality of cardiovascular disease care in private managed care plans.
        • Bird C.E.
        • Fremont A.M.
        • Bierman A.S.
        • et al.
        Does quality of care for cardiovascular disease and diabetes differ by gender for enrollees in managed care plans?.
        • Kim C.
        • Kerr E.A.
        • Bernstein S.J.
        • Krein S.L.
        Gender disparities in lipid management: the presence of disparities depends on the quality measure.
        Table 2Summary of Studies That Analyzed the Association Between Sex and the Control of LDL Cholesterol Among People With Type 2 Diabetes Mellitus
        CHD = coronary heart disease; CVD = cardiovascular disease; LDL = low-density lipoprotein; NR = not reported; ↔ = no difference.
        LDL cholesterol was considered controlled if ≤100 mg/dL, unless otherwise indicated.
        Reference, yearSettingsNo. of participantsWomen: mean LDL cholesterol ± (% controlled)Men: mean LDL cholesterol ± (% controlled)Differences in drug treatmentRemarks
        Al-Salameh et al,
        • Al-Salameh A.
        • Bucher S.
        • Bauduceau B.
        • et al.
        Gender-related differences in the control of cardiovascular risk factors in primary care for elderly patients with type 2 diabetes: a cohort study.
        2017
        Prospective cohort, primary care, France517 Men

        466 Women
        105.2 mg/dL94.9 mg/dL
        Billimek et al,
        • Billimek J.
        • Malik S.
        • Sorkin D.H.
        • et al.
        Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification.
        2015
        Cross-sectional study, USA555 Men

        814 Women
        101.8 mg/dL (55% Controlled)92.5 mg/dL (69.7% Controlled)Total cholesterol 177.7 and 159.6 mg/dL in women and men, respectively
        Schroeder et al,
        • Schroeder E.B.
        • Bayliss E.A.
        • Daugherty S.L.
        • Steiner J.F.
        Gender differences in cardiovascular risk factors in incident diabetes.
        2014
        Retrospective cohort study, USA3509 Men

        3038 Women all with incident diabetes
        104 mg/dL98.2 mg/dLMen more likely to be on lipid-lowering drugs or on statinsDifference in LDL cholesterol was not important in subjects aged <50 y
        Franch-Nadal et al,
        • Franch-Nadal J.
        • Mata-Cases M.
        • Vinagre I.
        • et al.
        Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
        2014
        Cross-sectional study, Spain153,987 Men

        132,804 Women
        115.6 mg/dL (34.2% Controlled)109.7 mg/dL (41.3% Controlled)50.6% vs 49.7% of women and men were taking lipid-lowering drugs, respectively
        Vimalananda et al,
        • Vimalananda V.G.
        • Miller D.R.
        • Hofer T.P.
        • Holleman R.G.
        • Klamerus M.L.
        • Kerr E.A.
        Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
        2013
        Retrospective cohort study, USA646,429 Men

        21,780 Women all were veterans
        102 mg/dL (55% Controlled)89 mg/dL (68% Controlled)
        Yu et al,
        • Yu M.K.
        • Lyles C.R.
        • Bent-Shaw L.A.
        • Young B.A.
        Sex disparities in diabetes process of care measures and self-care in high-risk patients.
        2013
        Cross-sectional study, USA2479 Men

        2360 Women
        115.9 mg/dL107.8 mg/dL26.5% vs 35.4% of women and men were taking statins, respectively
        Penno et al,
        • Penno G.
        • Solini A.
        • Bonora E.
        • et al.
        Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
        2013
        Cross-sectional study, diabetes clinics, Italy8960 Men

        6813 Women
        110 mg/dL (37.8% Controlled)103 mg/dL (45% Controlled)43.5% vs 41.7% of women and men were taking statins, respectivelyTotal cholesterol 191 vs 178 mg/dL in women and men, respectively
        Franzini et al,
        • Franzini L.
        • Ardigò D.
        • Cavalot F.
        • et al.
        Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
        2013
        Cross-sectional study, diabetes clinics, Italy1297 Men

        1168 Women
        14.2% Controlled18.6% Controlled
        Rossi et al,
        • Rossi M.C.
        • Cristofaro M.R.
        • Gentile S.
        • et al.
        Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative.
        2013

        Russo et al,
        • Russo G.
        • Pintaudi B.
        • Giorda C.
        • et al.
        Age- and gender-related differences in LDL-cholesterol management in outpatients with type 2 diabetes mellitus.
        2015
        Cross-sectional study, diabetes clinics, Italy227,169 Men

        188,125 Women
        112.5 mg/dL (38.4% Controlled)106.6 mg/dL (44.6% Controlled)38.2% vs 37.2% of women and men were taking statins, respectivelyTotal cholesterol 194.4 vs 182.3 mg/dL in women and men, respectively
        Sekerija et al,
        • Sekerija M.
        • Poljicanin T.
        • Erjavec K.
        • Liberati-Cizmek A.-M.
        • Prašek M.
        • Metelko Z.
        Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
        2012
        Cross-sectional study, diabetes clinic, Croatia4578 Men

        4197 Women
        113 mg/dL110 mg/dLNR
        Vimalananda et al,
        • Vimalananda V.G.
        • Miller D.R.
        • Palnati M.
        • Christiansen C.L.
        • Fincke B.G.
        Gender disparities in lipid-lowering therapy among veterans with diabetes.
        2011
        Cross-sectional study, USA89,431 Men

        22,475 Women all were veterans
        110 mg/dL101 mg/dL80% vs 84% of women and men were taking lipid-lowering drugs, respectively
        Göbl et al,
        • Göbl C.S.
        • Brannath W.
        • Bozkurt L.
        • et al.
        Sex-specific differences in glycemic control and cardiovascular risk factors in older patients with insulin-treated type 2 diabetes mellitus.
        2010
        Cross-sectional study, Austria131 Men

