At the Fifth Annual Heart in Diabetes (HiD) Conference, held in New York 10-12 September 2021, a variety of topics were addressed related to the cardiovascular disease (CVD) risks and CV complications of diabetes. This is the first of a two-part summary of some of the presentations at the meeting, reviewing risk factors.

Brendan Everett, Boston, MA, reviewed a biomarker approach to risk stratification, pointing out that age, sex, cigarette use, blood pressure, total and high-density lipoprotein (HDL) cholesterol, a variety of markers of glycemia, and use of aspirin, statins, and antihypertensive agents can all be considered markers to be used in assessment of atherosclerotic CVD (ASCVD) risk, with familial hypercholesterolemia and family history of premature CVD, and elevated triglyceride, apolipoprotein B, and lipoprotein (a) levels additional factors. He termed high-sensitivity cardiac troponin (hs-cTnT), C-reactive protein (hsCRP), and B-type natriuretic peptides, such as the N-terminal prohormone of brain natriuretic peptide (NT-proBNP), novel “risk enhancing factors.” Everett compared these with the coronary artery calcium (CAC) score in guiding discussion of risk and of intensity of therapy with patients having borderline or intermediate (5%-20%) 10-year event rate risk. He showed evidence using the C-statistic, the area under the curve of sensitivity vs specificity, that NT-proBNP gives modest additional improvement in ASCVD risk prediction, similar to that of the CAC score.1, 2 Ambarish Pandey, Dallas, TX, discussed the identification of persons with diabetes at risk for heart failure based on hs-cTnT, NT-proBNP, hsCRP, and left ventricular hypertrophy on the electrocardiogram, showing that having two or more of these markers abnormal vs just one, and using this information to initiate sodium-glucose cotransporter-2 inhibitors (SGLT2i), would allow prevention of 103 heart failure events per 1000 persons over a decade.3 Norman Lepore, Los Angeles, CA, expanded on the discussion of use of risk markers and risk factors to allow personalization of risk for a given individual. CAC screening, he suggested, gives a specific and reproducible means of assessing risk, mechanistically based on production of a variety of local factors in the inflamed atherosclerotic plaque, including bone morphogenetic protein, leading to ectopic bone formation. The CAC score can be used in recommending statin and aspirin therapy and in recommending higher or lower statin intensity.4

Leslee Shaw, New York, NY, reviewed evidence that risk scores may be less useful in women in the identification of ASCVD, pointing out that the commonly accepted 7.5% 10-year risk threshold would lead to nearly a two thirds reduction in statin use for women. The finding of a positive CAC test in women as an index both of atherosclerotic plaque and of the likelihood of more extensive CVD, although lower than that in men, is still sizable and increases in prevalence after menopause.5 Furthermore, nonobstructive CAD prevalence is greater in women than in men6 and is associated with plaque erosion leading to thrombus formation, increasing risk of adverse outcome.7 Use of computed tomography (CT) angiogram-guided treatment to increase use of antiplatelet agents and statins improves outcome,8 further evidence of the importance of imaging approaches.

Matthew Budoff, Los Angeles, CA, discussed a variety of noninvasive technologies as options for assessment of CV risk of asymptomatic persons with diabetes. He opined that the exercise tolerance test (ETT) has more false positive than true positive results, making it not useful for this purpose, that carotid intima-media thickness (IMT) has low cost but poor reproducibility, although the finding of an atherosclerotic plaque is important evidence of CVD. CT and magnetic resonance imaging coronary angiography have not been widely studied, and the echocardiographic ETT does not have favorable evidence of benefit in screening asymptomatic patients, leading him to conclude that the strongest evidence is in support of CAC measurement. Compared with a clinical risk score alone, CAC score improves discrimination of CVD risk more than the ankle-brachial index, hsCRP, or carotid IMT,9 particularly among persons with diabetes,10 and Budoff showed evidence from his study of adults with diabetes that there is a direct relationship between the CAC score and total and CV mortality rates. He also pointed out the usefulness of biomarkers such as albuminuria and NT-proBNP in assessment of risk in type 2 diabetes (T2D), stressing the importance of imaging in disease prevention rather than treatment of disease that has already become full blown.

