Should patients with type 2 diabetes asymptomatic for coronary artery disease undergo testing for myocardial ischemia?
Robert A O'Rourke About the author
Correspondence Division of Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
Email orourke@uthscsa.edu
A marked increase in the incidence of impaired glucose tolerance and the subsequent development of diabetes has resulted in a worldwide health-care crisis.1 The prevalence of type 2 diabetes has increased by more than 61% since 1990,2 due mainly to more-sedentary lifestyles, the ensuing obesity, and the rising age of patients in the US. More than 75% of diabetes-related hospitalizations are caused by atherosclerosis and its complications.3 Furthermore, severe proximal and distal coronary artery disease (CAD) and coronary artery plaque alterations, including inflammation and thrombosis, are more-frequently observed on coronary arteriography and intravascular ultrasound in individuals with diabetes than in those without.4
Risk factors for the development of cardiovascular disease in patients with diabetes include obesity, cigarette smoking, systemic hypertension, dyslipidemia, albuminuria and chronic renal disease. Glycemia control lowers the risk of vascular diseases, by reducing the production of advanced glycosylation end-products,5 the accumulation of which is thought to promote atherosclerosis.6 The atherosclerosis-promoting effects of advanced glycosylation end-products are listed in Supplementary Box 1 online. Progression from impaired glucose tolerance or the metabolic syndrome to overt diabetes can be slowed or even prevented by lifestyle changes and pharmacotherapy. Weight reduction and an exercise program should be instigated early, and the use of angiotensin-converting-enzyme inhibitors, statins and several oral hypoglycemic agents (such as thiazolidinediones and metformin) can be useful.6 Nevertheless, more than 25% of patients with diabetes have severe myocardial ischemia, myocardial infarction or both, without chest pain or chest discomfort.7 This finding raises an important question: should asymptomatic patients with type 2 diabetes be investigated for CAD and, if present, how should they be treated?
Modification of the coronary artery anatomy with remodeling of segmental CAD can result luminal stenosis remaining unseen on angio- graphy, even when intravascular ultrasound indicates a marked reduction in target coronary blood flow.8 Such patients might also have stress-test-induced myocardial ischemia, identifiable by myocardial perfusion imaging, or inducible echocardiographic wall-motion abnormalities. In these patients reserve coronary blood flow might fail to increase during intracoronary adenosine infusion, as occurs in normal coronary arteries. MRI and intravascular ultrasonography can detect intracoronary atheromas. Several methods for diagnosing CAD in asymptomatic patients with diabetes are listed in Supplementary Box 2 online.
Exercise-induced stress testing in patients with diabetes and hypertension frequently gives false-positive results for myocardial ischemia. This is caused by electrocardiogram repolarization abnormalities that become evident during exercise in patients with left ventricular hypertrophy. False-negative results are also common, particularly in patients with diabetes and physical disabilities that limit the extent to which they can exercise. Ambulatory electrocardiogram recordings often reveal asymptomatic nonspecific ST-segment depression in individuals without chest pain; many such patients have hypertension and left ventricular hypertrophy. A better approach to detect silent ischemia would be to include myocardial perfusion imaging with a technetium-based isotope during treadmill exercise testing or pharmacologic stress, with use of persantine or adenosine, followed by a repeat resting study several hours later. In the prospective DIAD study,9 113 of the 522 patients with asymptomatic type 2 diabetes had silent ischemia. Most abnormalities involved less than 5% of the left ventricle; however, 33 patients had moderate or large perfusion abnormalities. By limiting the selection of asymptomatic diabetics to those with two or more additional coronary risk factors, the study would have missed 41% of patients with silent ischemia. Thus, the selection criteria for screening asymptomatic diabetics for myocardial perfusion imaging remain controversial. Most investigators would perform such testing in all patients with peripheral vascular disease, dyslipidemia or other high-risk features predictive of CAD. Myocardial perfusion imaging is being used in the BARI 2D and the COURAGE trials to define the results of aggressive medical therapy with or without revascularization treatment for coronary artery stenosis. Supplementary Box 3 online lists my reasons for using noninvasive testing for detecting myocardial ischemia in patients with diabetes who do not have chest discomfort.
