Pathologic evidence supports unique sex-specific mechanisms as precursors for acute cardiovascular (CV) events. Current evidence on long-term CV risk among women when compared with men based on measures of coronary artery calcium (CAC) remains incomplete. A total of 63 215 asymptomatic women and men were enrolled in the multicentre, CAC Consortium with median follow-up of 12.6 years. Pooled cohort equation (PCE) risk scores and risk factor data were collected with the Agatston score and other CAC measures (number of lesions and vessels, lesion size, volume, and plaque density). Cox proportional hazard models were employed to estimate CV mortality (n = 919). Sex interactions were calculated. Women and men had average PCE risk scores of 5.8% and 9.1% (P < 0.001). Within CAC subgroups, women had fewer calcified lesions (P < 0.0001) and vessels (P = 0.017), greater lesion size (P < 0.0001), and higher plaque density (P = 0.013) when compared with men. For women and men without CAC, long-term CV mortality was similar (P = 0.67), whereas detectable CAC was associated with 1.3-higher hazard for CV death among women when compared with men (P < 0001). Cardiovascular mortality was higher among women with more extensive, numerous, or larger CAC lesions. The relative hazard for cardiovascular disease (CVD) mortality for women and men was 8.2 vs. 5.1 for multivessel CAC, 8.6 vs. 5.9 for ≥5 CAC lesions, and 8.5 vs. 4.4 for a lesion size ≥15 mm³, respectively. Additional explorations revealed that women with larger sized and more numerous CAC lesions had 2.2-fold higher CVD mortality (P < 0.0001) as compared to men. Moreover, CAC density was not predictive of CV mortality in women (P = 0.51) but was for men (P < 0.001), when controlling for CAC volume and cardiac risk factors. Our overall findings support that measures beyond the Agatston score provide important clues to sex differences in atherosclerotic plaque and may further refine risk detection and focus preventive strategies of care.

Background: Sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) mitigate cardiovascular risk in individuals with type 2 diabetes, but most eligible patients do not receive them. We characterized temporal trends in SGLT2i and GLP‐1RA use by cardiologists compared with other groups of clinicians. Methods and Results: We conducted a descriptive analysis of serial, cross‐sectional data derived from IQVIA’s National Prescription Audit, a comprehensive audit capturing ≈90% of US retail prescription dispensing and projected to population‐level data, to estimate monthly SGLT2is and GLP‐1RAs dispensed from January 2015 to December 2020, stratified by prescriber specialty and molecule. We also used the American Medical Association’s Physician Masterfile to calculate average annual SGLT2is and GLP‐1RAs dispensed per physician. Between January 2015 and December 2020, a total of 63.2 million SGLT2i and 63.4 million GLP‐1RA prescriptions were dispensed in the United States. Monthly prescriptions from cardiologists increased 12‐fold for SGLT2is (from 2228 to 25 815) and 4‐fold for GLP‐1RAs (from 1927 to 6981). Nonetheless, cardiologists represented only 1.5% of SGLT2i prescriptions and 0.4% of GLP‐1RA prescriptions in 2020, while total use was predominated by primary care physicians/internists (57% of 2020 SGLT2is and 52% of GLP‐1RAs). Endocrinologists led in terms of prescriptions dispensed per physician in 2020 (272 SGLT2is and 405 GLP‐1RAs). Cardiologists, but not noncardiologists, increasingly used SGLT2is over GLP‐1RAs, with accelerated uptake of empagliflozin and dapagliflozin coinciding with their landmark cardiovascular outcomes trials and subsequent US Food and Drug Administration label expansions. Conclusions: While use of SGLT2is and GLP‐1RAs by cardiologists in the United States increased substantially over a 6‐year period, cardiologists still account for a very small proportion of all use, contributing to marked undertreatment of individuals with type 2 diabetes at high cardiovascular risk.

Background: There are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations. Methods: Our study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Results: Compared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm ² ), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63–6.11), 7.57- (5.50–10.42), 4.86-(3.32–7.11), and 1.94-fold (1.57–2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25–2.16), 1.66- (1.22–2.25), 1.51- (1.03–2.23), and 1.34-fold (1.05–1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57–2.41) and 1.43-fold (1.12–1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups. Conclusions: Individuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.