The Association of Coronary Artery Calcium with Subsequent Cardiovascular Disease in Patients with or Without Type 1 Diabetes

Educational Objectives

After completing the activity, the clinician will be better able to compare the value of measuring coronary artery calcium in various types of patients, including those with type 1 diabetes mellitus.

Summary

Interviewer: Peter A. McCullough, MD, MPH, FACC

Take-home Messages:

• There is a broad evidence base supporting coronary artery calcium (CAC) scoring to more accurately assess cardiovascular (CV) risk and select preventive therapy.
• While less well studied than in type 2 diabetes mellitus (DM), investigators recently evaluated CAC scoring in patients with type I DM.
• In this large analysis of patients with type 1 DM, CAC scores >100 Agatston units were significantly associated with an increased risk of subsequent cardiovascular disease (CVD) and major adverse cardiac events (MACE). Importantly, CAC score was also useful in determining which patients are not at high CV risk.

On a population basis, risk factors are tied tightly to the presence of atherosclerotic cardiovascular disease (ASCVD) and subsequent CV events, but at the individual level, results vary. Winston Churchill, a walking compilation of CV risk factors, lived to 90 years of age. Conversely, Jim Fixx — who is credited with helping start America’s fitness revolution by popularizing running and demonstrating the health benefits of jogging — died of a myocardial infarction at 52 years of age.

Even today, it is challenging to estimate CV risk. As recently as 2016, investigators found a substantial gap between estimated risk for ASCVD and actual observed coronary events and stroke. This was demonstrated in an analysis of the 2013 American College of Cardiology/American Heart Association Pooled Cohort Risk Equation, which substantially overestimated ASCVD risk in adults without diabetes mellitus and had suboptimal accuracy across sociodemographic subgroups as well as in adults with diabetes who were not receiving statin therapy for primary prevention.¹

In looking for a more accurate measure of predicting risk, the best warranty available today seems to be coronary artery calcium. In a recent study, the presence of CAC clearly identified patients who were most likely to benefit from statins for the primary prevention of CVD; at the same time, those who had no detectable CAC — popularly known as the “power of zero” — did not benefit from long-term statin use.²

While CAC, ankle-brachial index, high-sensitivity C-reactive protein, and family history are all independent predictors of incident coronary heart disease (CHD)/CVD in intermediate-risk individuals, a recent study showed that CAC showed superior discrimination and risk reclassification compared with the other risk markers.³

Even in younger patients (i.e., adults 32 to 46 years), there is an association of CAC with incident CHD and death.⁴ In these patients, even very low CAC scores show elevated risk of clinical CHD/CVD and death, suggesting that selective screening for CAC may be considered in individuals with risk factors in early adulthood to better inform discussions about primary prevention.

And sometimes a picture is worth a thousand words. Budoff and colleagues have shown the motivational effects of CAC scores on statin adherence and weight loss.⁵

What about functional testing? Matthew Budoff, MD (David Geffen School of Medicine at UCLA), and colleagues have specifically looked at this among stable outpatients presenting with suspected CAD. Most patients (84.2%) experiencing MACE had measurable CAC at baseline, but fewer than half (43.2%) had any abnormalities on functional testing.⁶

What About Type 1 Diabetes?

Recently, Dr. Budoff and colleagues noted that while new therapies have brought attention to type 2 DM, there is less known about CV risk in patients with type 1 DM.

What is known is that patients with type 1 DM are quite different from those with type 2. Compared to those with type 2 DM, type 1 patients do not have the same metabolic risk or the same elevated cholesterol. They are less likely to have hypertension and more likely to be within normal limits of weight and body mass index.

Given the differences between these diabetic populations, Budoff and colleagues assessed CAC scores in 1,205 participants with type 1 DM in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study between 2001 and 2003 (mean age 42.8 years; 1,156 at risk of an initial CVD event; 1,187 at risk of an initial MACE event).⁷ CAC scores were measured in Agatston units and categorized as 0, >0 to 100, >100 to 300 or >300.

