Clin Ther. 2014 Dec 1;36(12):1924-34. doi: 10.1016/j.clinthera.2014.06.011.

Risk of vascular disease in premenopausal women with diabetes mellitus.

García NH1, Pérez HA2, Spence JD3, Armando LJ2.
  • 1Instituto de Investigaciones en Ciencias de la Salud, FCM (INICSA-CONICET), Córdoba, Argentina. Electronic address:
  • 2Blossom DMO Argentina, Córdoba, Argentina.
  • 3Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada.



PURPOSE: The aims of this study were (1) to estimate the prevalence of cardiovascular disease risk factors among premenopausal and menopausal Argentinean women with and without type 2 diabetes mellitus and (2) to assess the contribution of total plaque area (TPA) to risk stratification when added to Framingham risk scores.

METHODS: A descriptive cross-sectional study in primary prevention in 1257 women (ages 19-84 years) from Argentina. TPA was measured by ultrasonography. Framingham sex-specific risk equations were used to predict the risk of developing cardiovascular disease, coronary heart disease, and stroke during the next 10 years. Patients were divided into diabetic (n = 293) and control groups (n = 964), and then each group was divided according to age (>40, 40-49, 50-59, and ≥60 years).

FINDINGS: No difference was observed between diabetic and control groups in the incidence of smoking or the presence of early family cardiovascular event. Overall, diabetic patients had higher body mass index, blood pressure, and TPA versus the control group. The Framingham risk score was higher in the diabetic group in all age groups. The mean (SD) coronary heart disease scores for the diabetic group at <40, 40 to 49, 50 to 59, and ≥60 were 6% (1.7%), 19% (2.5%), 38% (2.0%), and 60% (1.5%), respectively, whereas the scores in the control group 3% (0.8%), 7% (0.9%), 17% (0.9%), and 40% (0.9%), respectively. The stroke score was also enhanced in diabetic women, independent of their age. These data indicate that diabetic women in the premenopausal age or the early years of menopause age (40-50 years) are at intermediate or higher risk of developing a cardiovascular event.

IMPLICATIONS: Premenopausal diabetic women should be considered at possibly high risk of cardiovascular events compared with nondiabetic women. Direct assessment of atherosclerotic burden, such as TPA, should be used early in this population instead of relying on traditional risk scores.

KEYWORDS: cardiovascular disease; imaging; subclinical atherosclerosis; women

PMID: 24998421



The role of diabetes mellitus (DM) in the pathogenesis of cardiovascular disease is evident from the Framingham Heart Study identifying diabetes as a major cardiovascular risk factor . The last report from the AHA 2013 (1) indicated that of the estimated 19.7 million American adults with physician-diagnosed diabetes, more than 51% are women, and since 1984 the number of female deaths by cardiovascular disease (CVD) has exceeded those for males. In 2009, CVD in females represented 51.0% of deaths in United States. Another important observation is that 26% of women age 45 and older who have an initial recognized heart attack die within a year compared with 19% of men, more women than men have angina in total numbers (4.1 million vs. 3.7 million) and 64% of women who died suddenly of coronary heart disease had no previous symptoms, and finally the incidence for death stroke in 2009 was also superior in women (59.6% of total stroke deaths) than in men. All of these data indicate that women are at least equally sensitive to have a cardiovascular disease compared to men.

Classically, in women, determination of cardiovascular risk is not intense and investigators have applied the term “bikini medicine” to actual preventive medicine practice in women (2), referring to a focus on the breasts and the reproductive system during premenopausal years, with cardiovascular prevention considered only after menopause.

In women, as well in men, CAD events are the result of a complex interaction of multiple risk factors including diabetes mellitus (3). However, for women, up to 20% of all coronary events occur in the absence of these major risk factors (4), whereas many women with traditional risk factors do not experience coronary events, indicating that the algorithm used is not sensitive enough to prevent most of the cardiovascular events. In addition, physicians and other healthcare providers continue to underestimate cardiovascular risk in women, with consequent underutilization of preventive therapies (5), (6) such as statins at early age in the absence of evident target organ damage (intermittent claudication, coronary disease, etc).

Diabetes accelerates the development of atherosclerosis, such that women with DM are at 2- to 4-fold increased risk of CVD compared with age-matched patients without DM (7). Coronary heart disease constitutes more than two-thirds of all deaths in older patients with DM. This has stimulated interest in reducing CHD and CVD-related morbidity and mortality through primary prevention among such patients (8).

Despite this changing view of pathophysiology, variables included in current risk algorithms for women are largely unchanged from those recommended 40 years ago. Recently, the measurement of atherosclerosis burden as a predictor of cardiovascular event has been proposed, using the determination of total plaque area (9).

Atherosclerosis develops silently over decades before symptoms occur. Thus there is opportunity for timely detection and personalized prevention. However, the period preceding development of symptoms (subclinical atherosclerosis) is not efficiently used, neither to prevent events, nor to categorize the risk of patients in primary care. Subclinical atherosclerosis can be detected, very accurately and non-invasively, by means of the determination of carotid total plaque area (TPA) by ultrasound (9). A recent meta-analysis showed that TPA was a stronger predictor of cardiovascular risk than the more widely used carotid intima-media thickness (10) and coronary calcium score (11). This well-developed technique can be used at the patient’s first visit and at follow-up visits to determine the effectiveness of different therapies. Figure 1 and 2 shows 2 different patients with regression and progression of an atherosclerosis plaque.



NG fig1a


NG fig1b

Figure 1. Measurement of carotid plaque area. Each plaque seen in the internal, common or external carotid artery on either side is isolated in a longitudinal view, choosing the plane in which it is biggest; the perimeter of the plaque is then traced to obtain plaque area; total plaque area is the sum of areas of all plaques seen. Right distal common carotid artery, distal segment in a diabetic 50 yo woman, A , TPA 21mm2. B, after 12 months of intense treatment, TPA decreased to 10 mm2, plaque regression.



NG fig2a


NG fig2b

Figure 2. Plaque progression in the carotid artery in a diabetic 35 yo woman. Of note, this subject was normotensive and had surprisingly normal blood lipids level in 2012 (total chol. 156 mg/dl, HDL chol. 47mg/dl and tryglicerides 108 mg/dl). In 2013, TPA increased from 20 mm2 in 2012 to 48 mm2 in 2014. Her post-test risk score increased from 13.9% to21.9%, indicating that the patient should receive statins based on classical recommendations. This figure shows the progression of a 5 mm2 plaque at the left bulb measured in 2012 (A) and in 2014, this plaque increased to 12mm2 (B).


The objectives of this study were (i) to estimate the prevalence of CVD risk factors among premenopausal and menopausal Argentinean women with and without type 2 DM, and (ii) to assess the contribution of TPA to risk stratification when added to a Framingham risk score.

The importance of this study is two-fold. First, young diabetic women may have subclinical atherosclerosis leading in some cases to increased the cardiovascular risk, this new patient condition should the physician redirect the preventive strategy for his/her patient. Second, determination of subclinical atherosclerosis by TPA, is very accurate and non-invasive and can be used at the patient’s first visit and at follow-up visits to determine the effectiveness of different therapies.



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Acknowledgements: This study was supported by unrestricted institutional Grant from Blossom DMO, Córdoba, Argentina.



Nestor H Garcia, MD, PhD


CONICET National University of Cordoba

Instituto de Investigaciones en Ciencias de la Salud

Enfermera Gordillo s/n

Ciudad Universitaria – UNC

Córdoba, 5016



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