Should Individuals With Diabetes Be Screened for Subclinical CVD?

Editor's Note: This point/counterpoint Hot Topic is based on a Current Issues debate "Subclinical Cardiovascular Disease in Diabetes—to Screen or Not to Screen?" at the American Diabetes Association Scientific Sessions, June 15, 2014.

There is interest and debate on the question of whether or not patients who have diabetes should automatically be screened for cardiovascular disease (CVD). Because diabetes is associated with an increased risk for CVD, and the majority of persons with diabetes will die of myocardial infarction or stroke, one might assume such screening could be useful. But current guidelines recommend intensive CVD risk reduction for all patients with diabetes, so the answer is not so simple.

"Cardiovascular complications are the most common complications of diabetes, but at an individual level, they are still relatively uncommon events," said Silvio Inzucchi, MD, Professor of Medicine, Clinical Director of Endocrinology and Director of the Yale Diabetes Center at the Yale School of Medicine, New Haven, CT. "So most patients with diabetes do pretty well in terms of cardiovascular outcomes, especially if they are on a good prevention program. In most circumstances, we are already recommending aggressive cardiovascular disease prevention strategies in all patients with diabetes."

Nathan D. Wong, PhD, Professor and Director of the Heart Disease Prevention Program at the University of California, Irvine, CA notes that while most people with diabetes will die of CVD, diabetes confers a wide spectrum of risk and is not, as previously thought, a coronary heart disease (CHD) risk equivalent, as shown by a recent large meta-analysis1 as well as by risk estimation in U.S. adults with diabetes.2 The risk of CHD for someone with uncomplicated and recently diagnosed diabetes is a fraction of the risk for someone who has long-standing diabetes accompanied by multiple CHD risk factors. Dr. Wong said that screening asymptomatic patients with diabetes for subclinical atherosclerosis can be a highly effective method to distinguish lower-risk patients from higher-risk patients, helping to motivate clinicians and patients alike to more intensively manage those at highest risk who will provide the most benefit in terms of outcomes.

"Any screening modality must meet three criteria in order to improve patient outcomes," Dr. Inzucchi said. "The disease itself must occur with sufficient frequency to be detected by screening and the screening test must be sufficiently specific and sensitive to reliably identify patients with disease. CHD screening meets both of those criteria", he said, "but no one has yet proven the third criterion—changing clinical outcomes."

Dr. Inzucchi was the co-investigator for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study that compared cardiac outcomes in patients with type 2 diabetes. DIAD compared five-year outcomes in a group of more than 500 individuals who were randomized to screening with nuclear stress testing to a similarly sized group of individuals who were not screened. Patients then received treatment as recommended by their own physicians. After five years of follow-up, researchers saw the same very low 0.6% CHD event rate in both groups.3

"The data suggest that screening patients and finding their disease early doesn't make much of a difference in outcomes," Dr. Inzucchi, said. "We are already recommending aggressive attention to cardiovascular risk factors. So most patients, those who were screened and those who were not screened, were already on reasonably intensive prevention programs. Even if you find early disease, most of that disease is mild, actually sometimes reversible, and the great majority of patients do quite well clinically—without cardiac events."

Dr. Wong agreed that the relatively low incidence of myocardial ischemia and subsequent cardiac events that occurred in the asymptomatic DIAD cohort may have made it difficult to show the impact of screening for myocardial ischemia. Therefore, he felt that the DIAD trial was underpowered and, as a result, inconclusive in being able to answer the question of whether screening for subclinical CVD could be effective. Dr. Inzucchi responded that the low event rate was merely a reflection of the current state of affairs—low event rates in asymptomatic diabetic patients. Although a larger study could conceivably have shown differences, the sheer numbers required and the anticipated modest benefit would calculate to a large 'number needed to screen' —which would not be cost effective.

Dr. Wong, however, noted that screening for subclinical atherosclerotic burden by the less costly coronary artery calcium (CAC), as opposed to finding functional abnormalities by nuclear stress testing, may be more appropriate. Other screening modalities for atherosclerosis are much less sensitive or predictive of outcomes. American College of Cardiology (ACC)/American Heart Association (AHA) guidelines from 2010 recommend consideration of calcium screening in persons with diabetes aged 404 and over, and the American Association of Clinical Endocrinologists' 2012 guideline5 notes carotid ultrasound or CAC can be used in certain clinical situations to refine risk stratification and the need for aggressive preventive therapies. In addition, the earlier 2007 American Diabetes Association consensus statement recommended considering testing for atherosclerosis or ischemia,6 with CAC scanning as the initial test in those where medical treatment goals cannot be met or where there is suspicion of very high risk of CAD. Published data also support CAC screening to rule out those at low risk of having myocardial ischemia, and only those with high CAC scores (≥400) are at significantly increased likelihood of demonstrating myocardial ischemia,7,8 supporting screening for myocardial ischemia in those with diabetes might be best limited to those with significant atherosclerotic burden is already present.

