Introduction
The publication of the Framingham Study and epidemiology data have shown that diabetes mellitus (DM) confers an increased risk for coronary heart disease (CHD) and cardiac mortality [1]. Features of this association are:-
- Relative risk of CHD and fatal CHD are greater in diabetic women than diabetic men.
- Classic and diabetes-related risk factors both contribute to the total CHD risk.
- Insulin treatment may be associated with a worse cardiovascular outcome.
Diabetes develops over decades: women have pre-diabetes for 10 years on average, while men have pre-diabetes for 8 years, before it progresses to overt diabetes [2]. Indeed, there is accumulating evidence to support the hypothesis that women’s metabolic and vascular risk factor profile has to deteriorate to a greater extent, i.e., women have to “travel further” than men, before becoming diabetic. The Nurses Health Study, an observational study including 117,000 female nurses followed since 1976, also found that cardiovascular risk increased in women at least 15 years before a clinical diagnosis of diabetes [3].
The risk of acute myocardial infarction (MI) is 150% greater in diabetic than non-diabetic women, but only 50% greater in diabetic than non-diabetic men, according to the Framingham data, which was among the first studies to provide evidence of the higher risk of cardiovascular disease (CVD) in diabetic women than in diabetic men [4].
Several authors have suggested that intermediate (pre-diabetic) levels of hyperglycemia are even more dangerous for women than for men. Since 1984, the annual cardiovascular (CV) mortality rate has remained greater for women than for men. Despite improvements in CV mortality in the last 2 decades, CHD remains understudied, underdiagnosed and undertreated in women.
New data have emphasized important sex differences in the pathophysiology, clinical presentation, and clinical outcomes of CHD [5]. Most women with diabetes mellitus will develop CVD years earlier than their non-diabetic counterparts.
Summarizing data from a recent pooled analysis of 64 cohorts, including nearly 900,000 individuals and over 28,000 incident CHD events, showed that the presence of diabetes nearly tripled the risk of incident CHD in women, whereas it little more than doubled the risk in men. In addition, a pooled analysis on data from 750,000 individuals and more than 12,000 stroke events provided strong evidence that women with diabetes mellitus have a 27% greater increased risk of stroke compared with their male counterparts. The pooled relative risk of stroke associated with diabetes was 2.28 (95% CI: 1.93, 2.69) in women and 1.83 (95% CI: 1.60, 2.0) in men [2].
Many women spend one third of their lives in an “estrogen-free” state, and the abrupt increase in cardiac mortality in post-menopausal diabetic women is attributed to the overt higher risk of heart diseases in women when associated with diabetes.
Cardiovascular risk factors
Data from the literature have shown that there are significant differences in how diabetes affects the risk of CVD in men and women. Behavioral and biological sex differences may support the excess risk of diabetes-related cardiovascular risk in women. Pre-menopausal women usually have a lower risk of CVD than age-matched men and post-menopausal women. However, this “female advantage” disappears once a woman becomes diabetic [6]. Endothelial function has been shown to be impaired to a greater extent in women than in men with type 2 DM.
Diabetic women have greater relative differences in many established and novel risk factors than diabetic men, such as markers of coagulation, fibrinolysis, lipids and blood pressure, which are potentially mediated by differences in central adiposity and insulin resistance in women [2]. Furthermore, higher levels of cardiovascular risk factors and relative undertreatment in women compared with men contribute to CVD in women [7].
Females with diabetes have higher prevalent abdominal obesity, increasing the incidence of hypertension, a worse lipid profile (low levels of HDL cholesterol, small amount of LDL cholesterol, and high levels of triglycerides), a more marked endothelial dysfunction, and also an increased prevalence of hypoglycemic events compared to male diabetic patients. Women have some unique risk profiles such as hypoestrogenemia and protracted dysmetabolic state which may promote an inflammatory milieu [8, 9].
Low-grade inflammation may have a greater role in disturbing insulin action in women, and inflammatory factors may interact with female sex hormones, resulting in a decrease in the protective effects of estrogens on body fat distribution and insulin action [10].
The role of glucose
Diabetes mellitus is commonly perceived as a condition resulting from chronically elevated blood glucose level. Hyperglycemia results from both insulin deficiency and insulin resistance. Clinical studies have shown that poorer glycemic control increases arterial stiffness and intima-media thickness, suggesting that diabetes exerts some of its detrimental effects directly by damage to the vascular wall and its function [4]. In particular, the increased risk associated with poor glycemic control was 8.5-fold among women in gender-stratified multivariable-adjusted models; no association was observed among men [11].
Endothelial dysfunction
Sex differences in endothelial function may be one mechanism by which diabetes exerts differential effects on women. Nitric oxide-dependent vascular tone and endothelial-dependent vasodilation are enhanced in non-diabetic pre-menopausal women compared with men. Men with DM do not appear to have reduced endothelium-dependent vasodilation beyond that observed with obesity. In contrast, obese women with DM have impaired endothelium-dependent vasodilation beyond that observed with obesity alone [4].