        107 Women all receiving insulin and aged ≥60 y
        109.3 mg/dL94.8 mg/dLThe difference between men and women was significant in multiple linear regression but borderline in multiple logistic regression
        Ferrara et al,
        • Ferrara A.
        • Mangione C.M.
        • Kim C.
        • et al.
        Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) study.
        2008
        Cross-sectional study, data, USA3201 Men

        3472 Women
        70.7% Controlled (<130 mg/dL)75% Controlled (<130 mg/dL)NRDifference in LDL cholesterol was evident only in subjects with CVD
        Gouni-Berthold et al,
        • Gouni-Berthold I.
        • Berthold H.K.
        • Mantzoros C.S.
        • Böhm M.
        • Krone W.
        Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
        2008
        Cross-sectional study, Germany21,938 Men

        22,955 Women
        43.2% and 40.5% of women with and without CVD were controlled (<130 mg/dL)50.2% and 45.1% of men with and without CVD were controlled (<130 mg/dL)41.8% vs 48.6% of women and men with CVD were taking lipid-lowering drugs, respectively
        Wexler et al,
        • Wexler D.J.
        • Grant R.W.
        • Meigs J.B.
        • Nathan D.M.
        • Cagliero E.
        Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
        2005
        Cross-sectional study, USA1896 Men

        1943 Women
        65% and 50% of women with and without CHD were controlled73% and 56% of men with and without CHD were controlled51% vs 54% of women and men with CHD were taking lipid-lowering drugs, respectively
        Chou et al,
        • Chou A.F.
        • Scholle S.H.
        • Weisman C.S.
        • Bierman A.S.
        • Correa-de-Araujo R.
        • Mosca L.
        Gender disparities in the quality of cardiovascular disease care in private managed care plans.
        2007
        Cross-sectional study, USA6094 Men

        4931 Women
        37.7% Controlled43.3% ControlledNR
        Bird et al,
        • Bird C.E.
        • Fremont A.M.
        • Bierman A.S.
        • et al.
        Does quality of care for cardiovascular disease and diabetes differ by gender for enrollees in managed care plans?.
        2007
        Cross-sectional study, USA571 and 1371 Men

        671 and 1034 Women
        33.4% and 27.6% controlled (<130 mg/dL)41.3% and 33% Controlled (<130 mg/dL)NR
        Kim et al,
        • Kim C.
        • Kerr E.A.
        • Bernstein S.J.
        • Krein S.L.
        Gender disparities in lipid management: the presence of disparities depends on the quality measure.
        2006
        Retrospective cohort study, USA1219 Men

        1370 Women
        74% Controlled (<130 mg/dL)78% Controlled (<130 mg/dL)NR
        Nilsson et al,
        • Nilsson P.M.
        • Theobald H.
        • Journath G.
        • Fritz T.
        Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
        2004
        Cross-sectional study, primary care, Sweden5082 Men

        4293 Women
        128 mg/dL in women of all age groups124 mg/dL in men of all age groupsDifference in LDL cholesterol was evident only in the 60-75–y age group
        a CHD = coronary heart disease; CVD = cardiovascular disease; LDL = low-density lipoprotein; NR = not reported; ↔ = no difference.
        b LDL cholesterol was considered controlled if ≤100 mg/dL, unless otherwise indicated.
      • Importantly, when mean LDL cholesterol levels (or the on-target percentage) were stratified according to statin therapy, women on statin therapy
        • Gamboa C.M.
        • Colantonio L.D.
        • Brown T.M.
        • Carson A.P.
        • Safford M.M.
        Race-sex differences in statin use and low-density lipoprotein cholesterol control among people with diabetes mellitus in the reasons for geographic and racial differences in stroke study.
        and untreated women tended to have worse control of LDL cholesterol than men.
        • Vimalananda V.G.
        • Miller D.R.
        • Hofer T.P.
        • Holleman R.G.
        • Klamerus M.L.
        • Kerr E.A.
        Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
        • Al-Salameh A.
        • Bucher S.
        • Bauduceau B.
        • et al.
        Gender-related differences in the control of cardiovascular risk factors in primary care for elderly patients with type 2 diabetes: a cohort study.
        The reasons for such a disparity are not completely understood, but it is possible that female sex per se confers higher LDL cholesterol levels. Nonadherence to statin therapy in women with T2DM (because of adverse effects or cost) may be partially responsible for this difference in the treated group, as suggested by some authors.
        • Billimek J.
        • Malik S.
        • Sorkin D.H.
        • et al.
        Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification.
        Of note, female sex is associated with a higher risk of statin-associated muscle symptoms
        • Thompson P.D.
        • Panza G.
        • Zaleski A.
        • Taylor B.
        Statin-associated side effects.
        although these symptoms are especially reported in observational studies but not in randomized controlled ones.
        • Gupta A.
        • Thompson D.
        • Whitehouse A.
        • et al.
        Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.
      Other drugs are also used as second-line treatment to treat diabetic dyslipidemia. Ezetimibe as an add-on to statin therapy improved MACE in people with diabetes, and its effect seems to be comparable between women and men.
      • Chang S.H.
      • Wu L.S.
      • Lee C.H.
      • et al.
      Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: a population-based dynamic cohort study.
      Fenofibrate reduced the occurrence of total CVD in people with T2DM when used in individuals without statin,
      • Keech A.
      • Simes R.J.
      • Barter P.
      • et al.
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
      whereas it failed to do so when added to statin therapy.
      • Ginsberg H.N.
      • Elam M.B.
      • et al.
      ACCORD Study Group
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      Interestingly, the results of the ACCORD study demonstrated that fenofibrate as an add-on to statin therapy was associated with a possible benefit for men and possible harm for women (P=.01 for interaction by sex). A subsequent analysis of the data from the FIELD study concluded that fenofibrate reduced CVD similarly in both sexes.
      • d’Emden M.C.
      • Jenkins A.J.
      • Li L.
      • et al.
      Favourable effects of fenofibrate on lipids and cardiovascular disease in women with type 2 diabetes: results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
      Recently, evolocumab led to a substantial reduction in cardiovascular outcomes in people with diabetes who were on statin therapy.
      • Sabatine M.S.
      • Leiter L.A.
      • Wiviott S.D.
      • et al.
      Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial.
      The authors did not report separate HR values for men and women with diabetes but, in the original study (people with and without diabetes), evolocumab reduced cardiovascular outcomes similarly in both sexes.
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.

