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This symposium focused on current research of emerging markers, associated risk factors, and optimal patient management.

Update on the Metabolic Syndrome

Scott M. Grundy, MD, PhD, Professor of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

The metabolic syndrome is a specific clustering of metabolic and underlying risk factors: atherogenic dyslipidemia, insulin resistance, hypertension, abdominal obesity, a prothrombotic state, and a pro-inflammatory state. The pathogenesis is most importantly related to two important states: abdominal obesity and susceptibility factors. The susceptibility factors include primary insulin resistance, physical inactivity, advancing age, racial and ethnic factors, endocrine dysfunction, and genetic predisposition.
With regard to abdominal obesity, a body mass index (BMI) of ≥25 is desirable; but some obese people do not have abdominal obesity. This is a key difference in the metabolic syndrome because abdominal obesity, which contains excessive adipose tissue, produces nonesterified fatty acids, inflammatory cytokines, an increased inflammatory state, adiponectin, and angiotensinogen. Adipose tissue is insulin resistant. Muscle insulin resistance promotes hyperglycemia; liver insulin resistance results in increased triglyceride synthesis.

There are differing views of the metabolic syndrome. The clustering of risk factors described above is the definition of the National Cholesterol Education Program. Diabetologists place more emphasis on prediabetes and diabetes, which also consist of a clustering of risk factors; and they contend that prediabetes and diabetes and diabetes are essentially equivalent to the metabolic syndrome. They therefore question the value of making the diagnosis of the metabolic syndrome.

Dr. Grundy pointed out that both views involve the clustering of risk factors. This clustering phenomenon has underlying etiology. The metabolic syndrome overlaps in 75% of people with prediabetes; 85% of type 2 diabetics have the metabolic syndrome. Further, the synergistic risk is more than the sum of its parts. The increase in risk with each component is geometric, not additive.

Treatment of the metabolic syndrome consists of lowering both conventional risk factors such as reducing dyslipidemia and hypertension, but also diminishing residual risk, with a foundation of lifestyle modification and, if necessary, drug intervention, ie, global risk intervention. This consists of treating atherogenic dyslipidemia (low-density lipoprotein cholesterol–lowering drugs such as statins with or without nicotinic acid); treatment of hypertension, preferably with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), with other agents as needed to reach the blood pressure (BP) goal; lowering glucose if needed; diminishing the prothrombotic state, often with low-dose aspirin; and reducing the pro-inflammatory state, which can be accomplished by utilizing all of the above methods.

Among the important trials that have been conducted in patients with the metabolic syndrome are the Scandinavian Simvastatin Survival Study (4S), which showed that patients with the metabolic syndrome but without overt diabetes were 1.4 times more likely to have major cardiac events than those without the metabolic syndrome; the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which showed that the risk was 1.5 times greater; and the Veterans Administration High-Density Lipoprotein Intervention Trial (VA-HIT), which supports the view that fibrates should be considered as a first-line therapy to reduce the cardiovascular risk associated with the metabolic syndrome.

Paul Ridker, MD, MPH, Eugene Braunwald Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Inflammation is the common denominator of all components of the metabolic syndrome, says Dr. Ridker. Adipose tissue as seen in central obesity may represent an important site for the production of pro-inflammatory cytokines and acute-phase reactants. These are associated with endothelial dysfunction. Thus, inflammatory mediators such as C-reactive protein (CRP) add to the definition of the metabolic syndrome. Treating any component of the metabolic syndrome—even central obesity alone—lowers CRP and the risk of the metabolic syndrome. Dr. Ridker proposes a new definition of the metabolic syndrome that includes a CRP level of ≥3 as a component. He suggests that it should be measured as a part of evaluating the metabolic syndrome.

Dr. Ridker suggested four conclusions:

1. Inflammation is a critical process of coronary atherogenesis and the development of stable/unstable coronary lesions.
2. Inflammation provides a link between the metabolic syndrome and type 2 diabetes.
3. CRP is the best inflammatory biomarker, but others may become available.
4. Inflammation as a biomarker and as a target of therapy is the focus of ongoing research.

