Women are not just smaller men, and sex differences in cardiovascular disease (CVD) risk are well-established.¹ Women historically have had poorer outcomes after myocardial infarction (MI);² thus, it is imperative to elucidate the contributing risk factors and intensify preventive efforts to improve outcomes. Currently, identified risk factors are categorized between the traditional atherosclerotic CVD (ASCVD) risk factors and non-traditional risk factors that are predominant or specific to women (including those related to multi-parity, adverse pregnancy outcomes (APOs), sex hormones, early menopause status, and autoimmune disorders).^1,3 Interestingly, traditional CVD risk factors affect women differently and to a greater extent.³ Specifically, diabetes affects cardiovascular risk in women to a greater degree than in men,⁴ with a higher risk for acute MI and a 40% greater risk of all-cause mortality.^5,6 In the setting of diabetes, female sex is no longer a protective factor against premature CVD as it is in the general population.⁴

For both men and women, the 2019 American College of Cardiology (ACC) and American Heart Association (AHA) guideline recommends the use of at least a moderate intensity statin among individuals with diabetes for the primary prevention of ASCVD.⁷ In patients with diabetes with multiple CVD risk factors, a high intensity statin would be recommended. In addition, the 2019 guideline put forth by the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) recommends further risk-stratifying patients with diabetes into moderate, high, and very high-risk groups.⁸ This is because high and very high risk patients with type 2 diabetes would additionally be recommended to have SGLT2 inhibitors or GLP-1 receptor agonists initiated as monotherapy (or added to metformin) to reduce risk of cardiovascular events.⁸

Coronary artery calcium (CAC) scores are an established measure of the total burden of subclinical coronary atherosclerosis, and elevated scores are prognostic of CVD and mortality risk among individuals with and without diabetes.^9,10 Although diabetes had historically been considered a coronary heart disease (CHD)-risk equivalent, more recent data have challenged that notion and shown heterogeneity of CVD risk in diabetes, with the CAC score playing a role in improving risk classification.¹¹ Notably, CVD risk is relatively low among individuals with diabetes with the absence of calcified plaque (CAC=0).⁹ Some prior studies have suggested that CAC scores more strongly predict CVD and mortality risk in women compared to men,^10,12-14 while other studies suggested CAC has similar risk by sex.^15-18 However, it was previously unknown whether sex differences in the risk associated with CAC were also observed in patients with diabetes.

Wong et al. eloquently addressed this question in a recent publication in Diabetes Care.¹³ The authors studied 4,503 asymptomatic adults with diabetes enrolled in the prospective CAC Consortium study, which pooled data from four US clinical sites among individuals referred for a clinically indicated CAC score. The CAC score was calculated using the Agatston method on non-contrast cardiac-gated computed tomography (CT) with standard protocol. Scans were also evaluated for number of calcified lesions, number of calcified vessels, CAC volume score, and lesion size. The primary outcome was defined as cause-specific mortality with first-order categorization into CVD and non-CVD mortality, using linkage with the National Death Index. Individuals were grouped by CAC scores (0, 1-100, 101-400, >400), and CHD, CVD, non-CVD, and total mortality rates over a median of 11.5 years were calculated for each group stratified by sex.

Among individuals with diabetes, women had an overall lower prevalence of subclinical coronary disease than men. Women with diabetes had a greater prevalence of CAC=0 than men with diabetes (38.8% vs. 19.6%, respectively) and were less likely to have a very elevated score of CAC >400 (16% vs. 29%). Women with CAC had similar lesion size as men but fewer CAC lesions, fewer calcified vessels, and lower volume score. This current analysis supports the concept of a sex-specific plaque signature among individuals with diabetes.

Confirming prior work that the presence of diabetes alone is not a CHD-risk equivalent, both men and women with diabetes with CAC=0 had low mortality rates from CHD and CVD of <1 per 1,000 person-years. On the other hand, the presence of CAC was associated with an elevated risk, a relationship that was stronger among women. For high CAC score >400, CVD and total mortality rates were higher in women (15.2 and 33.4, respectively) than in men (8.0 and 19.0, respectively) per 1,000 person-years. Even after adjustment for age and CVD risk factors, women with diabetes had higher risk for total mortality compared to men with hazard ratios (HR) per log unit increase in CAC score of 1.28 (1.19-1.38) versus 1.18 (1.12-1.25), respectively; p-interaction by sex=0.01.

A given CAC score was also associated with greater risk of CVD mortality in women compared to men. Compared to CAC=0, CAC scores of 101-400 and >400 was associated with HRs of 1.63 (0.64-4.14) and 3.48 (1.44-8.37) in men but 3.67 (1.30-10.38) and 6.27 (2.27-17.28) in women, p-interaction by sex=0.04. Risks of CVD mortality were also greater for women versus men for having calcium volume and lesion size above the median and for having ≥3 calcified vessels. Interestingly CAC was also associated with non-CVD mortality among individuals with diabetes (likely serving as a marker of less favorable overall biological aging), but there was no interaction by sex.

This study by Wong et al. adds to previous literature on the disparity in risk profiles between men and women, with a focus specifically among individuals with diabetes.¹³ Despite having a lower prevalence of disease, the presence of more advanced atherosclerosis in women compared to men portends a greater risk. Recent ACC/AHA guidelines have incorporated the use of CAC to refine risk stratification and guide shared decision making about initiation/intensification of statin therapy among primary prevention patients without diabetes (IIa recommendation).⁷ Notably, the recent ESC/EASD guidelines also stated it was reasonable to consider CAC score in primary prevention patients with diabetes, who are at moderate estimated risk, as a risk-modifying factor (IIb recommendation).⁸ We agree. Considering the heterogeneity of risk shown by Wong et al., CAC scores appear helpful to guide shared decision making about preventive interventions among individuals with diabetes too, and we urge further categorization by sex. These findings can guide clinical practice by exposing suboptimal traditional risk assessments and identify sub-populations of individuals with diabetes who have clinically reassuring CAC results (CAC=0) and those who have a worse prognosis (women with CAC >100). Based on the above, there should be a greater focus on CAC screening and prevention in women with diabetes.

Although statin use for the primary prevention of CVD among individuals with diabetes is endorsed by guidelines, a recent study using NHANES data from 2015-2018 reported only 43% of patients who have diabetes but without ASCVD were on a statin,¹⁹ suggesting great opportunity for improvement for preventive efforts. Compared to men, women are less likely to be offered a statin for prevention and women are more likely to decline or discontinue statin therapy.²⁰ However "seeing is believing", and knowledge of one CAC score can potentially confer better adherence to lifestyle changes and preventive medications such as statins.²¹

Lastly, understanding the phenotype, risk factors, and underlying mechanisms are essential for developing appropriate medical strategies for prevention and treatment. Future studies in women with diabetes should examine interactions of risk by menopausal status, sex hormone levels (such as testosterone to estradiol ratio), parity status, and history of APOs to further expand hypotheses on the underlying pathophysiologic phenomena of why significant plaque burden is even riskier in women than in men. Additionally, as this cohort was predominantly white (>75%), further data are needed to understand the intersectionality of risk conferred by race/ethnicity with sex among individuals with diabetes.

In sum, the data from Wong et al.¹³ support that CAC has the potential to identify the lower- and high-risk individuals with diabetes so that preventive therapy can be appropriately tailored, particularly among women with advanced CAC scores who are at greater risk.

References

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Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Nonstatins, Novel Agents, Statins, Diabetes and Cardiometabolic Disease

Keywords: Coronary Artery Disease, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Diabetes Mellitus, Type 2, American Heart Association, Metformin, Prospective Studies, Prevalence, Women

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