Association of Coronary Artery Calcification With Subsequent Incidence of Cardiovascular Disease in Type 1 Diabetics

Autopsy studies have consistently shown that the presence of calcium in coronary arteries indicates the presence of atherosclerosis, and the extent of coronary calcification correlates with the risk of future atherosclerotic cardiovascular disease (ASCVD) events.1

The coronary artery calcium (CAC) scan is a reproducible noninvasive test to detect asymptomatic coronary artery disease (CAD). Its advantages include lower cost, reproducibility, greater sensitivity for nonobstructive coronary artery lesions, and excellent prognostic value.2,3

CAC is detected using a high resolution non contrast chest computed tomography (CT) scan acquired with ECG triggering and breath holding protocol. CAC is measured throughout the entire proximal epicardial coronary arteries. CAC lesion is defined as a lesion above a threshold of 130 Hounsfield units, with an area of at least 1 mm2. The CAC score is a product of the calcified plaque area and calcium lesion density (from 1 to 4 based on Hounsfield units) and summed up for all the slices.4

Standardized categories for the calcium score have been developed with scores of 0 indicating the absence of calcified plaque, 1 to 10 minimal plaque, 11 to 100 mild plaque, 101 to 300 moderate plaque, and >300 severe plaque.5,6

Every prognostic registry to date has validated the value of a CAC score, with relative risks surpassing all other traditional risk factors for CAD.5 Using data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, Detrano et al. evaluated the relationship between CAC and future coronary events in all four major ethnic groups. After a follow up period of 3.9 years, the results were consistent with increased risk of coronary events with increasing CAC scores p < 0.001.7 Budoff et al. extended this observation out beyond 10 years.5 Event rates in those with CAC = 0 Agatston units ranged from 1.3% to 5.6%, while for those with CAC > 300, the 10-year event rates ranged from 13.1% to 25.6% across different age, gender and racial subgroups. At 10 years of follow-up, all participants with CAC > 100 were estimated to have >7.5% risk regardless of demographic subset. Ten-year ASCVD event rates increased steadily across CAC categories regardless of age, sex or race/ethnicity. Malik et al. evaluated the MESA cohort after 11.1 years follow-up and found the CAC score was independently associated with incident CHD in multivariable analyses in those with diabetes (HR, 1.30; 95% CI, 1.19-1.43), metabolic syndrome (HR, 1.30; 95% CI, 1.20-1.41), and neither condition (HR, 1.37; 95% CI, 1.27-1.47).26 For incident CHD, net reclassification improvement with addition of CAC score in those with diabetes was 0.23 (95% CI, 0.10-0.37), 0.22 (95% CI, 0.09-0.35) in those with metabolic syndrome and 0.25 (95%CI, 0.15-0.35) in those with neither condition. The CAC score was also a prognostic indicator of CHD and ASCVD after controlling for diabetes duration of >10 years at baseline, insulin use and glycemic control.

Increased cardiovascular morbidity and mortality in patients with both type 1 and type 2 diabetes mellitus (DM) is well established.8-12 Patients with diabetes have higher increased prevalence of CAC.9,13-15 The mechanisms of extensive CAC in DM is multifactorial from hyperglycemia mediated vascular smooth muscle alteration via osteopontin expression, elevated levels of multiple ligands capable of activating pro-arterial calcific receptors of the innate immune system and excess adiposity mediated pro-inflammation.16-18

However, since 2013 it has been re-established that DM is not a CAD risk equivalent,8 as a significant number of adults with DM can be classified as low risk based on a CAC score of zero.9 This is consistent from previous studies that have showed significant heterogeneity exists in CAD risk among DM patients.19,20 Guidelines acknowledge the differences in risk and have suggested that additional risk stratification in patients with diabetes is warranted before collective treatment.8,21,22

CAC incorporated with other conventional risk scores resulted in better discriminative ability for incident CAD in T2DM and was also a better predictor of incident CV events and mortality.23,9 Furthermore, the absence of CAC (score of zero) indicated a low short-term risk of death for diabetic patients.9 Guidelines have previously recommended CAC scanning for screening for CAD in asymptomatic T2DM age greater than 40 years and expert groups corroborated that it was the most sensitive noninvasive risk stratification tool in this population.8,22

Even though the pathophysiology of T1DM differs significantly from T2DM, it has been established that both T1DM and T2DM share many cardiometabolic risk factors, and they are both are important causes of arterial calcification.17,12 Nonetheless, risk factors appear to affect the risk for CVD differently in T1DM versus T2DM and coronary findings suggest atherosclerosis in T1DM is more diffuse and more concentric.18

Observational studies have previously studied the risk factors for CAD in T1DM and have shown that aside from established CAD risk factors, they had early occurrences of CAD manifested by significant CAC in young adults,24,25 CAC was greatly increased in premenopausal women (this was attributed to gender differences in insulin resistance-associated fat deposition),10,26 HbA1c >7.5% associated with increasing atherosclerotic plaque burden and the LIPC-480 T allele increases the susceptibility to subclinical CAD.27,28