Managing Dyslipidemia and Dysglycemia in Type 2 Diabetes and the Metabolic Syndrome

Antonio M. Gotto, Jr., MD, DPhil, Professor Medicine, Weill Medical College of Cornell University, New York, New York

Four important studies have shown that it is possible to prevent the onset of diabetes with weight loss: the Diabetes Prevention Study, the Finnish Diabetes Prevention Study, the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), and the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study. Weight loss is the foundation of the American Diabetes Association recommendations for drug therapy for diabetes.

However, other components of risk reduction are important in diabetic patients. Statin trial subgroup analyses show similar, and in some cases slightly better, reduction in coronary heart disease risk in diabetic patients when low-density lipoprotein cholesterol is lowered.

However, the Collaborative Atorvastatin Diabetes Study (CARDS) was terminated early because of a 37% relative risk reduction in cardiovascular events in patients with type 2 diabetes. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed that most strokes and myocardial infarctions (MIs) can be reduced by 50% by combining newer antihypertensives such as amlodipine and perindopril, plus effective lowering of cholesterol, which also reduced new cases of diabetes by 30%.

The value of fibrates is not as clear in diabetic patients. Their benefit is explained primarily by improvements in lipids with insulin resistance. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study suggests a beneficial effect of fenofibrate on the microvasculature, which cannot be explained by changes in hemoglobin A1c or concomitant medications, or by the minor reduction in BP in the fenofibrate group. This is the first time that a lipid-lowering agent has been shown to reduce the risk of macrovascular and microvascular events in a large-scale clinical study in patients with type 2 diabetes. However, for the study's primary endpoint of coronary events (coronary artery disease, death, or nonfatal MI), patients treated with fenofibrate experienced an 11% reduction in events vs placebo, a nonsignificant difference.

The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIV) study showed that pioglitazone reduced a broadly defined composite primary endpoint by a statistically insignificant 10%, but narrowed the rate of death, MI, and stroke by 16% ( P<0.03). There was better control of blood glucose in those receiving pioglitazone, but an increased rate of congestive heart failure. This increase may be overstated because peripheral edema, which can be caused by pioglitazone, may have been confused with congestive heart failure.

The ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study is examining three promising approaches to lowering the risk of coronary heart disease and stroke in adults with type 2 diabetes: control of blood glucose, hypertension, and lipids. Novel drug approaches for diabetes include dipeptidyl peptidase-IV inhibitors, incretin mimetics (eg, pramlintide acetate, exenatide), and combination therapies that include hypoglycemic drugs with agents that reduce other risk factors for cardiovascular disease.

Treating Hypertension in Type 2 Diabetes and the Metabolic Syndrome

Michael A. Weber, MD, Professor of Medicine, SUNY Downstate College of Medicine, Brooklyn, New York

Not only is hypertension closely related to diabetes, but it has been recognized for some time that certain drugs used to treat hypertension may accelerate the appearance of new-onset diabetes. Both beta blockers and diuretics have been implicated. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that in high-risk hypertensive patients chlorthalidone was 43% more likely than lisinopril to produce diabetes, but was also 18% more likely than amlodipine to produce this adverse effect.

Like the ACE inhibitors, the ARBs appear to have beneficial effects on insulin and glucose metabolism. In the Losartan Intervention For Endpoint Reduction (LIFE) study, losartan was associated with a 25% relative-risk reduction in new-onset diabetes compared with atenolol. ARB studies in heart-failure patients also show a reduction in new-onset diabetes during treatment with one of these agents.

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial compared valsartan with amlodipine. There was a 23% relative-risk reduction in new-onset diabetes in the valsartan group. These results may have important implications. This was the first time that a drug in the ARB class was shown to have beneficial effects on insulin action and potentially played a role in protecting high-risk hypertensive patients from developing diabetes.

Dr. Weber concludes that for patients with evidence of the metabolic syndrome, particularly those with impaired glucose tolerance, an ARB or an ACE inhibitor are preferred as primary treatment. Nevertheless, diuretics may be useful in many hypertensive patients, including those with diabetes or even those with metabolic syndrome, as low-dose adjuncts to ARBs or ACE inhibitors. Optimal protection of all hypertensive patients, including those with diabetes or impaired glucose tolerance, demands full control of their BP. Renin-angiotensin system blockers often are not sufficient to achieve target BP goals.