Elizabeth Selvin, Baltimore, MD, discussed issues of the associations of obesity and diabetes with heart failure, reviewing the strong evidence from the Atherosclerosis Risk In Communities (ARIC) Study of a nonlinear relationship of diabetes duration with heart failure risk, particularly during the first decade of the disease, as well as the (lesser) increase in heart failure risk associated with prediabetes.11 She reviewed further ARIC studies using hs-cTnT, which may reflect chronic subclinical myocardial damage. In asymptomatic persons without CVD history, hs-cTnT ≥14 ng/L was associated with 6-fold, 4-fold, and 2.3-fold increases in likelihoods of heart failure, total mortality, and coronary heart disease (CHD).12, 13 Her studies further showed diabetes and prediabetes associations with elevated hs-cTnT. This relationship is further influenced by obesity, with body mass index and hs-cTnT independently associated with heart failure.14 Furthermore, in 17-year follow-up of 9477 persons in the ARIC population, “metabolically healthy” obesity was associated with higher overall CVD risk and, in particular, with higher heart failure risk in comparison with metabolically healthy normal weight. Erin Michos, Baltimore, MD, reviewed data from the Multiethnic Study of Atherosclerosis (MESA) showing direct relationships between the development of heart failure and atherosclerotic CVD and duration of hyperlipidemia.15 Similarly, with increasing duration of obesity,16 there is increasing risk of heart failure, each decade of obesity associated with a 20-30% increase in likelihood of elevated hs-cTnT,17 suggesting what Michos termed “long-term toxic effects of adiposity on the myocardium.”

Erica Gunderson, Oakland, CA, discussed interrelationships between gestational diabetes (GDM), subsequent glucose intolerance, and CAC development. She noted that GDM develops in 10%-12% of women in the United States, and 17-20% of women worldwide, with 20-50% of women who have had GDM subsequently developing T2D, and with a history of GDM associated with a 1.7-3.0-fold increase in risk of CVD. She showed a recently published analysis from the Coronary Artery Risk Development in Young Adults (CARDIA) study, in which women who had had GDM had increased risk of CAC at 15-25 year follow-up, even without subsequent development of diabetes, related to other risk factors, dyslipidemia, hypertension, and cigarette use.18 Gunderson commented on the need to enhance the follow-up of women who have had GDM, not only for subsequent diabetes, but also for intervention on these other CV risk factors.

Andrea Dunaif, New York, NY, discussed the polycystic ovary syndrome (PCOS), noting that approximately 70% of women with PCOS have a phenotype of metabolic risk with visceral obesity, with low HDL cholesterol, and with some elevation in low-density lipoprotein cholesterol related to hyperandrogenemia, associated with insulin resistance and with a 4-fold increase likelihood of diabetes, independent of weight, although obesity is present in 50%-80% of women with PCOS.19 PCOS is a strong risk factor for CVD. A useful question for population screening is ascertainment of whether a women has fewer than six menses annually, and Dunaif noted that having a menstrual cycle length of 40 days or more is associated with a 2.18-fold increase in development of diabetes20 and a 1.53-fold increase in likelihood of CVD events,21 although Dunaif pointed out that published studies are typically not of sufficient duration for CVD events to become prevalent. Michos gave a second presentation, addressing the impact of changes in sex hormones on CVD and heart failure, pointing out the well-recognized increase in CVD in women after menopause, tracking with elevation in free testosterone, which in turn is associated with greater left ventricular mass,22 with higher levels of NT-proBNP,23 with CAC progression,24 and with greater likelihood of CHD and heart failure.25 Lower levels of dehydroepiandrosterone sulfate (DHEA-S) in postmenopausal women are also associated with development of heart disease, further underscoring the complexity of the androgen–heart disease relationship.26 In men, in contrast, lower levels both of DHEA-S and of testosterone are generally associated with greater risk of CVD27 and of heart failure,28 although administration of testosterone may increase coronary artery plaque volume,29 which has led to a Food and Drug Administration Drug Safety Communication about using testosterone because of possible increased CVD event risk.30