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Joslin’s Diabetes Deskbook, Updated 2nd Edition, Excerpt #32: Macrovascular Complications, Part 4

Apr 28, 2013

Richard S. Beaser, MD
Michael Johnstone, MD



The weeks excerpt answers the following questions:


  • What are "anginal equivalents"?
  • When is cardiac testing indicated in patients with diabetes who have underlying CAD?
  • When is stress perfusion imaging or a stress echo an appropriate initial choice?
  • When is Doppler testing of carotid circulation needed?

Macrovascular End-Organ Damage

The end-organ damage resulting from macrovascular disease is the leading cause of death for people with diabetes. While preventive strategies aimed at risk factor reduction are theoretically the best approach, many people still present with the results of atherosclerosis. After prevention, early detection of end-organ damage is the next best thing.

Coronary Artery Disease

Coronary artery disease (CAD) is common in people with both type 1 and type 2 diabetes. Underlying abnormalities at presentation can include angina, congestive heart failure (CHF), myocardial infarction, or sudden cardiac death. On the other hand, the presenting symptoms may by atypical, or absent altogether. The underlying pathology in a person with diabetes is similar to that in a person without diabetes, although in the diabetic person the distribution of disease is often more diffuse and involves more of the smaller coronary vessels. This diffuse distribution of coronary involvement has been implicated as a cause of the increased incidence of CHF seen in this population. Impaired ventricular function, frequently including isolated diastolic dysfunction, in the absence of significant atherosclerotic disease has suggested however that a cardiomyopathic process specific to diabetes may also be present.

The onset of CAD in people with diabetes occurs at a much younger age than in those people who do not have diabetes. Trends toward earlier intervention in the diabetic population as suggested by the HOPE and MICRO-HOPE trials will undoubtedly continue.

Autonomic Neuropathy 

Autonomic neuropathy can also affect the heart. Initial manifestations may include increased resting heart rate and a decrease in the beat-to-beat interval variation with inspiration and expiration, progressing to loss of variation with Valsalva or postural change. Autonomic cardiac neuropathies increase the risk for sudden cardiac death. Diabetic cardiac neuropathies have also been implicated as the cause for the loss of classic anginal pain. Thus, clinicians must approach these patients with heightened scrutiny. He or she should carefully seek hints of "anginal equivalents," which might include jaw or tooth pain, indigestion, arm or shoulder pain, increased fatigue, or decreased exercise tolerance.

Early Diagnosis Essential

The benefits of making an early diagnosis of coronary artery disease are multiple, and thus early recognition of signs and symptoms of CAD is important. Symptoms of CAD in people with diabetes may be subtle. The presence of microalbuminuria should be a marker for the increased likelihood of coronary artery disease. Initiation of earlier, more aggressive risk factor reduction programs may significantly slow the progression of the atherosclerotic process. In particular, lipid-lowering has been demonstrated to have significant impact on disease progression and mortality in a number of trials as reflected in the guidelines. Hypertension treatment, demonstrated to be beneficial in the UKPDS, can also be approached more aggressively. Early intervention using an ACE inhibitor (ramipril) to reduce progression to macrovascular disease seems to be gaining acceptance. Aspirin therapy should also be initiated.

TABLE 15-3. Indications for Cardiac Testing in Patients with Diabetes


Adapted with permission from American Diabetes Association: Consensus Development Conference on the Diagnosis of Coronary Heart Disease in People with Diabetes, Table 1 — Indications for cardiac testing in patients with diabetes; Diabetes Care 32:S13-S61, 2009.


Treatment aimed at the coronary ischemia can also be initiated once the diagnosis is established. Initiation of therapies with medications such as ß-blockers might be indicated and can be quite beneficial in reducing the impact of ischemia.

Further cardiac testing may be indicated in patients with diabetes who have underlying CAD. As classic coronary symptoms may be absent in people with diabetes, the ADA has recommended that testing be initiated in patients with specific indications that would indicate an increased cardiac risk (see Table 15-3). 

