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.

Summary

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.

References

1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 2014;383:1068-83.
2. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34.
3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486-97.
4. 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;379:633–44.
5. Davis WA, Gregg EW, Davis TME. Temporal trends in cardiovascular complications in people with or without type 2 diabetes: the Fremantle Diabetes Study. J Clin Endocrinol Metab 2020;105:dgaa215.
6. Budoff MJ, Raggi P, Beller GA, et al. Noninvasive cardiovascular risk assessment of the asymptomatic diabetic patient: the Imaging Council of the American College of Cardiology. JACC Cardiovasc Imaging 2016;9:176-92.
7. 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
8. 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;74:1376-1414.
9. Martin SS, Blaha MJ, Blankstein R, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the Multi-Ethnic Study of Atherosclerosis. Circulation 2014;129:77–86.
10. Blaha MJ, Cainzos-Achirica M, Greenland P, et al. Role of coronary artery calcium score of zero and other negative risk markers for cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2016;133:849–58.
11. Valenti V, Hartaigh BÓ, Cho I, et al. Absence of coronary artery calcium identifies asymptomatic diabetic individuals at low near- term but not long-term risk of mortality: a 15-year follow-up study of 9715 patients. Circ Cardiovasc Imaging 2016;9:e003528.
12. Wong ND, Nelson JC, Granston T, et al. Metabolic syndrome, diabetes, and incidence and progression of coronary calcium: the Multiethnic Study of Atherosclerosis study. JACC Cardiovasc Imaging 2012;5:358–66.
13. 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.
14. Budoff M, Backlund JYC, 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;12:1341-49.
15. Madaj PM, Budoff MJ, Li D, Tayek JA, Karlsber RP, Karpman HL. Identification of noncalcified plaque in young persons with diabetes: an opportunity for early primary prevention of coronary artery disease identified with low-dose coronary computed tomographic angiography. Acad Radiol 2012;19:889-93.
16. 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;13:e011365.
17. Dzaye O, Dardari ZA, Cainzos-Achirica M, et al. Warranty period of a calcium score of zero: comprehensive analysis from the Multiethnic Study of Atherosclerosis. JACC Cardiovasc Imaging 2020;S1936-878X:30818-4.
18. Newman CB, Blaha MJ, Boord JB, et al. Lipid management in patients with endocrine disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2020;105:dgaa674.
19. McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med 2018;379:1499-1508.
20. Raju N, Sobieraj-Teague M, Bosch J, Eikelboom JW. Updated meta-analysis of aspirin in primary prevention of cardiovascular disease. Am J Med 2016;129:e35.
21. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo-controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.
22. 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.
23. Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Qual Outcomes 2014;7:453-60.
24. Silverman MG, Blaha MJ, Budoff MJ, et al. Potential implications of coronary artery calcium testing for guiding aspirin use among asymptomatic individuals with diabetes. Diabetes Care 2012;35:624–26.
25. 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.
26. Hecht H, Blaha MJ, Berman DS, et al. Clinical indications for coronary artery calcium scoring in asymptomatic patients: expert consensus statement from the Society of Cardiovascular Computed Tomography. J Cardiovasc Comput Tomogr 2017;11:157–68.
27. 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.
28. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
29. 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.
30. McEvoy JW, Martin SS, Dardari ZA, et al. Coronary artery calcium to guide a personalized risk-based approach to initiation and intensification of antihypertensive therapy. Circulation 2017;135:153-65.

Clinical Topics: Anticoagulation Management, 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, 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

< Back to Listings