The Metabolic Syndrome, Insulin Resistance and Cardiovascular Disease

by J. Ross Tanner, D.O.

Whether you are a primary care specialist or a sub-specialist, you are probably seeing more patients with diabetes as well as patients with metabolic syndrome (also known as “pre-diabetes”). There are several potential reasons for the “pandemic,” but most experts agree that the majority of patients possess the combination of improper behavior — over-eating and under-exercising — with genetic or ethnic tendencies. Subsequently, the development of obesity with other metabolic problems begins to occur concomitantly.

For most of the 20th century, cardiovascular disease (CVD) was identified as the major cause of morbidity and mortality in the developed world. During this period there was considerable effort to understand the underlying biology of the disease and to identify the contributing risk factors. As risk factors were identified, it became apparent that more than one was often present in the same individual. Toward the end of the century, the clustering of CVD risk factors was first described — most notably the simultaneous presence of obesity, type II diabetes, hyperlipidemia and hypertension. Although insulin resistance (i.e., resistance to insulin-stimulated glucose uptake) as a feature of type II diabetes was first described many years earlier, hyperinsulinemia was also found to be a key feature of type II diabetes, as well as hyperlipidemia, obesity and hypertension.

This risk-factor clustering, and its association with insulin resistance, led investigators to propose the existence of a unique pathophysiological condition, called the “metabolic” or “insulin resistance” syndrome. This concept was unified and extended with the landmark publication of Gerald Reaven in 1988 (1). Reaven postulated that insulin resistance and its compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia and diabetes, and was thus the underlying cause of much CVD.

As defined principally by the World Health Organization (2) and the Third Report of the National Cholesterol Education Program’s Adult Treatment Panel (ATP III) (3), the metabolic syndrome has been identified as the presence of three or more of these risk factors:

• Elevated triglycerides of greater than 150.

• Diminished HDL with gender specificity (women less than 50, and men less than 40). An ideal HDL is greater than 60 and actually will negate one of the other risk factors used in calculating a Framingham cardiovascular 10-year risk score of having a future event.

• Increased waist circumference. Also gender specific, with greater than 40 inches (102 cm) in men and greater than 35 inches (88 cm) in women. A simple tape measure can be used by the nursing staff as part of the vital signs taken at each visit. With the patient in a relaxed state, measure the largest circumference between the umbilicus and the top of the ilium. The greater the amount of visceral adiposity, the greater the risk of the development of metabolic syndrome. The visceral adipocytes are glandular in nature and produce adipocytokines, angiotensinogen, insulin resistance factors along with procoagulants (14).

• Elevated blood pressure: systolic blood pressure of greater
  than 130 mmHg and a diastolic blood pressure of greater than
  85 mmHg.

• Elevated fasting serum glucose of greater than 100 mg%.
  If greater than 126 mg%, the diagnosis of diabetes can
  be established.

There are currently no medications approved for the specific treatment of the metabolic syndrome as a constellation of disorders. But there are FDA-approved medications to treat each component of The Metabolic Syndrome, Insulin Resistance and Cardiovascular Disease this syndrome, with the exception of impaired fasting glucose. Many physicians have used anti-hyperglycemic medications “off-label” to treat impaired fasting glucose or impaired glucose tolerance. For example, thiazolidendiones (pioglitazone,rosiglitazone), biguanides (metformin), and more recently glucagon-like protein (GLP-1) inhibitors (exenetide).

The ADA and the European Association for the Study of Diabetes issued a controversial joint statement in September 2005 stating that the metabolic syndrome may be a group of disorders that have disparate pathologies. The syndrome, they contend, appears to confer no greater risk of CVD risk as a whole than does the sum total of its parts and can mislead patients in believing that they have a “disease” rather than a cluster of cardiovascular risk factors which should be treated individually (4). The primary basis for this recommendation has been based on data from the National Cholesterol Education Program, Adult Treatment Program III. The Framingham risk score has actually been shown to be superior to the clinical criteria for metabolic syndrome for predicting CVD events (3).

