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Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #29: Macrovascular Complications, Part 1

Mar 17, 2013

Richard S. Beaser, MD
Michael Johnstone, MD


 This week’s excerpt answers the following questions:

  • What are the risk factors for the premenopausal female?
  • What is the likelihood of macrovascular disease among those with diabetes? 

While diabetes is a result of a metabolic dysfunction resulting in hyperglycemia complications make diabetes mellitus a vascular disease. Diabetes is implicated in both microvascular and macrovascular diseases. Macrovascular disease, which includes coronary artery disease, peripheral vascular disease and stroke, is more prevalent in people with diabetes than in the general population. However, only in recent years have we begun to understand the magnitude and implications of the association between macrovascular disease and diabetes. Both type 1 and type 2 diabetes increase macrovascular risk, and, after glucose control itself, reducing the risk of macrovascular disease is probably the greatest challenge facing the clinician caring for people with diabetes….

Compared to the general population, macrovascular disease tends to occur at a younger age. In addition, the protection imparted by female gender (particularly being a premenopausal female) in the general population disappears when diabetes is present.

The likelihood of macrovascular disease among those with diabetes is two to three times that of the nondiabetic population. This risk of developing atherosclerosis only increases with the presence of frequently concurrent risk factors including hypertension, smoking, sedentary lifestyle, family history, or dyslipidemia. Macrovascular disease accounts for 65% of the deaths in patients with diabetes. The risk of death from cardiovascular disease is twice as high for males with diabetes than the nondiabetic male and up to four times higher among females with diabetes than the non-diabetic female. Cerebrovascular accidents are also more frequent in the diabetic patient than the non-diabetic.

Most of the macrovascular complications occur in patients with type 2 diabetes. The underlying cause of type 2 diabetes is insulin resistance. Some have referred to a constellation of key findings related to insulin resistance as the insulin resistance syndrome (IRS). These key manifestations of insulin resistance are:

  • central obesity
  • glucose intolerance/type 2 diabetes
  • atherosclerosis
  • hypertension
  • first degree relatives with type 2 diabetes
  • history of gestational diabetes
  • polycystic ovary syndrome
  • acanthosis nigricans
Biochemical Abnormalities: 
  • carbohydrate: glucose intolerance, hyperinsulinemia, insulin resistance
  • lipid: high triglycerides, low HDL-cholesterol, small, dense LDL particles
  • fibrinolysis: increased PAI-1 level
More recently, this list has been refined in an attempt to more clearly define cardiovascular risk into what is referred to as the metabolic syndrome, or alternatively the cardiometabolic syndrome. This syndrome is a subset of measurable components of the insulin resistance syndrome, and includes: 
  • abdominal obesity (men >40 in, women >35 in)
  • elevated triglycerides (>150 mg/dL)
  • low HDL-cholesterol (men <40 mg/dL, women <50 mg/dL)
  • elevated Blood pressure (>130/>85 mm Hg)
  • fasting glucose >100 mg/dL*

* ATP III definition is >110 mg/dL, but revised definition of diabetes uses the 100 mg/dL value which we have listed here.

People with 3 or more of these have the cardiometabolic syndrome. 

People with insulin resistance often have hyperinsulinemia, an attempted compensatory response to the insulin resistance. After some debate as to whether insulin plays a direct role in the etiology of atherogenesis, it is now believed that the hyperinsulinemia should be viewed primarily as a metabolic marker of this syndrome and the process leading to atherogenesis, rather than as playing a direct causal role in the pathogenic process. It is the many related conditions such as glucose intolerance and the others listed above that are manifestations of metabolic syndrome and constellation of findings often related to insulin resistance that are probably more directly linked to the atherogenic process. Therefore, from a clinical standpoint, it is imperative that these macrovascular risk factors be identified and treated as aggressively as possible. Many treatments directly targeting various of these abnormalities have been shown to reduce some atherosclerotic endpoints. However, taking it one step further, it has been speculated that treatments reducing the insulin resistance itself may have similar beneficial effects, although less evidence for this theory has been accumulated as yet.



Hypertension is discussed in detail in Chapter 14. It often occurs as a result of renal disease in people with type 1 diabetes. Among those with type 2 diabetes, hypertension is very prevalent whether renal disease is present or not. Macrovascular disease can cause, and in turn can be caused by, hypertension. The development of type 2 diabetes was found to be almost two and a half times higher in patients with hypertension than their normotensive counterparts after adjustment for age, sex, race, adiposity and physical activity level. Hypertension in the patient with diabetes has several unique features. Supine hypertension with orthostatic hypertension is not uncommon as a result of autonomic neuropathy. Furthermore many diabetes patients do not have the usual nocturnal drop in blood pressure. Aggressive treatment of hypertension must be part of an overall strategy for diabetes management, both to protect renal function and to preserve vascular patency.

Next Joslin excerpt: Dyslipidemia – Goals of Treatment

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