Dysmetabolic Syndrome: Reducing Cardiovascular Risk

When the National Cholesterol Education Program (NCEP) revised the Adult Treatment Panel III (ATP III) guidelines in 2001, dysmetabolic syndrome was added as a secondary focus for cardiovascular risk factor modification, but only after low density lipoprotein cholesterol (LDL-C) levels are optimized.1 The addition of dysmetabolic syndrome as a focus in risk reduction identified many individuals as at-risk for type 2 diabetes and/or cardiovascular disease who may have gone unrecognized and untreated until much later in the disease trajectory.2-4

Over the past 50 years, dysmetabolic syndrome has been studied under numerous other names (Syndrome X, insulin resistance syndrome, etc.,) and is closely associated with risk for both type 2 diabetes and cardiovascular disease.5-7

* Etiology

Central obesity is the cornerstone of dysmetabolic syndrome.8 Other components of the syndrome tend to cluster around central obesity as well.9-11 Hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, dysfibrinolysis (i.e., elevated plasminogen activator inhibitor-1 [PAI-I], fibrinogen) inflammation (i.e., elevated C-reactive protein [CRP]), and/or elevated fasting insulin have been associated repeatedly in individuals with an enlarged waist circumference, having met the criteria for central obesity even at normal levels of body mass index (BMI) (see Table: “Diagnostic Criteria for Dysmetabolic Syndrome Based on NCEP ATP III”).1,7,12

Diagnostic Criteria for the Dysmetabolic Syndrome Based on NCEP ATP III

* Pathophysiology

The deep visceral abdominal adipocytes or fat cells excrete deleterious metabolic substrates such as angiotensinogen and PAI-1, setting up a milieu for hypertension, inflammation, and dyfibrinolysis or a procoagulable state.7,13-15 While increased levels of plasma PAI-I are found in individuals with hypertriglyceridemia and/or hyperinsulinemia, both substances stimulate the deep visceral abdominal adipocytes to excrete excessive plasma levels of PAI-1.16,17 The deep visceral abdominal adipocytes are considered metabolically active, extremely lipolytic, and easily broken down into free fatty acids (FFA).18 It is then plausible to assume that FFA may overrun the liver, causing insulin resistance. The “Portal Theory” offers some insight into the likely pathological processes that occurs when the dysmetabolic syndrome is present.19 The theory suggests that due to the proximity between the deep visceral abdominal adipocytes and the portal veins, the adipose tissue is broken down into FFA as these substrates bombard the liver and insulin resistance develops.20-23 Thus, centrally obese individuals commonly present with components of the dysmetabolic syndrome, including insulin resistance.

* Clinical Presentation

There are several definitions of the dysmetabolic syndrome, however not all are practical for clinical screening at this time. The NCEP guidelines are the gold standard for clinical practice; however, in the future, adding separate components from other definitions of the dysmetabolic syndrome may prove to be clinically efficacious when combined with the NCEP criteria for determining early risk for cardiovascular disease. For example, a likely candidate for addition to the NCEP’ s criteria for the dysmetabolic syndrome is C-reactive protein (CRP), a marker of subclinical inflammation, closely associated with abnormal endothelial function and abnormal levels of hemostatic factors such as PAI-I, which are difficult to measure in clinical practice.24-26

C-reactive protein concentration can be severely elevated in individuals with autoimmune diseases, so a level greater than 10 mg/ L should be repeated in a few weeks when acute inflammation has gone into remission.27 Normally, a CRP level between 3 mg/L and 10 mg/L is strongly associated with inflammation and risk for cardiovascular events.28 The prognostic value of CRP makes it an efficacious test for screening an otherwise seemingly low-risk individual.

According to the NCEP guidelines, to diagnose dysmetabolic syndrome, an individual must possess at least three of five components: central obesity; hypertriglyceridemia; low HDL-C; hypertension; impaired fasting glucose.1 The Association of Clinical Endocrinologists (ACE) has similar criteria, but also include hyperinsulinemia, inflammation, and a procoagulable state among others in its criteria for making the diagnosis.12 In concurrence with other definitions of the dysmetabolic syndrome, the American Diabetes Association’s (ADA) Expert Committee recently suggested lower limits for impaired fasting glucose (IFG) to 100 mg/dL instead of 110 mg/dL, in an attempt to provide a viable method for earlier identification of individuals in their disease trajectory.29 The NCEP still defines IFG as > 110 mg/dL and ≤ 125 mg/dL.

