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Joslin’s Diabetes Deskbook, Updated 2nd Edition, Excerpt #31: Macrovascular Complications, Part 3

Apr 14, 2013

Richard S. Beaser, MD
Michael Johnstone, MD



This week’s excerpt answers the following questions: 


  • What are the three disorders of coagulation and fibrinolysis that increase the risk of developing macrovascular disease
  • When and who should be on aspirin therapy
  • How to reduce macrovascular risks
  • Which ACE inhibitor reduces the risk of MI by 22%, reduces cardiovascular death by 37%, and can reduce stroke by33%

Macrovascular Complications


There are three disorders of coagulation and fibrinolysis that have been associated with the resistance syndrome and which further increase the risk of developing macrovascular disease:

  • increased levels of plasminogen activator inhibitor (PAI-1)
  • increased levels of von Willebrand factor and factor VII
  • increased levels of fibrinogen and C-reactive protein (CRP)

How these coagulation findings relate to, and are perhaps caused by, insulin resistance and/or endothelial damage is the subject of much academic discussion. They clearly have an impact on coagulability. There is also an increased platelet aggregability in people with diabetes. The increase on PAI-1 probably has the direct effect of decreasing fibrinolysis.

Increased Von Willebrand factor implies endothelial damage. Elevated fibrinogen and CRP levels may result from endothelial damage or proinflammatory cytokines. Nevertheless, regardless of the mechanism, the resulting increase in coagulability seen in people with type 2 diabetes clearly increases their risk for macrovascular disease.

Preventive Strategies 

The cornerstone of therapy aimed at reducing hypercoagulability is aspirin therapy. Aspirin has been used in both primary and secondary prevention for people with and without diabetes. The current recommendation by the ADA for people with diabetes is to use aspirin therapy as a secondary therapy for people who already have evidence of macrovascular disease. In addition, it is recommended that aspirin be considered for use as primary preventive therapy in those people with diabetes who are at high risk for macrovascular disease. This category includes people with:

  • a family history of CAD
  • hypertension
  • obesity (>120% ideal body weight (IBW) or body mass index (BMI) >28 in women, >27.3 in men)
  • cigarette smoking
  • microalbuminuria or macroalbuminuria
  • dyslipidemia
  • age >30 years

Traditionally, the recommended aspirin dose has been 81 mg (a "low dose") of enteric-coated aspirin. However, more effective risk reduction has been seen with increased doses, up to a full enteric-coated aspirin tablet (325 mg) daily. Some experts suggest that the higher the risk factor profile, the higher the aspirin dosage. An alternative to aspirin therapy is clopidogrel (75 mg daily).

The major risk of aspirin therapy is bleeding, particularly from the upper gastrointestinal tract. Enteric-coated aspirin preparations may reduce this risk. Contraindications to aspirin therapy largely relate to this bleeding risk and include other bleeding disorders, anticoagulant therapy, history of recent gastrointestinal bleed, clinically active hepatic disease, or aspirin allergy. Aspirin therapy does not seem to increase the risk of retinal bleeding.


Obesity is also a macrovascular risk factor. Obesity is defined as being >20% over IBW. It has been estimated that about 80% of all people with type 2 diabetes are obese at the time of diagnosis or have a history of obesity. There are two classic patterns of obesity. One is the android, "apple" shape, or central obesity, which represents increased intra-abdominal fat and is associated with type 2 diabetes and insulin resistance. Alternatively, the gynoid or "pear" shape represents increased fat in the hips and thighs, classically seen in women.

Diabetes as a Macrovascular Risk Factor

Having diabetes does seem to increase the chances of developing macrovascular disease. However, the exact relationship has not been clearly demonstrated. Although the insulin resistance syndrome itself, with the associated conditions such as dyslipidemia and hypercoagulability, does seem to be a macrovascular risk factor, is the hyperglycemia of type 2 diabetes itself a direct risk factor as well? Many would argue that it is, but this association remains controversial until more direct data has been accumulated.

Clearly, hyperglycemia is a microvascular risk factor, so aggressive glucose control is still appropriate for all people with diabetes. While proof that hyperglycemia, per se, is a macrovascular risk remains elusive, it has been demonstrated or suggested that hyperglycemia is associated with multiple abnormalities that lead to an increased incidence of macrovascular disease. In the UKPDS study, the relationship between glucose control and macrovascular endpoints just missed statistical significance. Two other studies from Finland do suggest a weak but significant relationship for people with type 2 diabetes. A stronger relationship between glucose control and macrovascular disease has been noted for patients with type 1 diabetes in a number of observational studies. More recently, the DCCT/EDCIC study did show that glucose control does reduce the likelihood of clinical macrovascular events in patients with type 1 diabetes. To date, there are no studies that demonstrate that tight glucose control in patients with type 2 diabetes reduces cardiovascular events.