      Smoking

      Tobacco smoking is an independent risk factor for CVD that is associated with considerably increased relative risk of cardiovascular death and CVD in people with diabetes when compared with people with diabetes who do not smoke. Recent meta-analyses suggest that the combination of smoking and diabetes confers a higher relative risk of CHD and a lower relative risk of stroke in women compared with men,
      • Qin R.
      • Chen T.
      • Lou Q.
      • Yu D.
      Excess risk of mortality and cardiovascular events associated with smoking among patients with diabetes: meta-analysis of observational prospective studies.
      • Pan A.
      • Wang Y.
      • Talaei M.
      • Hu F.B.
      Relation of smoking with total mortality and cardiovascular events among patients with diabetes mellitus: a meta-analysis and systematic review.
      although more studies are needed to confirm such associations.
      The prevalence of smoking in people with diabetes varies widely across studies, but it remains relatively high. Worldwide, a far higher proportion of men than women in the general population smoke tobacco, whereas among people with diabetes this sex gap is attenuated. However, the global estimation of the population-attributable fraction for cardiovascular death and CVD remains about 4 times higher in men with diabetes than in women with diabetes.
      • Pan A.
      • Wang Y.
      • Talaei M.
      • Hu F.B.
      Relation of smoking with total mortality and cardiovascular events among patients with diabetes mellitus: a meta-analysis and systematic review.
      Smoking cessation is accompanied by a reduction in the risk of CVD in comparison to ongoing smoking, and its effects are broadly the same in both sexes.
      • Blomster J.I.
      • Woodward M.
      • Zoungas S.
      • et al.
      The harms of smoking and benefits of smoking cessation in women compared with men with type 2 diabetes: an observational analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial.
      Of note, smoking cessation is followed by weight gain, but this does not seem to offset the cardiovascular benefit.
      • Clair C.
      • Rigotti N.A.
      • Porneala B.
      • et al.
      Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes.
      This subject needs further research to determine whether women gain more or less weight than do men after smoking cessation.

      Sex-Related Differences in the Management of T2DM

      Diabetes Control

      In the past, studies of CVD in people with T2DM focused more on treatment targets than on drug choices. However, despite abundant evidence on the association between hyperglycemia and increased cardiovascular risk, intensive glucose control did not reduce cardiovascular mortality in randomized controlled trials. A small reduction in the risk of nonfatal myocardial infarction and lower limb amputation was found in some meta-analyses.
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • et al.
      Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
      • Seidu S.
      • Achana F.A.
      • Gray L.J.
      • Davies M.J.
      • Khunti K.
      Effects of glucose-lowering and multifactorial interventions on cardiovascular and mortality outcomes: a meta-analysis of randomized control trials.
      None of these studies provided evidence to suggest that the effect of intensive glucose control on CVD differs by sex, except for a recent meta-analysis that suggested a significant reduction in MACE (P=.022) only in studies with a male percentage of less than 70% when compared with studies composed of 70% or more men.
      • Fang H.J.
      • Zhou Y.H.
      • Tian Y.J.
      • Du H.Y.
      • Sun Y.X.
      • Zhong L.Y.
      Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: a meta-analysis of data from 58,160 patients in 13 randomized controlled trials.
      However, the interaction test was not significant (P=.724). Therefore, to reduce the risk of CVD in people with T2DM, guidelines targeted comprehensive control of CVRFs, as proposed by the Steno 2 study.
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      In this setting, many cross-sectional studies have found that women with T2DM have worse control of diabetes (higher glycated hemoglobin A1C levels or lower proportion on-target compared with men) with
      • Strom Williams J.L.
      • Lynch C.P.
      • Winchester R.
      • Thomas L.
      • Keith B.
      • Egede L.E.
      Gender differences in composite control of cardiovascular risk factors among patients with type 2 diabetes.
      or without poor control of other CVRFs (Table 3).
      • Vimalananda V.G.
      • Miller D.R.
      • Hofer T.P.
      • Holleman R.G.
      • Klamerus M.L.
      • Kerr E.A.
      Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative.
      • Sekerija M.
      • Poljicanin T.
      • Erjavec K.
      • Liberati-Cizmek A.-M.
      • Prašek M.
      • Metelko Z.
      Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      • Nilsson P.M.
      • Theobald H.
      • Journath G.
      • Fritz T.
      Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
      Table 3Summary of Studies That Analyzed the Association Between Sex and the Control of Glycated Hemoglobin A1C as Indicator of T2DM Control
      CHD = coronary heart disease; CVD = cardiovascular disease; NR = not reported; NS = not significant; OR = odds ratio; T2DM = type 2 diabetes mellitus; ↔ = no difference.
      A1C was considered controlled if ≤7%, unless otherwise indicated.
      Reference, yearSettingsNo. of participantsWomen: mean A1C ± (% controlled)Men: mean A1C ± (% controlled)Difference in drug treatmentRemarks
      Al-Salameh et al,
      • Al-Salameh A.
      • Bucher S.
      • Bauduceau B.
      • et al.
      Gender-related differences in the control of cardiovascular risk factors in primary care for elderly patients with type 2 diabetes: a cohort study.
      2017
      Prospective cohort, primary care, France517 Men

      466 Women
      7%6.9%NS
      Billimek et al,
      • Billimek J.
      • Malik S.
      • Sorkin D.H.
      • et al.
      Understanding disparities in lipid management among patients with type 2 diabetes: gender differences in medication nonadherence after treatment intensification.
      2015
      Cross-sectional study, USA555 Men

