Introduction

The International Diabetes Federation predicts the number of people worldwide with diabetes to grow from 463 million in 2019 to over 700 million by 2050.¹ Atherosclerotic cardiovascular disease (ASCVD) risk for patients with diabetes is very heterogeneous, posing challenges for the personalized management of patients.

Healthcare providers require better tools to forecast risk, stratify patients, and allocate more expensive therapies. Here, we summarize evidence from a recent review.²

CAC Score May Organize a Heterogenous Population into Risk Categories 

Individuals with diabetes represent a heterogeneous population. Adults with diabetes with well-controlled LDL-C, blood pressure, hemoglobin A1c (HbA1c), and absent albuminuria and smoking have similar ASCVD rates as those without diabetes,³ highlighting many variables that influence the risk spectrum.

The selective addition of the coronary artery calcium (CAC) score improves risk stratification and can identify candidates for aggressive preventive therapies. Malik et al. demonstrated a stepwise increase in ASCVD events with higher CAC scores, and the addition of CAC scoring improves ASCVD risk classification.⁴

Those with CAC ≥100 have event rates approaching those seen in secondary prevention cohorts, identifying a subgroup who may benefit from more aggressive management.⁴ The role of CAC scoring has been primarily studied in patients with type 2 diabetes, but recent studies have found similar predictive value in patients with type 1 diabetes.⁵ A proposed framework by Cardoso et al. for treatments according to CAC score is summarized in Figure 1.

Figure 1

Proposed Use of CAC to Guide Primary Prevention Therapies in Patients with Diabetes

Lipid Lowering

Statins: The 2019 ACC/AHA Primary Prevention Guideline recommends moderate-intensity statin for all individuals with diabetes between 40-75 years of age.⁶ It has been suggested that a CAC score of 0 can be used to "de-risk" diabetics and limit the dose, or initiation, of statins.⁷ While cohort studies have demonstrated very low event rates when CAC = 0 and no change in event rates on statin therapy, extrapolation of these findings is limited by subsequent initiation of statin therapy in some participants during follow-up.^4,8

While the 2018 AHA/ACC Multisociety Cholesterol Guideline recommends statin therapy in adults between ages 40-75, many patients with minimally elevated HbA1C may wish to defer statin therapy.⁹ The finding of CAC = 0 may be useful in the clinician-patient risk discussion.

Non-statins: CAC could potentially be used to identify adults who would benefit not only from statin intensification but from the addition of non-statin agents. The PREDICT study (Prospective Evaluation of Diabetic Ischemic Disease by Computed Tomography) followed 589 asymptomatic patients with diabetes over 4 years; the ASCVD event rate for those with CAC ≥100 was 10-fold higher than those with CAC ≤10.¹⁰

A CAC ≥100 may represent a useful clinical threshold to consider addition of non-statin therapies such as ezetimibe to further reduce LDL-C if lipid goals are not met with maximally tolerated statin. Findings from the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) invite further opportunities for allocation of icosapent ethyl based on a high CAC score.¹¹

Aspirin

The use of aspirin for primary prevention in patients with diabetes without established cardiovascular disease has been explored in the ASCEND trial (A Study on Cardiovascular Events in Diabetes), which randomized participants (n = 15,480) to aspirin versus placebo over a mean of 7.4 years.¹² The relative reduction in vascular events (12%) was largely counterbalanced by the increase in major bleeding (29%).

CAC can identify those at higher risk of ASCVD where the benefit likely outweighs potential harm. Findings from a subgroup of MESA aspirin-naïve participants <70 years of age and not at high bleeding risk (n = 3,540) demonstrated that CAC ≥100 marked a threshold where the number needed to treat (NNT) was significantly lower than the number needed to harm (NNH).¹³ In adults at low risk of bleeding, CAC ≥100 may be a useful threshold to consider aspirin initiation.