Risk Factors for the Dysmetabolic Syndrome

The ADA recommends a fasting plasma glucose as a preferred first line screening test.30 The ADA and the U.S. Prevcntativc Task Force” do not recommend screening asymptomatic patients for diabetes. The ADA clearly states that high-risk patients with multiple risk factors should be screened, and patients 45 years or older should be screened every 3 years (see Table: “Risk Factors for the Dysmetabolic Syndrome”).

While the NCEP has provided feasible guidelines for practitioner use, there has been recent criticism for not including a measure of insulin resistance in the definition of the dysmetabolic syndrome. Liao and colleagues32 argue that the NCEP’s definition of the dysmetabolic syndrome is not sensitive enough to detect insulin resistance in patients with normal fasting glucose levels who are already at risk by virtue of their dyslipidemia and/or presence of insulin resistance. Thus, many providers have begun measuring insulin levels as a proxy for evaluation of insulin resistance, especially during glucose tolerance testing.33 In addition, many practitioners who wish to determine the level of insulin resistance in patients often compute a Homeostatic Model Assessment (HOMA) as a proxy for level of insulin resistance (IR).34-36 The HOMA is compatible, but not necessarily equivalent, to estimates of insulin sensitivity and beta cell function from hyperinsulinemic clamps, hyperglycemie clamps, intravenous glucose tolerance tests, or oral glucose tolerance tests.37 One formula used for HOMA-IR is Fasting Plasma Insulin x Fasting Plasma Glucose/ 22.5. If the glucose is in mg/dL and the insulin is in microunits/mL, then the glucose must be converted from mg/dL to mmol/L and multiplied by 0.0551. The cut off to determine insulin resistance is 3 or greater.35,37 Findings from the San Antonio Heart Study indicated that HOMA-IR were very similar to fasting insulin levels, and elevated HOMA-IR were strongly associated with hypertriglyceridemia and low HDL-C.38 Nonetheless, using NCEP criteria for the cysmetabolic syndrome may underestimate risk in certain populations such as African Americans who are frequently insulin resistant, but do not have severe hypertriglyceridemia and commonly manifest higher HDL-C levels.39,40

* Treatment

NCEP ATP III treatment categories identify LDL-C as the primary objective for lowering risk of cardiac events and the dysmetabolic syndrome as a secondary intervention. Lifestyle modifications are the mainstay of first-line therapy. Determining a patient’s optimal cut point for LDL-C depends on his or her coronary heart disease (CHD) risk category. It is plausible that in 3 months of intensive lifestyle alterations (i.e., low-fat diet, increased physical activity, and intensified weight loss management), the LDL-C level may still be above the recommended cut point, in which case stadns should be considered.

* Three CHD Risk Categories

There are three CHD risk categories based on the NCEP ATP III strategies that guide treatment for management of LDL-C: 1) CHD risk equivalent; 2) individuals with two or more major CHD risk factors; and 3) individuals with less than two major CHD risk factors.1 The highest level of the CHD risk categories are those patients who have CHD or one of the following: diabetes mellitus, peripheral arterial disease, abdominal aortic aneurysm, or carotid artery disease. These patients are considered to have a CHD risk equivalent.1 A CHD risk equivalent occurs when an individual’s risk is equal to that of a patient who has already developed CHD. This group of patients should receive the most aggressive therapy and are undoubtedly in need of lipid-lowering pharmacologie interventions to meet optimal LDL-C level guidelines. For the CHD risk equivalent group, the goal of therapy is to reduce the LDL-C to less than 70 mg/dL. Likewise, patients with a CHD risk equivalent that manifest a LDL-C level of > 130 mg/dL will need aggressive lifestyle management as well as pharmacologie lipid lowering intervention. When LDL-C levels are between 100 mg/dL and 129 mg/dL, treatment may begin with lifestyle modification.

The second CHD risk category consists of individuals with two or more major risk factors, but who have not had a coronary event and do not possess any of the CHD equivalents. These individuals need to have an LDL-C of less than 1\30 mg/dl.1 Although aggressive lifestyle modification is the first line of recommended therapy for these individuals, they will probably not reach their treatment goals. Therefore, lipid lowering drug therapy often begins before or by the end of 3 months of lifestyle modification for individuals in this category. It is important for the provider to keep in mind that once the LDL-C goal has been reached in this risk category, the individual’s other major CHD risk factors should be addressed (i.e., obesity etc.,).