      814 Women
      67.3% Controlled (<8%)68% Controlled (<8%)Women more likely to be controlled in adjusted analysis
      Schroeder et al,
      • Schroeder E.B.
      • Bayliss E.A.
      • Daugherty S.L.
      • Steiner J.F.
      Gender differences in cardiovascular risk factors in incident diabetes.
      2014
      Retrospective cohort study, USA3509 Men

      3038 Women all with incident diabetes
      6.9%6.9%NRNS
      Collier et al,
      • Collier A.
      • Ghosh S.
      • Hair M.
      • Waugh N.
      Gender differences and patterns of cardiovascular risk factors in type 1 and type 2 diabetes: a population-based analysis from a Scottish region.
      2015
      Cross-sectional study, Scotland7313 Men

      5956 Women
      7.357.44NRNS
      Franch-Nadal et al,
      • Franch-Nadal J.
      • Mata-Cases M.
      • Vinagre I.
      • et al.
      Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
      2014
      Cross-sectional study, Spain153,987 Men

      132,804 Women
      7.1% (56.5% Controlled)7.2% (55.8% Controlled)75.9% vs 75.4% of women and men were taking glucose-lowering treatment, respectivelyIn multivariate analysis, men in secondary prevention had better control of T2DM (OR, 0.95) compared with women
      Vimalananda et al,
      • Vimalananda V.G.
      • Miller D.R.
      • Hofer T.P.
      • Holleman R.G.
      • Klamerus M.L.
      • Kerr E.A.
      Accounting for clinical action reduces estimates of gender disparities in lipid management for diabetic veterans.
      2013
      Retrospective cohort study, USA646,429 Men

      21,780 Women all veterans
      7.3%7.3%NR
      Yu et al,
      • Yu M.K.
      • Lyles C.R.
      • Bent-Shaw L.A.
      • Young B.A.
      Sex disparities in diabetes process of care measures and self-care in high-risk patients.
      2013
      Cross-sectional study of medical records, USA2479 Men

      2360 Women
      7.8% (33.9% Controlled)7.8% (31.7% Controlled)NRWomen were more likely to achieve A1C target in multivariate analysis (OR, 1.19)
      Penno et al,
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      2013
      Cross-sectional study, diabetes clinics, Italy8960 Men

      6813 Women
      7.38% (37.9% Controlled)7.22% (43.2% Controlled)36.7% vs 34.7% of women and men were taking combination treatment, respectively
      Franzini et al,
      • Franzini L.
      • Ardigò D.
      • Cavalot F.
      • et al.
      Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.
      2013
      Cross-sectional study, diabetes clinics, Italy1297 Men

      1168 Women
      33.8% Controlled40.2% Controlled16.6% vs 11.7% of women and men were taking insulin (alone or in combination), respectively
      Rossi et al,
      • Rossi M.C.
      • Cristofaro M.R.
      • Gentile S.
      • et al.
      Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative.
      2013
      Cross-sectional study, diabetes clinics, Italy227,169 Men

      188,125 Women
      7.5% (41.7% Controlled)7.4% (45.5% Controlled)
      Sekerija et al,
      • Sekerija M.
      • Poljicanin T.
      • Erjavec K.
      • Liberati-Cizmek A.-M.
      • Prašek M.
      • Metelko Z.
      Gender differences in the control of cardiovascular risk factors in patients with type 2 diabetes—a cross-sectional study.
      2012
      Cross-sectional study, diabetes clinic, Croatia4578 Men

      4197 Women
      7.05% (53% Controlled)6.86% (58% Controlled)51.3% vs 44% of women and men were taking insulin (alone or in combination), respectively
      Göbl et al,
      • Göbl C.S.
      • Brannath W.
      • Bozkurt L.
      • et al.
      Sex-specific differences in glycemic control and cardiovascular risk factors in older patients with insulin-treated type 2 diabetes mellitus.
      2010
      Cross-sectional study, Austria209 Men

      183 Women all receiving insulin and aged ≥60 y
      8%7.9%NS
      Ferrara et al,
      • Ferrara A.
      • Mangione C.M.
      • Kim C.
      • et al.
      Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) study.
      2008
      Cross-sectional study, USA3748 Men

      4345 Women
      58.8% Controlled (≤8%)57.9% Controlled (≤8%)33.7% vs 27.9% of women and men were taking insulin (alone or in combination), respectivelyNS
      Gouni-Berthold et al,
      • Gouni-Berthold I.
      • Berthold H.K.
      • Mantzoros C.S.
      • Böhm M.
      • Krone W.
      Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes.
      2008
      Cross-sectional study, primary care, Germany21,938 Men

      22,955 Women
      72.9% and 77.3% of women with and without CVD were controlled (≤8%)73.6% and 77.6% of men with and without CVD were controlled (≤8%)Women with CVD were at a higher risk to have noncontrolled diabetes in adjusted analysis
      Wexler et al,
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      2005
      Cross-sectional study, USA1896 Men

      1943 Women
      34% and 40% of women with and without CHD were controlled, respectively41% of men with and without CHD were controlled, respectively
      Nilsson et al,
      • Nilsson P.M.
      • Theobald H.
      • Journath G.
      • Fritz T.
      Gender differences in risk factor control and treatment profile in diabetes: a study in 229 Swedish primary health care centres.
      2004
      Cross-sectional study, primary care, Sweden5082 Men

      4293 Women
      6.5%, 6.9%, and 6.6% for women aged <59, 60-75, and >76 y, respectively6.7%, 6.6%, and 6.5% for men aged <59, 60-75, and >76 y, respectivelyDifference in diabetes control was evident only in subjects aged ≥60 y
      a CHD = coronary heart disease; CVD = cardiovascular disease; NR = not reported; NS = not significant; OR = odds ratio; T2DM = type 2 diabetes mellitus; ↔ = no difference.
      b A1C was considered controlled if ≤7%, unless otherwise indicated.