I currently recommend stress-induced myocardial perfusion imaging in patients with definite diabetes mellitus and no symptoms of chest discomfort. The subsequent follow-up depends upon the reasons for using noninvasive testing listed in Box 3. Patients negative for ischemia should receive therapy for modifiable risk factors of CAD, such as hypertension, smoking and lack of exercise. Patients with moderate to severe myocardial ischemia should undergo coronary arteriography with assessment of left ventricular function. Use of aggressive non-invasive treatment, with or without aggressive invasive therapy, depends upon the results of angiography.
In the original BARI trial, patients with diabetes who underwent coronary artery bypass grafting surgery had a 15% absolute survival advantage at 5 years (P = 0.003). These data were obtained, however, from a post hoc analysis of patients treated with angioplasty before stents and intravenous glycoprotein IIb/IIIa platelet inhibitors were clinically available. Even so, internal thoracic arteries were used as conduits in 81% of the patients with diabetes.
We await the results of an ongoing randomized clinical trial, the FREEDOM study, but this will not be completed for several years. The current BARI 2D trial has randomized 2,368 patients with diabetes, documented CAD and myocardial ischemia, with or without chest pain, to either surgical or coronary intervention plus aggressive medical therapy, or aggressive medical therapy alone. A second randomization compares the beneficial effect of insulin-providing medication with that of insulin-sensitizing medication. Enrolled patients undergo gated single-photon-emission CT at randomization and at 1 and 3 years of follow-up. The results should help define the role of noninvasive testing for myocardial ischemia in diabetes, with or without well-documented CAD and coronary disease risk factors.
When considering the severity of CAD in patients with diabetes, possible poor long-term response to aggressive medical therapy, revascularization therapy or both, and slowing or preventing the progression of coronary atheromas by early modification of risk factors, the use of noninvasive stress testing seems appropriate to define the risk of CAD. Noninvasive coronary angiography should be performed in patients with evidence of mild or moderate myocardial ischemia. Single-photon-emission CT, at rest and during exercise or pharmacologic stress, remains the most common technique. Little information is available for other techniques, such as CT for coronary calcification or CT angiography.
The results of the BARI trial suggest that many diabetic patients, even when asymptomatic, will benefit from multivessel bypass surgery when operated on earlier in the course of their CAD.
References
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- National Center for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2003 [http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2003.pdf] (accessed 15 August 2005)
- National Center for Health Statistics. Prevalence of overweight and obesity among adults: United States, 1999–2002 (results from the 1999–2002 National Health and Nutrition Examination Survey) [http://www.cdc.gov/nchs/products/pubs/pubd/hestats/obese/obse99.htm] (accessed 18 August 2005)
- Levin DC and Fallon JT (1982) Significance of the angiographic morphology of localized coronary stenosis: histopathologic correlations. Circulation 66: 316–320 | PubMed | ChemPort |
- Vlassara H (1996) Advanced glycosylation end-products and atherosclerosis. Ann Med 28: 419–426 | PubMed | ISI | ChemPort |
- Farkouh ME et al. (2004) Diabetes and cardiovascular disease. In The Heart 2077–2125 (Eds Fuster V et al.) New York: McGraw-Hill Publishing Company
- Cook SA et al. (2005) Therapy insight: heart disease and the insulin-resistant patient. Nat Clin Pract Cardiovasc Med 2: 252–259 | Article | ChemPort |
- Nissen SE and Yock P (2001) Intravascular ultrasound: novel diagnostic insights and current clinical application. Circulation 103: 604–616 | PubMed | ISI | ChemPort |
- Wackers FJT et al. for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators (2004) Detection of silent myocardial ischemia in asymptomatic diabetic subjects. Diabetes Care 27: 1954–1961 | PubMed |
Competing interests
The author declared no competing interests.
Supplementary information
Supplementary Box 1 (doc 28KB)
Atherosclerosis-promoting effects of advanced glycosylation end-products
Supplementary Box 2 (doc 22KB)
Methods of diagnosing coronary artery disease in asymptomatic patients with diabetes
Supplementary Box 3 (doc 28KB)
Reasons for using noninvasive testing for assessing coronary artery disease in patients who have diabetes with no chest pain
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Subject areas under which this article appears: Angina and coronary artery disease | Cardiomyopathy and heart failure | Imaging and other investigations