The third CHD risk category consists of those individuals with less than two major CHD risk factors.1 In most cases, these individuals are the most receptive to aggressive lifestyle therapies and the LDL-C treatment goal is less than 160 mg/dl. Once the LDL-C level has reached 190 mg or more, and 3-months of aggressive lifestyle has failed, lipid-lowering pharmacologie interventions are then considered cost-effective.

* Dysmetabolic Syndrome as a secondary Target

Central Obesity

Determining waist circumference with a simple tape measure can be an enlightening finding, as an individual who possesses a normal BMI and was previously judged to be at low risk for cardiovascular disease may posses considerable risk when screened for the dysmetabolic syndrome and found to be centrally obese.9,11,41 There are gender-specific cut points for determining central obesity; for men, waist circumference optimally should be less than 40 inches or 108 cm and for women less than 35 inches or 88 cm.14 Aggressive lifestyle alterations are a must for the management of central obesity and the potential sequellae of the dysmetabolic syndrome.

Dyslipidemia

Once the LDL-C goal has been reached, the next focus is to lower triglyceride and then raise HDL-C levels. Individuals who have reached their LDL-C goal, but have triglyceride levels equal to or greater than 200 mg/dL, need to maximize lifestyle modifications and may benefit from triglyceride lowering agents (i.e., fenofibrates such as Tricor or Niacin).1 The optimal goal for all patients is a triglyceride level equal to or less than 150 mg/dL.1 Individuals with hypertriglyceridemia often have other cardiovascular risk factors associated with the dysmetabolic syndrome (i.e., central obesity, hypertension, IFG or IGT, as well as hyperinsulinemia or insulin resistance and a low HDL-C).3

Likewise, increasing HDL-C levels may occur with lifestyle modifications such as weight loss, increased physical activity, and moderate alcohol consumption.43 However, when the LDL-C and triglyceride levels are brought into appropriate ranges, the HDL-C may rise.44 Specific agents that assist in the lowering of triglycerides, such as fenofibrates, or omega-3 fatty acids, may serve to raise HDL-C levels.45,46 The NCEP has gender-specific cut points for HDL-C, for men the optimal level for HDL-C is equal to or greater than 40 mg/dL and in women 50 mg/dL.1

Hypertension

The etiology of hypertension is not fully understood within the dysmetabolic syndrome. However, the abdominal adipocytcs have been found to excrete angiotensin, offering a partial explanation as to the role of hypertension within the dysmetabolic syndrome.47,48 Furthermore, angiotensin stimulates the abdominal adipocytes to produce increased plasma levels of PAI-I and contribute to dysfibrinolysis.49-52 These findings offer an explanation as to why the antihypertensive agents known as angiotensin converting enzyme (ACE) inhibitors have been found to improve the fibrolytic profile of the dysmetabolic syndrome by reducing plasma PAI-I levels.15,53 Therefore, the first line of antihypertensive management in the dysmetabolic syndrome should consist of ACE inhibitors, especially for individuals with any degree of abnormalities in glucose homeostasis or those that manifest frank type 2 diabetes.

* Procoagulable and Inflammation States

Elevated triglyceride levels stimulate the abdominal adiposities to release increased levels of PAI-I. Plasminogen activator inhibitor-1 is a natural substance that when elevated fosters an environment conducive for a hypercoagulable state, and is referred to as dyfibrinolysis. This state is strongly associated with the propensity to form clots, brittle plaque, and propagate vascular injury.24,54,55

Dysfibrinolysis, as indicated by elevated plasma levels of fibrin or PAI-I, has been associated with inflammation, elevated CRP, as well as with myocardial infarction, stroke, and other forms of vascular injury.14,28,56,57 Lifestyle factors that result in high levels of physical activity or antioxidants, such as diets rich in alpha-tocopherol (i.e., vitamin E) or moderate ethanol consumption, have shown the direct effect of reducing PAI-I levels.58-61 Likewise, low-dose aspirin, ACE inhibitors, and beta-blockers in combination have shown improvement in inflammation, reducing CRP levels and improving dysfibrinolysis by reducing PAI-I plasma levels.15,53,62-64