As the mechanisms underlying the metabolic syndrome continue to be debated, most physicians agree these patients are at increased risk for the subsequent development of vascular disease. Therefore, smoking cessation, reduction of LDL cholesterol, adequate blood pressure control and improvement of hyperglycemia are of the utmost importance for the prevention of vascular disease, whether or not the patient has the clinical criteria for metabolic syndrome.

These tasks can often be accomplished by weight reduction through dietary discretion, regular exercise of 120-150 minutes per week or 2000 calories of energy expenditure/week, and the introduction of medications when appropriate based on risks and benefits. Healthy eating habits should not only include calorie counting but also limitations of carbohydrates, saturated fats, trans-fats and cholesterol.

There has also been an association between markers of inflammation and insulin resistance (5), as well as inflammation and obesity (7, 8, 9), leading some investigators to conclude that inflammation is integrally related to the components of the metabolic syndrome (10).

One of the many markers identified is C-reactive protein (CRP), which has been studied in great detail. It has been found to be an independent CVD risk factor (11, 12) and an independent marker of insulin resistance (13). CRP is also strongly associated with adipose-derived cytokines — including interleukin-6 and tumor necrosis factor (14) — and is more likely to be elevated in obese insulin-resistant, but not obese insulin-sensitive, subjects (6).

Several other molecules/markers have also been found to be closely associated with insulin resistance, metabolic syndrome risk factors and the risk of CVD. These include increased levels of plasminogen activator inhibitor (PAI-1) (15), fibrinogen (16), factor VII activation and thus an increase in prothrombin, as well as increased platelet aggregation. These factors and others can contribute to the increased risk of thrombosis. With the development of unstable plaques which frequently ulcerate, this can prove to be a deadly combination.

PAI-1, produced by the visceral adipocyte, acts as a tissue plasminogen activator (TPA) inhibitor, which converts plasminogen to plasmin, leading to the degradation of fibrin on the vascular wall. It can be reduced by weight loss, exercise and thiazolidendiones (TZDs). The TZDs (pioglitazone, rosiglitazone) may have additional pleiotrophic vascular effects in addition to their known PPAR_ agonism for the treatment of insulin resistance/hyperglycemia. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that influence vascular function by altering gene expression in vascular tissue and indirectly via effects on other tissues. PPAR activation not only displays beneficial effects on glucose homeostasis but also on lipid metabolism, endothelial function and vessel wall inflammation. In small retrospective studies, these medications have shown to decrease carotid intimal media thickness and microaluminuria, both markers of endothelial dysfunction in diabetics and non-diabetic hypertensives. Also, there is evidence that TZDs may also decrease post stent restenosis rates following coronary stent placement in diabetics (17). More evidence in the form of large double-blinded prospective studies are necessary and currently underway. In the PROactive study — the first prospective double blind study involving a TZD — pioglitazone failed to reach clinically significant primary outcomes prevention but did reveal a decrease in secondary endpoints. The principal secondary endpoints of life threatening events showed that pioglitazone significantly reduced the risk of myocardial infarction, cerebrovascular events and death by 16 percent (p<0.027) (18).

Is diabetes a glucose issue or is it the etiology of why we have an elevated glucose problem? That question needs to be further elucidated. Does insulin resistance (as the underlying problem in most of these patients) and the co-existence of hypertension, hyperlipidemia and hyperglycemia predicate the inevitable development or aggressive progression of CVD? Since the metabolic syndrome does not include all known CVD risk factors, it should convey risk independently of other conventional risk factors (e.g., LDL, age, smoking and family history); however, the proportion of the global CVD risk captured by the syndrome is unknown. It would be invaluable to know, from a list of all known CVD risk factors, the hierarchy of combinations with the highest predictive value. Then, a true comparison between the metabolic syndrome or perhaps some new combination would tell us what is the best CVD predictive model.