Selection of the modality for further cardiac testing must be individualized based on specific patient considerations. When cardiac disease is suspected, but the patient’s electrocardiogram (EKG) is normal, an exercise tolerance test may be an appropriate first step. If this patient had multiple risk factors, an abnormal ECG, or had more typical anginal symptoms with a normal EKG, then stress perfusion imaging or a stress echo might be an appropriate initial choice. Evidence of more significant cardiac disease such as clear ischemia or a myocardial infarction (MI) on EKG, unstable angina, or congestive heart failure (CHF) would warrant referral to a cardiologist for evaluation and possible angiography. Follow-up evaluation of exercise tolerance testing should be based on test findings and overall assessment of risk. In particular the role of an invasive evaluation and potential need for revascularization should be weighed. When making such decisions, the patient’s overall condition, including the presence of other complications, must be considered as well.

Peripheral Vascular Disease

Like CAD, the symptoms of peripheral vascular disease may be variable. Activity-induced pain in thighs, buttocks, or calf that is relieved by rest may represent peripheral vascular disease. However, unlike CAD, a physical examination is often much more revealing. Decreased pedal pulses, a dusky blue color or dependent rubor of the feet, or decreased hair growth on the feet are suggestive findings.

Cerebrovascular Disease

Cerebrovascular disease may be more common in people with diabetes than may be evident from easily recognizable symptoms. Clearly, once a stroke or transient ischemic attack (TIA) occurs, the diagnosis is strongly suggested. However, the clinical challenge is to determine the presence of cerebrovascular disease prior to these events. The presence of carotid bruits, while not always reliable indications of vascular occlusions, certainly provide enough suggestive evidence to justify non-invasive Doppler testing of carotid circulation. Carotid endarterectomy may be indicated if this test shows a significant stenosis, even if the patient is asymptomatic. Prophylactic aspirin may be effective as a preventive strategy, while Coumadin anticoagulation is often prescribed once a neurologic event has occurred. Some of the newer studies have shown a reduction in the risk of stroke or TIAs by LDL cholesterol-lowering drugs, particularly statins, in patients with pre-existing macrovascular disease. Clopidogrel may also reduce the risk of stroke. The HOPE and MICRO-HOPE trials also suggested the benefits of ACE inhibitor (ramipril) treatment.

Major Psychoses and Increased Risk of Diabetes and the Metabolic Syndrome

It has been recognized that people with major psychoses such as schizophrenia have an increased risk of developing diabetes and the metabolic syndrome. It seems that the increased risk is related to schizophrenia itself, and it has been suggested that it could be due to either a genetic relationship and/or a reflection of the typical lifestyle (sedentary, poor nutritional habits, smoking) of these individuals. Obesity, which certainly contributes, is increased in this population.

There is also an apparent increase in the risk of developing these metabolic abnormalities with use of some of the antipsychotic medications. Case reports and minimal comparative studies suggest clozapine and olanzapine may more significantly increase the metabolic risk, although counter arguments look to the increased risk in the population as still being the key factor. However, growing evidence does point to some drug involvement, particularly with an increased risk for diabetic ketoacidosis, suggesting a possible drug effect on ß-cell function as well. Lesser risk is seen with newer agents ziprasidone and aripiprazole.

The evidence is still being collected to understand more fully the relationship between psychoses and their treatments with diabetes and the metabolic syndrome. Until the full story is understood, increased vigilance in this population is recommended, particularly if patients are using one of the medications implicated as a possible contributor to the problem. Antipsychotic medication selection based on metabolic risk profile should be considered. Interventions to reduce or treat macrovascular risks would be the same as for the non-psychotic population, but recognizing that most lifestyle and many pharmacologic interventions are more difficult to initiate and manage in this group.

Dental Disease — Its Role in Diabetes and Implications for Macrovascular Disease

Dental and periodontal diseases have long been recognized as being more common in people with diabetes. In addition, the prevalence of diabetes is higher in people who have periodontal diseases than in those who don’t. Conditions include dental abscess, gingivitis, and severe periodontitis with tooth loss. Oral conditions such as candidiasis, lichen planus, xerostomia, burning mouth syndrome, angular cheilitis and taste dysfunction are more commonly seen with poorly controlled diabetes. Oral conditions, particularly abscesses, can also lead to higher glucose levels, which may be the first or only manifestation of the oral condition. Oral candidiasis is associated with hyperglycemia, and can result from xerostomia, salivary hyperglycemia, and impaired immune function. More recently, there has been a suggestion that the inflammatory process seen in the mouth, particularly the gums, may relate in some way to the inflammatory process that is seen as a contributing factor in endothelial dysfunction. Some studies show that dental caries is more prevalent in people with diabetes, as well.