      Pharmacotherapy for T2DM

      Little is known about sex disparities in the effects of older antidiabetic drugs on CVD. It appears that the effects of metformin,
      • Lamanna C.
      • Monami M.
      • Marchionni N.
      • Mannucci E.
      Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials.
      rosiglitazone,
      • Home P.D.
      • Pocock S.J.
      • Beck-Nielsen H.
      • et al.
      Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.
      pioglitazone,
      • Lincoff A.M.
      • Wolski K.
      • Nicholls S.J.
      • Nissen S.E.
      Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.
      nateglinide,
      • McMurray J.J.
      • Holman R.R.
      • et al.
      NAVIGATOR Study Group
      Effect of nateglinide on the incidence of diabetes and cardiovascular events.
      and acarbose
      • Holman R.R.
      • Coleman R.L.
      • Chan J.C.N.
      • et al.
      Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.
      on CVD are not different between the sexes. A recent study from Italy compared the effects of pioglitazone vs sulfonylurea as add-on treatments with metformin on CVD in people with T2DM. The incidence of the primary outcome (all-cause death, nonfatal myocardial infarction including silent myocardial infarction, nonfatal stroke, or urgent coronary revascularization) was similar for both drugs and the effect was comparable in both sexes.
      • Vaccaro O.
      • Masulli M.
      • Nicolucci A.
      • et al.
      Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.
      In 2008, the US Food and Drug Administration issued guidance for industry that required the demonstration of cardiovascular safety of new antidiabetic drugs and recommended exploring the occurrence of CVD in subgroups determined by sex. Members of the dipeptidyl peptidase 4 inhibitors were the first drugs to be evaluated after this guidance. Their effects on CVD were found to be noninferior (and nonsuperior) to placebo in randomized controlled trials, and there was no sex heterogeneity in the occurrence of MACE.
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      TECOS Study Group
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      Of note, the rate of hospitalization for heart failure was increased with saxagliptin.
      • Scirica B.M.
      • Braunwald E.
      • Raz I.
      • et al.
      SAVOR-TIMI 53 Steering Committee and Investigators
      Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial.
      Recently, 2 classes of new antidiabetic drugs, which have favorable effects on CVRFs beyond their effects on hyperglycemia, showed a beneficial effect on CVD in people with T2DM, further supporting the need to simultaneously control many CVRFs:
      • -
        Two human glucagon-like peptide 1 receptor agonists showed favorable effects on CVD in people with T2DM. Liraglutide significantly reduced the occurrence of MACE in people with T2DM (P<.001); the reduction was comparable between men (6003 participants) and women (3337 participants).
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        Semaglutide, which was tested in a group of 3297 individuals with T2DM (2002 males and 1295 females), reduced the occurrence of MACE in men (HR, 0.68; 95% CI, 0.50-0.92) but not in women (HR, 0.84; 95% CI, 0.54-1.32), with P=.45 for interaction by sex.
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        Whether these results reflect a true sex difference or are the result of inadequate statistical power (related to underrepresentation of women) remains to be established although the latter possibility seems more probable. In contrast, lixisenatide and weekly exenatide did not decrease or increase the occurrence of MACE in people with T2DM when compared with placebo, regardless of sex.
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • et al.
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      • -
        Inhibitors of sodium-glucose cotransporter 2 proved effective in reducing the occurrence of MACE in people with T2DM. Although the HR for MACE was comparable between sexes in the EMPA-REG OUTCOME (cardiovascular outcome trial of empagliflozin) trial, the decrease in cardiovascular mortality was significant only in men (but not in women) treated with empagliflozin.
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        Again, the number of men (4687 participants) was twice the number of women (2333 participants), which raises questions of statistical power. Canagliflozin showed a similar reduction in MACE in both sexes.
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        Moreover, results from an observational analysis from Denmark, Norway, and Sweden (22,830 users of sodium-glucose cotransporter 2 inhibitors) suggest an equivalent effect on MACE between men and women.
        • Birkeland K.I.
        • Jørgensen M.E.
        • Carstensen B.
        • et al.
        Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis.
      Concerning insulin therapy, insulin glargine neither reduced nor increased cardiovascular outcomes in individuals with hyperglycemia, with similar results between sexes.
      • Gerstein H.C.
      • Bosch J.
      • et al.
      ORIGIN Trial Investigators
      Basal insulin and cardiovascular and other outcomes in dysglycemia.
      Recently, insulin degludec was compared with insulin glargine for its cardiovascular safety. Degludec was not inferior to glargine with respect to the incidence of MACE, although the results of subgroup analyses favored degludec in women (HR, 0.76; 95% CI, 0.76-0.99 for women vs HR, 0.99; 95% CI, 0.83-1.20 for men; P=.099 for interaction by sex).
      • Marso S.P.
      • McGuire D.K.
      • Zinman B.
      • et al.
      Efficacy and safety of degludec versus glargine in type 2 diabetes.

      Sex-Related Differences in Antiplatelet Therapy for Prevention of CVD in People With T2DM