The data from the DCCT (Diabetes Control and Complications Trial)/EDIC (Epidemiology of Diabetes Interventions and Complications) trials showed unequivocally that intensive therapy for T1DM reduced the risk of any CV event by 42% (p = 0.02) compared to conventional therapy. DCCT was a randomized control trial enrolled young patients (ages 13-39 years) with no antecedent CV disease or other CV risk factors and with minimal or no microvascular complication of T1DM, and this enabled the model setting for the longitudinal study of the development of incident CVD over a 20-year follow up period.29,30

Using the DCCT/ EDIC study subjects, Budoff et al. studied the relationship between CAC scores and subsequent CVD events in T1DM patients who underwent CAC scanning 7-9 years after the DCCT trial and had no previous CV or MACE event. After CAC scans, participants were followed for 10-13 years for ASCVD events. The results showed that 70% of subjects had a CAC of zero and about 5% of subjects had CAC > 300 Agatston units. The incidence of MACE and CVD increased significantly (p < 0.0001) with increasing CAC scores and CAC zero scores were generally associated with low event rates. This further validated that CAC is an important assessment tool for determining CV risk in participants with T1DM.31

These findings were similar to the CACTI (Coronary Artery Calcification in Type 1 Diabetes) study, which was the first study reporting a cross sectional association of CAC and clinical CAD in T1DM using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study made up of subjects with T1DM before age 17 years. CVD was the leading cause of death in T1DM patients after 20 years of disease duration, at rates of >3% per year.11 At the CAC score cut-point of 400, sensitivity and specificity for CAD were 80 and 92%, respectively. CAC was shown to be an independent risk for CAD. A score of 400+ was the best coronary calcium correlate of CAD.12

After risk stratification and identifying those with elevated CAD risk, the vast majority of patients will be started on a statin for primary prevention due to its anti-inflammatory properties. However, statins also increase CAC content when they stabilize plaques which can obscure the interpretation of successive CAC scores.2

No studies have yet studied the effect of statin on CAC scores and on the subsequent CV events in T1DM and statin trial results in T2DM may not be applicable T1DM patients.2 The DCCT/EDIC trials were initiated before widespread use of statin and statin use was documented at year 11 into the original DCCT trial after the participants received a CAC scan and hence the study by Budoff et al. could not answer this question.31

Conversely, given that the 2018 ACC/AHA cholesterol guideline recommends moderate dose statins for all patients with diabetes mellitus aged 40-75 years,32-35 one may argue that T1DM patients should be offered statin therapy based on this guideline and do not require further risk stratification by CAC. It is important to note, however, that there is evidence that the 2013 ACC/AHA cholesterol guidelines may have overestimated the number of patients who should be treated by statins.33 Furthermore, 70% of T1DM participants in the study by Budoff had a score of zero. This introduces a paradox, as the 2018 guidelines state "if CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD. statins to be withheld for 5-10 years."35 The guidelines do not delineate between type 1 and type 2, but prevalence of disease is much different, and risks differ between these groups. It may prove prudent to withhold (at least high intensity) statins in persons with T1DM with scores of zero and re-test in 5 years to look for the incidence of CAC over time.

One of the caveats to the use of CAC score has been due to non-calcified soft plaques which are not detected by CAC testing, but it is uncommon that a patient with imminent acute coronary syndrome would have had a CAC score of 0 as non-calcified plaques have been seen in only less than 10% of acute ischemic syndromes.34 The event rate in patients with a CAC score of 0 is also very low < 0.5%.7,9 Obstacles to widespread use of CAC scanning persist, including radiation exposure (although in low doses <1msv, and similar to mammography),5 less accessibility, and the fact that they may not be covered by some medical insurances.2

Nonetheless, the evidence remains valid that the use of CAC scanning offers excellent discrimination and stratification of individuals at risk for CAD beyond traditional risk factors. This will help physicians ascertain the individual risk of a CV event over the next 5 years and determine which patient should benefit from primary prevention therapy.

The recent 2018 cholesterol guideline includes consideration of statin therapy for those with T1D< of 20 years or greater duration when aged 20-39. For T1DM patients, current guidelines now approve the use of CAC scanning for CAD assessment in T1DM, similar to the recommendations for the general population.18


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Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Computed Tomography, Nuclear Imaging, Smoking

Keywords: Acute Coronary Syndrome, Adiposity, Atherosclerosis, Autopsy, Breath Holding, Cactaceae, Calcium, Cause of Death, Calcinosis, Cholesterol, Coronary Artery Disease, Cohort Studies, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Electrocardiography, Epidemiologic Studies, Ethnic Groups, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperglycemia, Immune System, Inflammation, Insulins, Insulin Resistance, Longitudinal Studies, Ligands, Mammography, Metabolic Syndrome X, Muscle, Smooth, Vascular, Osteopontin, Plaque, Atherosclerotic, Primary Prevention, Prognosis, Registries, Reproducibility of Results, Risk Factors, Smoking, Tomography, Tomography, X-Ray Computed

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