* Hyperinsulinemia and Fasting Glucose

Similar to hypertriglyceridemia, hyperinsulinemia is a direct stimulate of the abdominal adipocytes to produce elevated plasma levels of PAI-1.5,65,66 Early in the dysmetabolic syndrome, glucose levels may be normal, but hyperinsulinemia or insulin resistance is commonly present. Initially in the dysmetabolic syndrome, the fasting plasma glucose levels are within normal limits. During this initial phase when glucose levels are within normal ranges, the individual is often erroneously considered at low risk for diabetes or cardiovascular-related aliments. However, close examination for the other components of the dysmetabolic syndrome may identify a previously classified low-risk individual as at-risk. The opportunity for early intervention is present when insulin levels are elevated in association with the other components of the dysmetabolic syndrome, regardless of whether glucose levels are within normal ranges. Therefore, it is reasonable to assume that early interventions toward cardiac risk reduction may have the potential to occur when elevated insulin levels are found in a euglycemic individual.

It is imperative that individuals who have either a normal fasting glucose or IFG in association with other components of the dysmetabolic syndrome should undergo an oral 75-grams of glucola glucose challenge test to determine the presence of either IGT or type 2 0 diabetes.12,30 It is also optimal to screen for all the components of the dysmetabolic syndrome concomitant with obtaining a fasting insulin level. Several studies have shown the benefit of treating either IFG or IGT with oral antidiabetic agents such as metformin or GIucophage, prior to the development of frank type 2 diabetes.67-70 Knowler and colleges69 found that although increased physical activity had the best outcome when treating IGT individuals the use of metformin alone reduced the onset of type 2 diabetes by 58%. When aggressive lifestyle alterations are difficult to obtain, metformin may offer one source of an intervention to correct abnormal glucose levels. Metformin is also efficacious in the management of obese individuals with abnormal glucose home-ostasis as it may actually encourage weight loss. Metformin is available in combination with other helpful agents that may serve to have favorable effects on both glucose and lipids (i.e., lowering triglycerides and raising HDL-C). Another efficacious pharmacologie agent is Avandamet, a combination of rosiglitazone and metformin. Other commonly used combined medications are GlucoVance (a combination of glyburide plus metformin) or Metaglip (a combination of glipizide plus metformin). Because individuals with type 2 diabetes are usually obese, the sulfonylureas may be problematic because they tend to facilitate weight gain. Sulfonylureas will generally lower blood sugar rapidly and may also place individuals at risk for hypoglycemia. When choosing an antidiabetic agent for an overweight or obese patient, first consider metformin and one of the other categories before sulfonylureas.

* Other Associated Findings

When a female patient has an android-like appearance, acne, oily hair, male vertex balding, alopecia, or hirsutism, she may be at risk for, or more likely already has, the dysmetabolic syndrome.71 The practitioner should direct interview questions toward the patient’s menstrual and reproductive history. Women who experienced early menarche, irregular menses during childbearing years, or infertility often have polycystic ovarian syndrome; a severe form of the dysmetabolic syndrome. These women are at great risk at an earlier age, for the development of type 2 diabetes, accelerated cardiovascular disease, and cardiac events.72,73 Often, these women respond well to oral contraceptives and most of the antidiabetic agents, such as the insulin sensitizers; consequently, they develop a more favorable metabolic profile as a result of weight loss.74 An overriding concern for many of these woman is that they may become pregnant, as thiazolidinediones (TZD) and metformin are known for causing resumption of ovulation in a previously anovulatory women.75 In these cases, the patient may have given up on ever becoming pregnant, forgoing contraception, and may not view this time in her life as appropriate. Careful reproductive counseling is mandatory in treating insulin resistance in the PCOS patient.

Two notable clinical manifestations that female and male patients may demonstrate risk for dysmetabolic syndrome or type 2 diabetes are changes in skin tone and the presence of skin tags, especially when associated with central obesity. This change in skin tone is known as acanthosis nigricans (AN). This darkening in skin tone can be a clue related to hyperinsulinemia, especially among darkerskin individuals of either gender.76 Acanthosis nigricans are commonly associated with a velvety thickening and darkening of the skin in areas of skin folds and can be found in the axill\ae, groin, or back of the neck. The mechanism responsible for AN is the elevated insulin level which stimulates the receptors of the keratinocytes and fibroblast to produce augmentation of the skin cells to become hyperplasic.77 Another skin proliferation seen in insulin resistance is cutaneous papillomas or skin tags found in similar areas as AN.71 These subtle abnormalities can alert the practitioner to ask more questions to determine an individual’s risk for cardiovascular disease. It is important to remember that individuals in the early stages of carbohydrate disequilibrium may manifest nonspecific symptomology (see Table: “Screening Questions to Recognize Metabolic Symptomology”).