Routine dental examinations are therefore recommended for all people with diabetes. At an initial visit, the presence of diabetes should be discussed with the dentist, with consideration of visits every 6 months. People with a history of poorly controlled diabetes and periodontal diseases may need dental visits even more frequently. The exam should include specifically screening for the common dental and oral complications seen in people with diabetes as noted above. Non-dental clinicians caring for people with diabetes should encourage dental consultations, particularly if symptoms of the above conditions are noted, such as sore, swollen, or bleeding gums, loose teeth, or persistent mouth ulcers. The healthcare team should reinforce the importance of proper oral health care, which includes tooth and gum cleaning and visits to the dentist at least twice a year, brushing at least twice a day, flossing at least once a day, use of fluoride-containing toothpaste, and smoking cessation. With sudden deterioration of glycemic control without any other obvious explanation, dental conditions should be considered.

Suggested Reading 

American Diabetes Association. Standards of medical care in diabetes — 2007. DiabetesCare. 2007 Jan;30 Suppl 1:S4–S41.

Stern M.Natural history of macrovascular disease in type 2 diabetes: role of insulin resistance. Diabetes Care 22 (Suppl. 3):C2–C5, 1999.

Steiner G. Risk factors for microvascular disease in type 2 diabetes. Diabetes Care 22 (Suppl. 3): C6–C9, 1999.

Beaser R, Levy P: The Metabolic Syndrome: A Work In Progress, But A Useful Construct . Circulation. 115: 1812–1818, 2007

Kahn R: Metabolic Syndrome: Is It a Syndrome? Does It Matter? Kahn Circulation. 115: 1806–1811, 2007

Yusuf S et al. Effect of potentially modiªable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 364:937–952, 2004.

American Diabetes Association position statement: Dyslipidemia Management in Adults With Diabetes Diabetes Care 27 (Suppl. 1):S68–S71, 2004.

Haffner SM.Management of dyslipidemia in adults with diabetes (Technical Review). Diabetes Care 21:160–178, 1998.

Stamler J, Vaccaro O, Neaton JD. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434–444, 1993.

Sacks FM, Pfeffer MA, Moye LA, Roleau JL, Rutherford JD, Cole TG, Brown L,

Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001–1009, 1996.

4S Study Group: Randomized trial of cholesterol lower in 4444 patients with coro- nary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383–1389, 1994.

Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, Houston-miller N, Kris-Etherton P, Krumholz HM, LaRosa J, Ockene IS, Pearson TA, Reed J, Smith SC, Grundy S. et al. for the Coordinating Committee of the National Cholesterol Education Program Endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association.

Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 110:227–239, 2004.

Yudkin JS: Abnormalities of coagulation and ªbrinolysis in insulin resistance. Diabetes Care 22 (Suppl. 3): C25–C30, 1999.

American Diabetes Association position statement: Aspirin Therapy in Diabetes Diabetes Care 27 (Suppl. 1):S72–S73, 2004.

Colwell JA: Aspirin therapy in diabetes (Technical Review). Diabetes Care 20:1767–1771, 1997.

American Diabetes Association Consensus Development Conference Report: Consensus Development Conference on the Diagnosis of Coronary Heart Disease in People with Diabetes. Diabetes Care 21: 1551–1559, 1998.

Pyörälä K, Pedersen TR, Kjeksus J, Faergeman O, Olsson AG, Thorgeirsson G: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 20:614–620, 1997.

Sacks FM, Pfeffer MA, Moye LA, Fouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis DR, Brunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001–1009, 1996.

Haffner SM et al. 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 339: 229–234, 1998.

American Diabetes Association Consensus Development Conference Report: Consensus Development Conference on the Treatment of Hypertension in Diabetes. Diabetes Care 16:1394–1401, 1993

HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE and MICRO-HOPE substudy. Lancet 355:253–259; 2000.

HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342–145–153; 2000.

ADA. Standards in medical care in diabetes- 2006. Diabetes Care, Volume 29, Supplement 1, January 2006

The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72

The ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59

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