Cardiometabolic Agents

SGLT2 inhibitors and GLP-1 agonists reduce the risk of major events by 12-14% in patients with diabetes and established ASCVD.^14,15 Data for their use in primary prevention is limited. The REWIND (Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes) trial had a large primary prevention subgroup (n=6221) and notably the relative risk reduction in myocardial infarction (MI), stroke, and CV death was similar in primary and secondary prevention subgroups; however, the absolute reduction was much higher in the latter.¹⁶

In pooled analyses of primary prevention subgroups of GLP-1 studies, the estimated NNT to prevent one adverse event is high at 229.¹⁵ To avoid over-allocation of costly therapies, CAC could be used to identify higher-risk subgroups with a significantly lower NNT. Whereas the pooled ASCVD event rate for primary prevention subgroups of GLP-1 trials was 14 events per 1000-years, CAC ≥100 and ≥400 predict event rates of 20 to 30 events per 1000-years, respectively; this identifies individuals who may derive greater absolute risk reduction from these agents.¹⁴

Role of Screening for Coronary Artery Disease and Ischemia in the Asymptomatic Patient

This question has been explored using single-photon emission computed tomography (SPECT) in DIAD (Detection of Ischemia in Asymptomatic Diabetics). In DIAD, 1,123 asymptomatic patients with diabetes were randomly assigned to screening with SPECT or no screening; cardiac event rates over 7 years were not reduced by use of SPECT.¹⁷

Future Research

Higher HbA1c is associated with CAC progression in individuals without diabetes.^18,19 The earlier application of CAC before the A1c threshold of 6.5% is crossed might eventually shift the paradigm of statin initiation, expanding its use to certain adults with pre-diabetes.

Conclusion

With the increase in ASCVD expected to follow the global rise in diabetes, selective use of CAC scoring to personalize primary prevention offers great promise.

References

1. IDF Diabetes Atlas 9th Edition 2019 (International Diabetes Federation website). Available at https://www.diabetesatlas.org/en/ . Accessed 07/03/2020.
2. Cardoso R, Dudum R, Ferraro RA, et al. Cardiac computed tomography for personalized management of patients with type 2 diabetes mellitus. Circ Cardiovasc Imaging 2020;Sep 09:[Epub ahead of print].
3. Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633–644.
4. Malik S, Zhao Y, Budoff M, et al. Coronary artery calcium score for long-term risk classification in individuals with type 2 diabetes and metabolic syndrome from the multi- ethnic study of atherosclerosis. JAMA Cardiol 2017;2:1332–40.
5. Budoff M, Backlund J-YC, 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;12:1341-9.
6. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.
7. Blankstein R, Gupta A, Rana JS, Nasir K. The implication of coronary artery calcium testing for cardiovascular disease prevention and diabetes. Endocrinol Metab (Seoul) 2017;32:47-57.
8. 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.
9. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.
10. Elkeles RS, Godsland IF, Feher MD, et al. Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study. Eur Heart J 2008;29:2244–51.
11. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
12. Bowman L, Mafham M, Wallendszus K, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379:1529–39.
13. Cainzos-Achirica M, Miedema MD, McEvoy JW, et al. Coronary artery calcium for personalized allocation of aspirin in primary prevention of cardiovascular disease in 2019: the MESA study (multi- ethnic study of atherosclerosis). Circulation 2020;141:1541–53.
14. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
15. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85.
16. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet 2019;394:121-30.
17. Young LH, Wackers FJT, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:1547-55.
18. Tashtish N, Al-Kindi S, Sarode A, Derieux J, Gilkeson R, Rajagopalan S. Abstract 15779: Coronary artery calcium score and cardiovascular events in patients with diabetes, prediabetes, and no diabetes: The Clarify Registry. Circulation 2019;140:A15779.
19. Carson AP, Steffes MW, Carr JJ, et al. Hemoglobin a1c and the progression of coronary artery calcification among adults without diabetes. Diabetes Care 2015;38:66-71.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hemoglobin A, Calcium, Cholesterol, LDL, Prediabetic State, Aspirin, Blood Pressure, Secondary Prevention, Albuminuria, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1

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