Coronary Artery Calcium to Personalize Risk Assessment and Primary Prevention Therapies in Patients with Diabetes Mellitus

Quick Takes

  • Heterogeneity of ASCVD-risk exists among asymptomatic primary prevention adults with type 2 diabetes mellitus (DM2).
  • The use of coronary artery calcium (CAC) testing may provide more precise allocation of preventive therapies among adults living with DM2.
  • Individuals with DM2 and CAC=0 have a low event rate of <7.5 per 1000 person-years.
  • Individuals with DM2 and CAC≥100 have a high ASCVD risk at >20 per 1000 person-years.

Type 2 diabetes (DM2) is a progressive metabolic disease that is characterized by insulin resistance and eventual functional failure of pancreatic beta cells.1 Importantly, impaired glucose metabolism is linked to high rates of atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. This led to the historical and incorrect classification of DM2 as a 'coronary heart disease risk equivalent' (implying a 10-year ASCVD-risk of ≥20% for every patient with DM2).2,3

More contemporary data, however, has shown reductions in ASCVD risk in asymptomatic individuals with DM2, varying according to the presence of other risk factors.4,5 As such, this heterogeneity in risk among persons with DM2 poses a welcome and unique challenge with respect to accurate risk stratification and selection of appropriate preventive therapies.

Noninvasive testing has been adopted to further risk stratify asymptomatic patients with DM free of known ASCVD.6-8 Specifically, the detection of subclinical atherosclerosis as measured by coronary artery calcium (CAC) has emerged as the most sensitive noninvasive risk stratification tool in this population.6 Elevated CAC (CAC>0) is associated with a higher risk of coronary heart disease (CHD) and ASCVD events, while the absence of CAC (CAC=0) portends very low absolute event rates.9,10 In a single-center cohort of 810 asymptomatic individuals with DM2, followed for approximately 15 years, CAC significantly improved discrimination and reclassification of all-cause mortality beyond risk factors alone.11 Wong et al. found a higher risk of all-cause or cardiac mortality and incident cardiovascular events with increasing severity of CAC among those with DM2.12

Statin Therapy in the Absence of CAC

The 2018 AHA/ACC/Multisociety Cholesterol Guideline recommends the initiation of a moderate-intensity statin for those aged 40-75 years and DM2, irrespective of ASCVD risk score.7 In addition, diabetes-specific risk-enhancers (≥10 years for DM2 and 20 years for type 1 DM, ≥30 mcg albumin/mg creatinine, eGFR <60 ml/min/1.73 m2, retinopathy, neuropathy, ankle-brachial index <0.9), can be used to consider intensifying statin therapy.7 Alternatively, CAC=0 may be used to justify withholding or delaying statin therapy in this group. In a large multi-ethnic population free of ASCVD at baseline (mean follow-up time 11.1 years), Malik et al. reported that observed ASCVD event rate for those with DM2 and CAC=0 was 2.5 and 5.2 per 1000 person-years in those with a baseline 10-year predicted ASCVD risk of <7.5% and ≥7.5%-<15%.13 Among those with DM1 and CAC=0 followed for 10-13 years, the observed ASCVD events rate was 5.6 per 1000 person-years.14

However, the absence of CAC in adults with DM2 should not automatically be tantamount to very low risk and certainly not "zero" risk. Indeed the 2018 AHA/ACC/Multisociety Cholesterol Guideline specifically mentions that the presence of DM may warrant consideration of statin therapy even in the absence of CAC.7 A prior study has shown that ASCVD event rates (per 1000 person-years) were high among those with zero CAC in the setting of insulin use (18.2) and hemoglobin A1c ≥7% (9.1).13 Furthermore, young patients with DM2 are more likely to have non-calcified plaque in the presence of CAC=0 which predisposes them to development of ASCVD.15 For those who have elected to defer statin therapy (i.e., strong preference to avoid statin therapy and statin intolerance), a repeat CAC scan at a 3-year interval may be considered to evaluate for conversion to CAC>0 and is endorsed by both the current US Endocrine and Cardiovascular Societies.16-18

CAC to Guide Aspirin Therapy

Aspirin use in secondary prevention is a widely accepted practice; however, uncertainty and controversy has increasingly been raised with respect to its use in primary prevention. Three large trials in 2018 showed less net benefit of prophylactic aspirin use, largely counterbalanced by an increased risk of bleeding.19-22 For example, results from the ASCEND trial for primary prevention in adults with DM2, aspirin use prevented vascular events (HR, 95%CI: 0.88, 0.79-0.97, p=0.01), but it also caused major bleeding events (1.29, 1.09-1.52, p=0.003) when compared to placebo.22

The 2019 ACC/AHA Primary Prevention Guideline recommends consideration of aspirin in adults who are at higher ASCVD risk (strong family history of premature myocardial infarction [MI], inability to achieve lipid or BP or glucose targets, or significant elevation in CAC), but not at increased risk of bleeding.8 Recent evidence has suggested a threshold of CAC≥100 in which a net benefit would be derived from aspirin therapy; this is an approach endorsed by the Society of Cardiovascular Computed Tomography.23-26

Using CAC Scoring to Intensify Therapy

Individuals with CAC ≥100 have event rates closer to stable secondary prevention populations (ASCVD risk ≥20%).9 Specific to those with diabetes, the ASCVD event rate (per 1000 person years) was 10-20 in CAC 1-99, 20-30 in CAC 100-399, and ≥30 in CAC≥400.13 The presence of any CAC has been suggested to inform not only the initiation of statin therapy, but also the escalation of additional preventive therapies.16

For example, the 2018 AHA/ACC/Multisociety Cholesterol Guideline suggests the addition of non-statin therapy, such as ezetimibe, for a 10-year ASCVD risk of risk ≥20% to reduce LDL-C by at least 50% (strength of recommendation, level of evidence: Class IIb, Level C).7 However, the presence of CAC ≥100 can identify higher-risk patients with DM1 and DM2 and could be used to guide the intensification of lipid-lowering therapy or addition of non-statin therapies. Indeed, in a study of 589 patients with DM2 (median 4 year follow up), those with CAC ≥100 had a 10-fold increase in ASCVD events compared with individuals with CAC ≤10.27 Additionally, the 10–13-year ASCVD incidence was 23% among those with CAC >100–300.14

In the context of limited healthcare resources and high medication costs, a CAC-guided approach to the allocation of icosapent-ethyl, cardiometabolic agents [SGLT2 (sodium-glucose cotransporter 2) inhibitors and the glucagon-like peptide-1 receptor agonists (GLP1-RAs)], as well as intensification of anti-hypertensive therapy has been proposed, particularly for those with CAC≥100.16,28-30 Ultimately, further research is required to validate this approach.


ASCVD-risk in patients with DM2 is heterogenous, underscoring the importance of personalized medicine based on a patient's age, other traditional risk factors, test availability, and patient preferences. In these patients, CAC may provide a more precise allocation of preventive therapies, such as aspirin, statins, and non-statins, cardiometabolic drugs, and anti-hypertensive agents.


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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Coronary Vessels, Diabetes Mellitus, Type 2, Insulin Resistance, Metabolic Syndrome X, Insulin-Secreting Cells, Factor XI, Cardiovascular Diseases, Atherosclerosis, Risk Factors, Coronary Disease, Morbidity, Risk Assessment, Glucose, Cohort Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Antihypertensive Agents, Cholesterol, LDL, Sodium-Glucose Transporter 2, Aspirin, Secondary Prevention, Follow-Up Studies, Primary Prevention, Myocardial Infarction, Resource Allocation, Delivery of Health Care, Tomography, Cholesterol

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