With a follow-up of 10 to 13 years (median >11 years), among study participants at risk of subsequent CVD, 105 had an initial CVD event (8.5 per 1,000 patient-years); of those at risk of MACE, 51 had an initial MACE event (3.9 per 1,000 patient-years).

One big difference between this DCCT/EDIC cohort and individuals with type 2 DM: 70.7% of these type 1 DM patients had a calcium score of 0, despite having had diabetes, on average, for >20 years. These study patients with CAC scores of 0 were at very low risk of developing CVD (5.6 per 1000 patient-years). Based on current guidelines, they would not be candidates for statin therapy, since their events rates were well below 1%.

As for patients with CAC scores classified as high risk, levels >100-300 (hazard ratio [HR]: 4.17, 5.40) and >300 (HR: 6.06, 6.91) were associated with higher risks of CVD and MACE, respectively, compared to CAC = 0 (p < 0.0001). Put another way, patients with a CAC >100-300 had a 20% event rate at 10 years. So, one-fifth of these patients in their 40s had a CV event over the next decade. For those with a score >300, the 10-year CV event rate went up to about 30%.

What about intermediate CAC scores (>0-100)? Patients with a score in this range were nominally associated with CVD (HR: 1.71; p = 0.0415) but not with MACE (HR: 1.11; p = 0.8134). Similar results were observed after adjusting for mean HbA1c and traditional CVD risk factors.

Overall, Dr. Budoff said, CAC scores in this DCCT/EDIC cohort performed nearly as well prognostically as they do in the general population.

Guidelines note that assessing CAC is likely to be the most useful of the current approaches to improve risk assessment among individuals at intermediate risk after formal risk assessment, but there is no recommendation regarding the use of CAC in patients with type 1 DM (based on lack of evidence). Therefore, the study⁷ by Budoff and colleagues is critical to understand the implications for clinicians, given the increased risk seen with higher CAC scores in these asymptomatic patients.

Given that higher CAC scores are associated with CV events in this population of type 1 DM patients, Dr. Budoff said the data suggest that CAC scoring is an important assessment tool for determining CV risk in participants with type 1 DM.

Readings

1. Rana JS, Tabada GH, Solomon MD, et al. Accuracy of the Atherosclerotic Cardiovascular Risk Equation in a Large Contemporary, Multiethnic Population. J Am Coll Cardiol 2016;67:2118-30. www.onlinejacc.org/content/67/18/2118
2. Mitchell JD, Fergestrom N, Gage BF, et al. Impact of Statins on Cardiovascular Outcomes Following Coronary Artery Calcium Scoring. J Am Coll Cardiol 2018;72:3233-42. www.onlinejacc.org/content/72/25/3233
3. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-95.
4. Carr JJ, Jacobs DR Jr, Terry JG, et al. Association of Coronary Artery Calcium in Adults Aged 32 to 46 Years with Incident Coronary Heart Disease and Death. JAMA Cardiol 2017;2:391-9.
5. Kalia NK, Cespedes L, Youssef G, Li D, Budoff MJ. Motivational effects of coronary artery calcium scores on statin adherence and weight loss. Coron Artery Dis 2015;26:225-30.
6. Budoff MJ, Mayrhofer T, Ferencik M, et al. Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). Circulation 2017;136:1993-2005.
7. Budoff M, Backlund JC, Bluemke DA, et al. The Association of Coronary Artery Calcification with Subsequent Incidence of Cardiovascular Disease in Type 1 Diabetes: The DCCT/EDIC Trials. JACC Cardiovasc Imaging 2019 Mar 8. doi: 10.1016/j.jcmg.2019.01.014. [Epub ahead of print]

Disclosures

Matthew J. Budoff, MD, FACC
Janssen Global Services LLC (C); Pfizer Inc (C); General Electric (G); Amarin Corporation (B); Amgen Inc (G); Sanofi (G)

Interviewer: Peter A. McCullough, MD, MPH, FACC
This author has nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC510513

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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