      Primary Prevention

      The platelets of people with diabetes are characterized by several abnormalities in their functions (enhanced adhesion, activation, and aggregation), leading to increased reactivity. They also have an accelerated turnover, leading to a larger number of less mature platelets entering the circulation. Augmented oxidative stress and impaired endothelial function further participate in platelet dysfunction in diabetes, which plays a pivotal role in atherothrombosis. Nevertheless, the effectiveness of aspirin therapy for primary prevention of CVD in people with diabetes remains unproven. Randomized controlled trials report conflicting results, whereas 7 meta-analyses that included different combinations of trials concluded that aspirin is not associated with a statistically important reduction in CVD.
      • Capodanno D.
      • Angiolillo D.J.
      Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus.
      Interestingly, 3 of these meta-analysis suggested differences in the effect of aspirin according to sex: De Berardis et al
      • De Berardis G.
      • Sacco M.
      • Strippoli G.F.M.
      • et al.
      Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials.
      reported that aspirin significantly reduced the risk of myocardial infarction in men (P=.03) but not in women
      • De Berardis G.
      • Sacco M.
      • Strippoli G.F.M.
      • et al.
      Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials.
      ; Zhang et al
      • Zhang C.
      • Sun A.
      • Zhang P.
      • et al.
      Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis.
      reported a lower relative risk for myocardial infarction in trials with a male percentage of 50% or more and a lower relative risk for stroke in trials with a male percentage of less than 50%; and Kunutsor et al
      • Kunutsor S.K.
      • Seidu S.
      • Khunti K.
      Aspirin for primary prevention of cardiovascular and all-cause mortality events in diabetes: updated meta-analysis of randomized controlled trials.
      found that aspirin significantly reduced MACE in men (P=.033) but not in women. Data from the Swedish National Diabetes Register showed an increased risk of CHD in women with T2DM who received aspirin for primary prevention.
      • Ekström N.
      • Cederholm J.
      • Zethelius B.
      • et al.
      Aspirin treatment and risk of first incident cardiovascular diseases in patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register.
      However, these results concerning sex-related differences in the effects of aspirin should be interpreted with caution because of limited subgroup analyses and a subsequent lack of statistical power. Furthermore, these differences were not consistently found in studies of aspirin for primary prevention in the general population,
      • Guirguis-Blake J.M.
      • Evans C.V.
      • Senger C.A.
      • O’Connor E.A.
      • Whitlock E.P.
      Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force.
      nor were they continuously observed in secondary prevention trials in people with diabetes.
      • Baigent C.
      • Blackwell L.
      • et al.
      Antithrombotic Trialists’ (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      Hopefully, the results of ongoing studies, including A Study of Cardiovascular Events iN Diabetes (ASCEND) and Aspirin and Simvastatin Combination for Cardiovascular Event Prevention Trial in Diabetes (ACCEPT-D), will shed further light on the impact of sex on aspirin effects. The first trial, ASCEND, has recruited 15,480 individuals with diabetes
      • Aung T.
      • Haynes R.
      • Barton J.
      • et al.
      Cost-effective recruitment methods for a large randomised trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND).
      and ASCEND’s results are expected in 2018, whereas ACCEPT-D has recruited 5170 individuals with diabetes but no fixed date is provided for the results because ACCEPT-D is an event-driven study.
      • De Berardis G.
      • Sacco M.
      • Evangelista V.
      • et al.
      Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins.

      Secondary Prevention

      The efficacy of aspirin for secondary prevention of CVD is undisputed in both sexes. Nevertheless, many studies have suggested that aspirin is underused in women with T2DM,
      • Klinke J.A.
      • Johnson J.A.
      • Guirguis L.M.
      • et al.
      Underuse of aspirin in type 2 diabetes mellitus: prevalence and correlates of therapy in rural Canada.
      • Winston G.J.
      • Barr R.G.
      • Carrasquillo O.
      • Bertoni A.G.
      • Shea S.
      Sex and racial/ethnic differences in cardiovascular disease risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).
      notably for secondary prevention.
      • Franch-Nadal J.
      • Mata-Cases M.
      • Vinagre I.
      • et al.
      Differences in the cardiometabolic control in type 2 diabetes according to gender and the presence of cardiovascular disease: results from the eControl study.
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study.
      • Wexler D.J.
      • Grant R.W.
      • Meigs J.B.
      • Nathan D.M.
      • Cagliero E.
      Sex disparities in treatment of cardiac risk factors in patients with type 2 diabetes.
      • Baviera M.
      • Santalucia P.
      • Cortesi L.
      • et al.
      Sex differences in cardiovascular outcomes, pharmacological treatments and indicators of care in patients with newly diagnosed diabetes: analyses on administrative database.
      • Kautzky-Willer A.
      • Kamyar M.R.
      • Gerhat D.
      • et al.
      Sex-specific differences in metabolic control, cardiovascular risk, and interventions in patients with type 2 diabetes mellitus.
      Dual antiplatelet therapy is often needed for patients with acute coronary syndromes, especially those undergoing percutaneous coronary intervention. There are only sparse data about sex-related differences in the action of other antiplatelet drugs in people with T2DM. Indirect evidence suggests that clopidogrel and ticagrelor are as effective in women with diabetes as in male counterparts.
      • Zaccardi F.
      • Pitocco D.
      • Willeit P.
      • Laukkanen J.A.
      Efficacy and safety of P2Y12 inhibitors according to diabetes, age, gender, body mass index and body weight: systematic review and meta-analyses of randomized clinical trials.
      Prasugrel was associated with a trend toward a larger reduction in MACE in men with diabetes than in female counterparts.
      • Wiviott S.D.
      • Braunwald E.
      • Angiolillo D.J.
      • et al.
      Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel—Thrombolysis in Myocardial Infarction 38.

      Sex-Related Differences in the Prevalence and Effects of Novel (Emergent) Risk Markers of Cardiovascular Risk

      Excess risk of CVD in people with T2DM is not fully explained by traditional CVRFs. Moreover, the greater relative risk of CVD in women with T2DM is not completely accounted for by those CVRFs. Chronic low-grade inflammation, endothelial dysfunction, and procoagulant state play an important role in the pathogenesis of atherothrombosis in people with T2DM. Therefore, investigators looked for the association between biomarkers of inflammation, endothelial dysfunction, and hypercoagulability on one hand and the development of CVD in people with T2DM on the other hand. Only scanty evidence exists concerning sex-related differences in these biomarkers; results are not always consistent and sometimes conflicting results were reported. It is important to note that these biomarkers are interconnected but they are represented separately for the sake of simplification.