Dr. Wong also points to data he and his colleagues published from the Multiethnic Study of Atherosclerosis (MESA). "If you have a zero calcium score, you have a cardiovascular risk that is as low as in many people who do not have diabetes or metabolic syndrome," Dr. Wong said. In MESA, there was a ten-fold variation in annual risk of CHD from 0.4% in those with diabetes without CAC, which represented 38% of those with diabetes to 4% in those with a calcium score of 400 or higher (17%) of those with diabetes.9 Based on these data, one can show that the potential screening may have to identify those most likely to benefit from preventive therapies. Assuming a conservative 25% relative risk reduction from statin therapy would require treating just ten individuals to prevent a CHD event over 10 years for those with CAC ≥400, compared to treating 100 individuals without CAC to prevent a single CHD event. Dr. Inzucchi, however, retorted that such a study would need to be done to demonstrate that even a less expensive test actually improved clinical outcomes. He expressed concern that the discovery of more "high-risk" patients might simply lead to more invasive (and costly) tests. The implicit assumption that a screening test can benefit a patient simply because it identifies that patient as being at higher risk can be misleading.

Dr. Wong pointed to current guidelines that recommend controlling HbA1c, blood pressure, and lipids with appropriate medications; however, only about a quarter of all U.S. adults with type 2 diabetes currently achieve combined control of HbA1c, low-density lipoprotein cholesterol and blood pressure.10 Coronary calcium screening of asymptomatic patients could help physicians and patients better understand individual risks; those at greatest risk could benefit from more aggressive medical therapy.

"A picture of your calcified arteries may be worth a thousand words and be more motivating than telling you that your lipids or blood sugar are too high," Dr. Wong said. He and others have previously published data showing persons with coronary calcium (and the higher the calcium levels are) are more likely to initiate preventive therapies such as cholesterol-lowering medication or aspirin and even see their doctor.11 In addition, the Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) randomized trial of coronary calcium screening, while not specifically in those with diabetes, showed a person's estimated 10-year risk of CHD did not increase in those screened, compared to an increase in those who were not screened.12 Moreover, a more recently reported large prospective study involving computed tomography screening in those with diabetes showed that those screened versus a matched control group not screened had greater initiation of statins and decreases in lipids as well as reduced all-cause mortality at five years (4.5% vs. 6.8%).13 Dr. Wong points out, "We can do better at identifying the subset of patients with diabetes who could benefit from more comprehensive efforts to address their excess CHD risk." Dr. Inzucchi pointed out that the prospective study identified by his colleague was non-randomized and, therefore, predisposed to both measured and unmeasured confounding factors.

Both Dr. Inzucchi and Dr. Wong did agree, however, that large-scale randomized trials are needed to definitely show benefit in terms of clinical outcomes from calcium screening or other modalities, but realize that it is uncertain if these trials will ever be done.


References

  1. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idros I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med 2009;26:142-8.
  2. Wong ND, Glovaci D, Wong K, et al. Global cardiovascular disease risk assessment in United States adults with diabetes. Diab Vas Dis Res 2012;9:146-52.
  3. Young LH, Wackers FJ, Chyun DA, et al., on behalf of the DIAD Investigators. 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.
  4. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50-103.
  5. Jellinger PS, Smith DA, Mehta AE et al. American Association of Clinical Endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocrine Practice 2012;18(suppl 1):1-78.
  6. Bax JJ, Young LH, Frye RL, et al. Consensus statement: screening for coronary artery disease in patients with diabetes. Diabetes Care 2007;30:2729-36.
  7. Wong ND, Rozanski A, Gransar H, et al. Metabolic syndrome and diabetes are associated with an increased likelihood of inducible myocardial ischemia among patients with subclinical atherosclerosis. Diabetes Care 2005;28:1445-50.
  8. Anand DV, Lim ETS, Hopkins D, et al. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Eur Heart J 2006;27:713-21.
  9. Malik S, Budoff MJ, Katz R, et al. Impact of subclinical atherosclerosis on cardiovascular disease events in persons with metabolic syndrome and diabetes: the Multiethnic Study of Atherosclerosis. Diabetes Care 2011;34:2285-90.
  10. Wong ND, Patao C, Wong K, et al. Trends in control of cardiovascular risk factors among US adults with Type 2 diabetes 1999-2010: comparison by prevalent cardiovascular disease status. Diabetes and Vascular Disease Res 2013;10:505-13.
  11. Wong ND, Detrano RC, Diamond G, et al. Does coronary artery screening by electron beam computed tomography motivate healthy lifestyle behaviors? Am J Cardiol 1996;78:1220-3.
  12. Rozanaski A, Gransar H, Shaw LJ, et al. Impact of coronary calcium scanning on coronary risk factors and downstream testing: the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011;57:1622-32.
  13. Yang HK, Lee SH, Cho JH, et al. Beneficial role of coronary multidetector computed tomography screening in 5-year all-cause mortality among asymptomatic diabetic subjects. Diabetes 2014;63(suppl 1):A2(abstract).

Keywords: Cardiovascular Diseases, Diabetes Mellitus, Myocardial Infarction, Risk Reduction Behavior, Stroke


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