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Type 2 Diabetes, the Metabolic Syndrome, Inflammation, and Arteriosclerosis:

Type 2 Diabetes, the Metabolic Syndrome, Inflammation, and Arteriosclerosis:

Up to 10% of Americans older than 20 years have type 2 diabetes, and more than 20% have the metabolic syndrome.1,2 The prevalence of both diseases has risen by 33% over the past decade as a result of an increasingly sedentary lifestyle, the obesity epidemic, the growth of ethnic groups at risk for the disease, and the aging of the population. The prevalence of the metabolic syndrome increases dramatically with age: 45% of persons older than 60 years are thought to have the syndrome. Type 2 diabetes mellitus will develop in many of these persons.1,2

In the United States, diabetes is the fifth leading cause of death; the leading cause of kidney failure, nontraumatic limb amputations, and blindness; and the foremost contributor to cardiovascular disease (CVD). CVD accounts for about 70% of deaths in adults with diabetes and is a stronger predictor than glycemic control of morbidity and use of health care resources in these patients.3-6 Moreover, 3 components of the metabolic syndrome--hypertension, glucose intolerance, and dyslipidemia--are major risk factors for CVD.

Despite better understanding of the pathophysiology and management of diabetes and the metabolic syndrome, patient outcomes have not shown a parallel improvement.7,8 Only 30% to 35% of patients with diabetes achieve 1 or more of the American Diabetes Association goals for the quality indicators of hemoglobin A1c, low-density lipoprotein cholesterol (LDL-C), and blood pressure (BP). Only 7% of patients achieve goal levels in all 3 indicators.9

Our current system of medical education and clinical care has not effectively addressed this issue. A major shift in the way we care for patients is crucial to reduce the burden of suffering associated with diabetes and the metabolic syndrome and to forestall the development of CVD.


The following case, a typical one seen in primary care, serves as a good framework to aid our understanding of the problem and how it might be addressed.

A 42-year-old Hispanic man presented for a physical examination at his wife's urging, although he had no specific complaints. He had recently gained 10 lb, which he attributed to the elimination of his daily walking and a new job that involved more deskwork. He had a family history of diabetes, and his father had had a stroke at age 60 years.

The patient's body mass index (BMI) was 29, his waist circumference was 42 inches, and his BP was 138/88 mm Hg. Other examination results were normal. His fasting laboratory results included a serum glucose level of 108 mg/dL; total cholesterol, 190 mg/dL; LDL-C, 100 mg/dL; high-density lipoprotein cholesterol (HDL-C), 30 mg/dL; and triglycerides, 300 mg/dL.

Consider the following questions as you continue reading: With the above history, examination, and laboratory values, what is the patient's risk of a cardiovascular event? How would you treat this man? Would you prescribe anything other than diet and exercise?

The patient was advised to exercise and to reduce his intake of saturated fat. During the next 8 years, he returned on several occasions for acute conditions such as upper respiratory tract infections and knee pain. His BP had risen to 148/94 mm Hg, and hydrochlorothiazide, 25 mg/d, was started. No further laboratory tests were performed during that period.

At age 50 years, he was admitted to the hospital with a myocardial infarction (MI). His serum glucose level was 350 mg/dL; the hemoglobin A1c was 9. His lipid levels were unchanged. He was treated with metformin, and his hemoglobin A1c decreased to 7.5. Because his LDL-C level was 100 mg/dL, no treatment was prescribed for his other lipid abnormalities. A b-blocker was added for hypertension; his BP averaged about 140/85 mm Hg. Three years later, he had a stroke.Five years after that, at age 58 years, he had a massive MI and died.


Given our current knowledge, could his MI, stroke, and premature death have been prevented? In trying to make that assessment, let us go back and calculate his risk at age 42 years. According to the risk calculator recommended by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), the patient's risk of a cardiovascular event in the next 10 years was 2% to 3%.10

These calculations are driven by many factors, the most important of which is age. Projecting age forward with the calculator and not changing the risk factors, an increase in risk is apparent. By age 55 years, the risk increases to 16%, and by age 60 years, it increases to 20%. However, if the patient's diabetes had been included in the calculation by age 50 years, the risk would have been 20% at that age. Risk calculators can give a false sense of security in younger persons; projecting forward gives a more realistic assessment.

The other critical factor in this patient is his lipid profile. At first glance, his LDL-C level seems ideal. However, this is misleading because it is a calculated value. The calculation is not valid when the triglyceride level is higher than 200 mg/dL; this patient's level was 300 mg/dL. ATP III recommends using non-HDL-C instead of LDL-C to help make management decisions when triglyceride levels are higher than 200 mg/dL.10 The non-HDL-C level is total cholesterol minus HDL-C, which in this patient is 160 mg/dL (190 2 30 = 160).The ideal non-HDL-C level is 100 to 130 mg/dL in patients who are at elevated risk for CVD.

This patient also had atherogenic dyslipidemia (high triglyceride and low HDL-C levels). This combination indicates a high concentration of small, dense LDL-C particles that are highly atherogenic and can lead to significant CVD if not treated.

More aggressive treatment would certainly have been warranted in this patient. At a minimum, in addition to significant changes in his diet and level of physical activity, much closer follow-up of his lipid status and hemoglobin A1c was warranted. If his non-HDL-C level had failed to decrease to 130 mg/dL or less with lifestyle changes, statin therapy should have been strongly considered.

A test for high-sensitivity C-reactive protein (hsCRP) is more sensitive than the test for CRP and would also have helped guide this patient's treatment. An elevated value (ie, higher than 3 mg/L) would have placed him in a high-risk category that required aggressive treatment. His elevated BP warranted use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), in addition to the diuretic, to reduce his BP to more acceptable levels. Because he had diabetes, an acceptable goal according to current recommendations would be less than 130/80 mm Hg.11


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