      Endothelial Dysfunction

      It is widely accepted that T2DM and the accompanying hyperglycemia/insulin resistance alter the endothelial function and contribute to the development of CVD in people with T2DM. When damaged, endothelial cells secrete molecules such as von Willebrand factor and express adhesion molecules such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin. It is worth mentioning that estrogens reduce the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 by endothelial cells via nongenomic mechanisms and participate in maintaining the endothelial function.
      • Morselli E.
      • Santos R.S.
      • Criollo A.
      • Nelson M.D.
      • Palmer B.F.
      • Clegg D.J.
      The effects of oestrogens and their receptors on cardiometabolic health.
      von Willebrand factor has been linked to the development of CVD and cardiovascular mortality in people with T2DM, whereas E-selectin was found to be associated with CVD in those people but none of these results were stratified by sex.
      Women without diabetes have a more healthy endothelial function, as assessed by endothelium-dependent vasodilation, when compared with men. In contrast, women and men with T2DM have similar endothelial dysfunction, suggesting that women deteriorate their endothelial function to a greater extent before being diagnosed with T2DM.
      • Steinberg H.O.
      • Paradisi G.
      • Cronin J.
      • et al.
      Type II diabetes abrogates sex differences in endothelial function in premenopausal women.
      One study found that the differences in von Willebrand factor levels between individuals with and without T2DM were more pronounced in women than in men (P=.04 for interaction by sex).
      • Wannamethee S.G.
      • Papacosta O.
      • Lawlor D.A.
      • et al.
      Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women’s Heart Health Study.
      However, these results still need to be confirmed.

      Inflammation

      Different markers of inflammation were evaluated to assess their relation to the development of CVD in people with T2DM. The list includes, among others, white blood cells, C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, tumor necrosis factor-α, and interleukin-1 receptor antagonist. Detailed description of the role of these markers in the pathophysiology of CVD in people with T2DM is beyond the scope of this review, and we report only those results that are related to the sex aspect (difference between sexes in the prevalence or effect of these markers):
      • Point estimate for the association between inflammatory markers (especially CRP and fibrinogen) and cardiovascular end points were generally comparable between men and women with T2DM.
        • Kengne A.P.
        • Batty G.D.
        • Hamer M.
        • Stamatakis E.
        • Czernichow S.
        Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies.
        Only 1 study found an association between CRP and coronary artery calcification (subclinical atherosclerosis) in women with T2DM but not in men (P<.001 for interaction).
        • Qasim A.N.
        • Budharaju V.
        • Mehta N.N.
        • et al.
        Gender differences in the association of C-reactive protein with coronary artery calcium in type-2 diabetes.
      • A study from Finland found that women with T2DM had higher levels of inflammatory markers (high-sensitivity CRP and interleukin-1 receptor antagonist) when compared with men with T2DM. Interestingly, women experienced a greater increase in inflammatory markers during their travel from normal glycemia to T2DM than did men.
        • Saltevo J.
        • Kautiainen H.
        • Vanhala M.
        Gender differences in adiponectin and low-grade inflammation among individuals with normal glucose tolerance, prediabetes, and type 2 diabetes.
        Similar patterns were found in the Strong Heart Study (fibrinogen)
        • Howard B.V.
        • Cowan L.D.
        • Go O.
        • Welty T.K.
        • Robbins D.C.
        • Lee E.T.
        Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. The Strong Heart Study.
        and in an analysis of data from the British Regional Heart Study and British Women’s Heart Health Study.
        • Wannamethee S.G.
        • Papacosta O.
        • Lawlor D.A.
        • et al.
        Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women’s Heart Health Study.
        However, the latter analysis did not find any difference between sexes in CRP or IL-6 levels, whereas others had found that women with T2DM had higher levels of CRP (with or without IL-6 or fibrinogen) when compared with male counterparts.
        • Mojiminiyi O.A.
        • Abdella N.
        • Moussa M.A.
        • Akanji A.O.
        • Al Mohammedi H.
        • Zaki M.
        Association of C-reactive protein with coronary heart disease risk factors in patients with type 2 diabetes mellitus.
        • Bruno G.
        • Fornengo P.
        • Novelli G.
        • et al.
        C-reactive protein and 5-year survival in type 2 diabetes: the Casale Monferrato Study.
        • Lowe G.
        • Woodward M.
        • Hillis G.
        • et al.
        Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE study.
        • Mascarenhas-Melo F.
        • Marado D.
        • Palavra F.
        • et al.
        Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women.
        Put together, these results point toward a higher burden of inflammation in women with T2DM compared with male counterparts.

      Coagulation

      Type 2 diaetes mellitus is characterized by an imbalance between anticoagulant factors and procoagulant ones that favors procoagulant factors and, coupled with decreased fibrinolysis, contributes to the increased risk of atherothrombosis. Some studies had found that women with T2DM, when compared with male counterparts, had higher levels of factor VII coagulant activity,
      • Chan P.
      • Pan W.H.
      Coagulation activation in type 2 diabetes mellitus: the higher coronary risk of female diabetic patients.
      • Mansfield M.W.
      • Heywood D.M.
      • Grant P.J.
      Sex differences in coagulation and fibrinolysis in white subjects with non-insulin-dependent diabetes mellitus.
      factor VIII,
      • Wannamethee S.G.
      • Papacosta O.
      • Lawlor D.A.
      • et al.
      Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women’s Heart Health Study.
      and/or plasminogen activator inhibitor-1,121,122 a potent inhibitor of fibrinolysis that was found to be associated with CVD (especially peripheral arterial disease) among people with T2DM. Regardless of coagulation factors and plasminogen activator inhibitor-1 levels, Alzahrani et al
      • Alzahrani S.H.
      • Hess K.
      • Price J.F.
      • et al.
      Gender-specific alterations in fibrin structure function in type 2 diabetes: associations with cardiometabolic and vascular markers.
      analyzed clot structure/fibrinolysis in 875 individuals with T2DM and found that women, when compared with men, had compact fibrin clot resistant to fibrinolysis “prothrombotic phenotype.” Increased BMI and decreased HDL cholesterol were associated with the “prothrombotic phenotype” in women, whereas hyperglycemia was associated with adverse clot phenotype in men.
      • Alzahrani S.H.
      • Hess K.
      • Price J.F.
      • et al.
      Gender-specific alterations in fibrin structure function in type 2 diabetes: associations with cardiometabolic and vascular markers.
      Together, these quantitive and qualitative changes in coagulation/fibrinolysis could be partly responsible for the increased relative risk of CVD in women with T2DM (Table 4).
      Table 4Summary of Sex Differences in the Prevention of, and Predisposition to, Cardiovascular Disease in People With T2DM
      Risk factor/risk markerSex differences in prevalence and intensitySex differences in treatment and interventions
      Diabetes control and treatmentT2DM less well controlled in women in many cross-sectional studies