Nevertheless, having diabetes clearly correlates with a worse overall risk of problems associated with coronary disease. In fact, a study by Haffner et al demonstrated that having diabetes is equal in conferring subsequent risk for an MI to having already had an MI but not having diabetes. Further, individuals with diabetes who have heart disease are at much greater risk for:

  • congestive heart failure
  • a second heart attack
  • involvement of multiple coronary arteries

Therefore, it seems reasonable to state that the benefits of glucose control have been demonstrated for all patients, but the level of A1C control needed to provide a clear reduction of macrovascular risk, independent of other risk factors, remains controversial. Two recent, large randomized trials of intensive glucose lowering — ACCORD and ADVANCE – have provided more information. With an A1C goal <6.5%, ADVANCE showed no overall reduction in macrovascular events, while ACCORD, with an A1C goal <6.0%, showed no reduction in major cardiovascular events and increased mortality in the intensive therapy group. The findings of another study, the Steno trial, suggest that addressing multiple risk factors concurrently is the most effective approach, and is thus the current standard of care that is recommended by most experts. This attention to blood pressure and lipid goals, as well as glycemic control, is behind the continuing improvement in cardiovascular outcomes that is being documented in people with diabetes. The current A1C goal of 7.0% or less is appropriate for achieving these goals. 

The reduction of macrovascular risk is clearly an important imperative in the approach to treatment of people with diabetes. With the trends seen in recommendations such as the new NCEP guidelines, it is clear that diabetes itself, independent of the specific risk factors that accompany it, is being thought of as a risk factor for macrovascular disease. Indeed, many consider diabetes itself a disease entity that is a precursor to macrovascular disease, and thus approach people with diabetes as if they already have commenced the pathophysiologic process that results in atherosclerosis.

Classic evidence supporting this approach was demonstrated in the HOPE (Heart Outcomes Prevention Evaluation) study and the substudy, MICRO-HOPE, that looked at a diabetic subpopulation. The MICROHOPE trial showed that patients with diabetes who were treated with an ACE inhibitor, ramipril, 10 mg daily, showed an overall reduction in the risk of MI of 22%, reduction of cardiovascular death of 37%, and stroke of 33%. Treatment with ramipril was independent of the traditional indications, hypertension or microalbuminuria. This study suggests that pharmacologic intervention in people over 55 with diabetes and one other cardiac risk factor (criteria for the Micro-Hope population) may have a significant impact in reducing macrovascular risk. In the HOPE trial itself, people 55 years or older who had a history of CAD, Stroke, or PVD and were thus at high risk of having a major cardiovascular event showed similar reductions in events, plus had a 34% lower risk of developing diabetes. Ramipril is now indicated for use as part of preventive strategies in patients with these risk profiles. Whether or not these benefits are shared by other ACE inhibitors will have to await confirmatory data.

Gender Issues in Assessing Macrovascular Risk Factors

Premenopausal women with diabetes lose the natural protection from the development of macrovascular disease that their female gender would otherwise have conferred. The Framingham Heart Study data suggest that, correcting for all other risk factors, diabetes doubles a woman’s risk of developing coronary heart disease. In addition, women with diabetes are more likely to die after a myocardial infarction, with a marked increased incidence of congestive heart failure, than either diabetic men or nondiabetic women. As a result, the focus on macrovascular risk reduction for women with diabetes should be as aggressive as for men, and symptoms suggestive of macrovascular end-organ damage should be taken very seriously.

Cigarette Smoking

The fact that cigarette smoking can be hazardous to one’s health is a fact that should be known to everyone by now. Nevertheless, many people still smoke and others are affected by second-hand smoke. Smoking can increase macrovascular risk as well as increase the risk of diabetic retinopathy.

The focus on diabetes healthcare interventions is most often on glucose control, lipid management, treatment of hypertension, and dyslipidemic therapy, with time remaining dealing with foot care, insuring ophthalmologic exams have occurred, and the like. The chance to address cigarette smoking cessation is often squeezed into the ever-shortening time allotted for primary care visits. Yet, if successful, this change in personal habits can often impact health and longevity as much, if not more, than interventions aimed at some of the other risk factors.

Specific actions focusing on smoking cessation that a healthcare professional can take include:

  • Taking a detailed smoking history at each visit, including the amount smoked and ongoing efforts to stop. This attention reinforces the importance of smoking as a health risk.
  • Counseling people about the negative impacts of smoking on overall health and, in particular, on diabetes and its complications.
  • Recommending smoking cessation medications or patches, or referring people to formal cessation programs, if other efforts have been unsuccessful.

Next Joslin text: Chapter 15: Macrovascular End Organ Damage – Autonomic Neuropathy – Peripheral Vascular Disease – Cerebrovascular Disease


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