* Management of High Risk Patients

Once the practitioner identifies a patient at risk, the next step is an oral glucose challenge test. Obtaining blood samples for all components of the dysmetabolic syndrome (i.e., insulin, lipids, glucose, and CRP), measuring of waist circumference, along with blood pressure, will provide the most detailed analysis of the patient’s risk status. The abnormal findings within this battery of tests will assist in determining what risk factors need to be treated or modified. Lifestyle modifications are the primary forefront of therapy. Low density lipoprotein cholesterol levels should be optimized first, along with blood pressure, and then the specific component of the dysmetabolic syndrome. However, early introduction of pharmacologie interventions can significantly reduce risk by delaying or avoiding development of type 2 diabetes or cardiovascular disease among individuals with the dysmetabolic syndrome.

* Conclusion

There is a strong association between insulin resistance and the development of type 2 diabetes and the development of coronary artery disease. This relationship likely comes before the definite diagnosis of type 2 diabetes because individuals with altered glucose metabolism such as IFG or IGT possess a much greater risk of cardiovascular disease than euglycemic individuals. Individuals who have either IFG or IGT are in a transitional phase consisting of a disequilibrium of carbohydrate metabolism. Therefore, individuals with either IFG or IGT are at high risk for the development of type 2 diabetes and may have already begun the pathologic process of vascular injury leading to cardiovascular disease. It is critical to identify these individuals as early as possible and implement lifestyle interventions such as weight loss, increased physical activity, and low-fat diets. Although not all of the individuals with the dysmetabolic syndrome will manifest insulin resistance or type 2 diabetes, their risk is similar for development of coronary heart disease. Many individuals with the dysmetabolic syndrome will remain nondiabetic because they are able to balance their insulin resistance by producing more insulin, and to some extent, are able to maintain normal glucose levels. However, those individuals predisposed to type 2 diabetes by virtue of family history are very likely to transition from the dysmetabolic syndrome to type 2 diabetes and experience the sequelae of cardiovascular disease. Nurse practitioners are in an excellent position to identify individuals early in their disease trajectory toward cardiovascular disease and intervene.

The first line of antihypertensive management in the dysmetabolic syndrome should consist of ACE inhibitors.

A hypercoagulable state is strongly associated with the propensity to form dots, brittle plaque, and propagate vascular injury.

Screening Questions to Recognize Metabolic Symptomology

Do you have difficulty losing weight despite exercising regularly?

Do you have a close relative who has had heart disease, high blood pressure, type 2 diabetes, polycystic ovarian syndrome (PCOS), infertility problems, or obesity?

Do you experience frequent cravings for sugars or other high carbohydrate foods?

Do you often feel tired after a meal?

Do you eat meals that consist of pasta, rice, potatoes, and corn more than 2 to 3 times per week?

Do you awaken at night 2 or more times to urinate?

Have you either gained or lost more than 5 lbs in the last 3 months?

For women: Do you feel that you have more facial hair than other women in your family, racial, and/or ethnic group?

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DISCLOSURE

The authors have disclosed they have no significant relationship or financial interest in any commercial companies that pertain to this education activity.

Susan J. Appel, PhD, ACNP, FNP, BC, CCRN Joyce Newman Giger, APRN, BC, FAAN Natalie A. Floyd, MS, ANP, BC

ABOUT THE AUTHORS

Dr. Appel is an Assistant Professor, Graduate Division, in the School of Nursing, University of Alabama at Birmingham. Joyce Newman Giger is a Professor and Hassenplug Endowed Chair at the School of Nursing, UCLA, Los Angeles, Calif. Natalie A. Floyd is a Doctoral Student at the University of Alabama at Birmingham, and an Adult Nurse Practitioner at the Veterans Hospital, Birmingham.

Copyright Springhouse Corporation Oct 2004

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