Diabetes and pre-diabetes poses a greater threat of endothelial dysfunction in women than men. One study demonstrated that women with pre-diabetes had significantly higher biomarker levels of endothelial dysfunction (E-selectin and soluble intracellular adhesion molecule) and fibrinolysis (plasminogen activator inhibitor, VWF, and t-PA) than their counterparts without pre-diabetes, while men with and without pre-diabetes had similar biomarker levels [3]. These biomarkers have been shown to predict CHD. Diabetes was associated with a more adverse effect on t-PA in women than in men [12].
Left ventricular hypertrophy and obesity
The influence of diabetes on the left ventricular structure is reported to be different according to sex. There are differences in the determinants of left ventricular mass and geometry in pre-diabetic and type 2 diabetic subjects, with women being significantly more susceptible to increased fat mass than men. Insulin resistance itself stimulates left ventricular mass growth. In the Framingham Study, insulin resistance was significantly more related to left ventricular mass in women than in men. It is attributable to a trophic stimulating effect of insulin resistance that leads to increases in wall thickness and ventricular dimensions. The observed associations between obesity and left ventricular geometry are more pronounced in women than in men: the explanation for these changes is that the post-menopausal hormonal changes render the female heart highly susceptible to hypertrophic stimuli. Diabetic women are more often obese than diabetic men, and therefore may be more prone to the development of concentric hypertrophy [13]. Left ventricular hypertrophy is independently associated with congestive heart failure and cardiovascular mortality.
Heart failure
The most common cause of heart failure in men and women is CHD. However, the progression of CHD to heart failure in women is different from that in men. There are risk factors related to the post-menopausal state for the development of heart failure: diabetes, atrial fibrillation, myocardial infarction, renal insufficiency, hypertension, obesity, current smoking, left bundle branch block, and left ventricular hypertrophy. Diabetes was detected as the strongest predictor of heart failure, particularly in the setting of concomitant renal insufficiency or morbid obesity. Furthermore, there is a graded association of impaired glycemic control and increased risk of heart failure among diabetics. The Framingham investigators described a diabetic cardiomyopathy that is associated with heart failure particularly in diabetic women, independent of coronary disease [14].
In one propensity-matched, longitudinal study of patients with cardiac heart failure, diabetes-associated increases in mortality were more pronounced in women than in men (HR 1.67 vs. HR 1.21) [3].
Clinical presentation
Females with diabetes have a higher prevalence of abdominal obesity (women have greater subcutaneous fat storage capacity), increasing the risk of hypertension, a worse lipid profile and a more marked endothelial dysfunction than males [8]. The clinical presentation of CVD is different in women than in men, which may, in turn, impact on early diagnosis. Atypical chest pain is more common in women and individuals with diabetes, and sudden death from myocardial infarction, especially silent MI, is more common in women. Jaw or neck and shoulder pain, nausea, vomiting, fatigue, or dyspnea, in addition to the more traditional substernal chest pain, are symptoms common in women [4].
Major forms of heart disease in men and women with diabetes are:
Men: coronary calcification, coronary artery disease, myocardial infarction, CHD (worse than in non-diabetic men), diastolic abnormality, autonomic neuropathy, congestive heart failure [6].
Women: coronary calcification, coronary artery disease, myocardial infarction (worse than in men), CHD (better prognosis than in men), diastolic abnormality (usually more severe in women), autonomic neuropathy, congestive heart failure (fivefold the frequency in non-diabetic women).
Treatment
Besides innate differences in sex physiology, disparities between sexes in the treatment of major cardiovascular risk factors also exist. These can be attributed to an underestimation of patient risk and a less aggressive approach, and the poorer compliance of females [8]. Women with diabetes are less frequently on target for cardiovascular risk factors. Literature data show that men with diabetes or established CVD are more likely to receive aspirin, statins, or antihypertensive drugs than are women. Therefore, more aggressive treatment of risk factors for CHD in men with diabetes may explain a large component of the excess risk associated with diabetes in women [15]. The often dramatically higher cardiovascular risk which is observed in women with diabetes highlights the need for more intensive treatment and optimized management of cardiovascular risk factors in diabetic and pre-diabetic women [10].
Finally, all physicians should be made aware that development of diabetes is associated with a greater increase in cardiovascular risk in women than in men. Therefore, that they should treat women with diabetes as aggressively as they do their male counterparts [2].
Conclusions
Heart disease is the major cause of mortality and disability in women.
Diabetes mellitus is an important risk factor and contributes to the disproportionate burden of CVD in women. This disparity requires a multifaceted approach in order to be corrected and should be recognized, publicized, and addressed. Providers should assess the quality of diabetes care by gender in order to identify any disparities. Extra clinical effort may be required to treat women with DM as aggressively as men. Researchers need to report real data in women rather than extrapolating from men to understand better how the presentation, diagnosis, treatment, and prognosis of CVD differ in diabetic women from those in diabetic men.
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