      Women were underrepresented in many trials of newer antidiabetic drugs
      ObesityHigher prevalence in women with T2DM

      Higher mean BMI in women than in men, even at the diagnosis of T2DM
      No sex difference in the impact of lifestyle intervention on CVD outcomes
      HypertensionMore common in women with T2DM after the age of 60-65 yLess well controlled in women with T2DM in many cross-sectional studies

      Women less likely than men to receive evidence-based treatments such as angiotensin-converting enzyme inhibitors
      DyslipidemiaMore common in women with T2DM after the age of 60 y

      Higher levels of total and LDL cholesterol in women but also higher levels of HDL cholesterol in women
      Worse control of LDL cholesterol in women with T2DM

      Women less likely than men to receive statin therapy

      Women were underrepresented in primary prevention trials of statin therapy
      SmokingHigher prevalence in men with T2DM
      Endothelial dysfunctionWomen experience greater deterioration of endothelial function during their travel from normal glycemia to overt T2DM
      InflammationWomen experience greater increase in inflammatory markers during their travel from normal glycemia to overt T2DM

      Higher levels of inflammatory markers in women
      Hypercoagulability stateMore pronounced changes in women with T2DM (coagulation factors’ levels and adverse clot phenotype)
      Platelet dysfunctionAspirin is underused in secondary prevention in women with T2DM
      BMI = body mass index; CVD = cardiovascular disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; T2DM = type 2 diabetes mellitus.

      Women With High Risk to Develop T2DM and CVD

      Unfortunately, once women are diagnosed with T2DM, they have already acquired a higher relative risk to develop CVD and it may be too late to reverse this high-risk status. Therefore, it is necessary to implement preventive measures for high-risk groups and to provide optimal management for women with prediabetes. Overweight and obese women, especially those with central obesity, are particularly at risk of developing T2DM. Postmenopausal women are also at risk to develop T2DM and CVD. In fact, menopausal transition is associated with increased adiposity and changes in fat distribution, which contributes to insulin resistance and T2DM although the impact of estrogens’ loss per se on the incidence of T2DM remains unclear.
      • Morselli E.
      • Santos R.S.
      • Criollo A.
      • Nelson M.D.
      • Palmer B.F.
      • Clegg D.J.
      The effects of oestrogens and their receptors on cardiometabolic health.
      • Clegg D.
      • Hevener A.L.
      • Moreau K.L.
      • et al.
      Sex hormones and cardiometabolic health: role of estrogen and estrogen receptors.
      Other high-risk groups include women with gestational diabetes and those with polycystic ovary syndrome. Interestingly, these 2 latter conditions represent 2 natural models of hyperglycemia and insulin resistance (the mechanisms at interplay in T2DM) that could help to understand the pathogenesis of the increased cardiovascular risk in women with T2DM. Women with gestational diabetes have a 7-fold increased risk of developing T2DM,
      • Bellamy L.
      • Casas J.P.
      • Hingorani A.D.
      • Williams D.
      Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis.
      and limited data suggest an increased risk of subsequent CVD. Women with polycystic ovary syndrome usually have insulin resistance, an androgen excess, and a higher prevalence of obesity and impaired glucose tolerance (or T2DM), but no large prospective cohort studies have been undertaken to confirm or negate the increased risk of subsequent CVD. Finally, women with hypertensive pregnancy disorders are at increased risk to develop T2DM and CVD.
      • Ahmed R.
      • Dunford J.
      • Mehran R.
      • Robson S.
      • Kunadian V.
      Pre-eclampsia and future cardiovascular risk among women: a review.

      Conclusion

      The main conclusions of our review are the following:
      • -
        Women with T2DM have been underrepresented in clinical trials focusing on CVD in general and in trials of statins in particular. Moreover, sex-specific analyses were often absent.
      • -
        The LDL cholesterol is less well controlled in women with T2DM, partly because of insufficient use of statins.
      • -
        During their transition from normoglycemia to T2DM, women put on more weight and accumulate a higher cardiometabolic risk burden, with a greater deterioration of endothelial function, inflammation, and hypercoagulability states than do their male counterparts.
      • -
        Aspirin might be underused in women with T2DM for secondary prevention of CVD, and is not beneficial for primary prevention.
      • -
        Blood pressure and diabetes seem to be less well controlled in women with T2DM compared with male counterparts.
      • -
        Some of these sex disparities, such as higher BMI at diagnosis of T2DM in women, are biological in nature, that is, related to female sex. The other dimension of these disparities (underuse of evidence-based treatment in women and underrepresentation of women in clinical trials) is of a psycho-socio-cultural nature and often coexists with other disparities related to socioeconomic status, race,
        • Gamboa C.M.
        • Colantonio L.D.
        • Brown T.M.
        • Carson A.P.
        • Safford M.M.
        Race-sex differences in statin use and low-density lipoprotein cholesterol control among people with diabetes mellitus in the reasons for geographic and racial differences in stroke study.
        or ethnicity. Low socioeconomic status is associated with unhealthy behaviors and with a higher prevalence of obesity and T2DM. Moreover, social, psychological, and cultural factors could influence health care access, adherence to health care interventions, engagement in healthy lifestyles, and participation in clinical trials. Thus, health care authorities should empower women, offer them equitable access to health care, and promote strategies that encourage women to adhere to health care interventions and to adopt healthy lifestyles. Moreover, health care authorities should promote high-quality research on sex differences in general and among people with diabetes in particular. Finally, health care authorities and medical societies must do more to ensure that the female half of the population is no longer represented by less than one-third of participants in clinical trials.

      Acknowledgements

      We thank Peter Kamenicky and Jacques Young for their advice and fruitful discussions.

      Supplemental Online Material

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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