US Pharm. 2009;34(2):HS12-HS15.
Metabolic syndrome, also referred to as Syndrome X or insulin resistance syndrome, consists of a number of metabolic risk factors that increase the risk for atherosclerotic cardiovascular disease (CVD) and other cardiovascular complications such as cardiac arrhythmias, heart failure, and thrombotic events.1,2 It is estimated that 47 million people in the United States have this multifactorial syndrome.3,4 Metabolic syndrome is generally observed with increased age, but may present in children and adolescents as well.3 The highest prevalence is seen in Mexican Americans (31.9%), followed by Caucasians (23.8%), African Americans (21.6%), and self-reported “other” races/ethnicities (20.3%).4 Although a genetic disposition exists in the development of metabolic syndrome, acquired causes also seem to play a role.3
According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) report, there are six major components of metabolic syndrome relating to the development of CVD: 1) abdominal obesity, 2) atherogenic dyslipidemia, 3) elevated blood pressure, 4) insulin resistance (with or without the presence of glucose intolerance), 5) proinflammatory state, and 6) prothrombotic state.2 The predominant underlying risk factors for the development of CVD are obesity and insulin resistance. Other major risk factors include physical inactivity, an atherogenic diet, cigarette smoking, hypertension, elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), a family history of premature coronary heart disease (CHD), and increased aged.1,5,6
Clinical Features and Diagnosis
As mentioned, metabolic syndrome is multifactorial—a combination of both metabolic and underlying risk factors are involved. The metabolic risk factors of greatest interest are those believed to be interrelated: atherogenic dyslipidemia, elevated blood pressure, insulin resistance, proinflammatory state, and prothrombotic state. The latter two are typically a result of the previous three.6
Atherogenic dyslipidemia is defined as an increase in serum triglycerides, presence of small LDL-C particles, and a low HDL-C level.2 Elevated blood pressure may be caused by various conditions and is strongly associated with obesity. Insulin resistance (and/or increased glucose levels) may also be related to obesity and may have genetic components as well.1,3,4 The lack of a connection between insulin resistance (and/or increased glucose levels) and the other components of metabolic syndrome has led to its exclusion from the diagnostic criteria proposed by the NCEP ATP III; however, insulin resistance is still considered an important emerging risk factor.2,3
The prothrombotic and proinflammatory states are also not included in the proposed criteria for metabolic syndrome due to the belief that these states are consequences of other risk factors. A prothrombotic state is characterized by abnormalities, specifically elevations, in procoagulant factors, antifibrinolytic factors, platelet alterations, and endothelial dysfunction.1,7 A proinflammatory state is characterized by elevations of circulating inflammatory molecules such as C-reactive protein (CRP), tumor necrosis factor-alpha, plasma resistin, interleukin (IL)-6, and IL-18.1,8-12 CRP is a general marker of inflammation that has been linked to CVD in patients with metabolic syndrome.13,14 Routine assessment is not encouraged; however, elevated levels of CRP are associated with many of the clinical features of the syndrome (i.e., increased waist circumference).15 Although a prothrombotic or a proinflammatory state is not involved with the clinical recognition of metabolic syndrome, both are found to aggregate with the diagnostic criteria.3
Underlying risk factors are those that lead to the development of metabolic risk factors and include abdominal obesity, which is assessed by waist circumference, and insulin resistance. Obesity in general is associated with a higher CVD risk and contributes to elevated blood pressure, elevated LDL-C levels, decreased HDL-C levels, and hyperglycemia.3,5 Increased waist circumference can, therefore, explain all the components of the metabolic syndrome.5 Other related underlying factors are physical inactivity, increased age, and hormonal imbalances.6 Essentially, much of the management of metabolic syndrome is aimed toward reducing the underlying risk factors.
Multiple organizations have recommended criteria for the diagnosis of metabolic syndrome, yet no standardization exists. Therefore, it is not recognized with an International Classification of Diseases (ICD-9) code. According to the NCEP ATP III guidelines, patients must meet three of five criteria for metabolic syndrome to be recognized (TABLE 1).2,3
In 2005, the National Heart, Lung, and Blood Institute (NHLBI) and American Heart Association (AHA) conferred to establish a definition of the metabolic syndrome, which was supported by the AHA and the American Diabetes Association as well. They concluded that metabolic syndrome is an important clustering of risk factors leading to the major clinical outcome of CVD. This collaboration also established six major components of the syndrome and determined that its identification should be based on concomitant findings (TABLE 2).3,6
To determine the CVD risk of patients with metabolic syndrome, the standard Framingham risk assessment should be used to determine the 10-year CHD risk. The algorithm includes cigarette smoking, blood pressure, total cholesterol, HDL-C, and age as influential factors for CHD risk. Other factors that are more specific to metabolic syndrome have shown little or no change in the power of prediction.5,6
Lifestyle Modifications: Management of metabolic syndrome is highly dependent on the control of all of the contributing factors. This includes both underlying risk factors as well as metabolic risk factors. Lifestyle modifications should be implemented immediately for all patients diagnosed with metabolic syndrome. Lifestyle modification includes weight reduction, increased physical activity, and nutritional therapy. Additional risk assessments should be performed in patients to assure appropriate goals of therapy throughout the course of the syndrome.6
The initial weight loss goal is to reduce baseline weight by approximately 7% to 10% during a period of six to 12 months. This may be achieved by reducing caloric intake by 500 to 1,000 calories per day, as well as increasing physical activity.3,6 In addition, the diet should consist of low amounts of saturated fats, trans fats, cholesterol, sodium, and simple sugars.2,16 Intake of fruits, vegetables, and whole grains is encouraged as well as an increase in fish (with caution to mercury content). Patients should be instructed that a diet very high in carbohydrates should be avoided.6
The AHA recommends at least 30 minutes of moderate-intensity exercise on all or most days of the week. However, exceeding these recommendations and increasing exercise to more than 60 minutes of intermittent or continuous aerobic activity will prompt weight loss or maintenance. Certain patients will require exercise testing before a vigorous exercise regimen can be decided upon. These patients include those with CVD, patients with symptoms of CVD, or those at high risk.6
Pharmacologic Treatment: Since metabolic syndrome is commonly associated with abnormal levels of LDL-C, HDL-C, and triglycerides (previously referred to as atherogenic dyslipidemia), LDL-C levels are always the primary concern when managing this risk factor. These levels should be reduced to achieve individual patient goal levels; however, once the LDL-C goal is achieved, other lipid factors should be further assessed and targeted for management. In the presence of atherogenic dyslipidemia, triglycerides should be the secondary target unless levels exceed 500 mg/dL. At this point, triglycerides become the primary target and immediate treatment is warranted with the use of a fibrate or nicotinic acid in order to avoid acute pancreatitis. Fibrate and nicotinic acid also favorably modify dyslipidemia in patients with metabolic syndrome. Statins generally yield similar lipid-lowering effects (i.e., LDL-C and non–HDL-C levels), but are frequently favored over other classes for their greater LDL-C–lowering effects. Combination therapy with a statin and a fibrate or nicotinic acid may also be an option for additional lowering of cholesterol levels. However, it is important to be aware of the potential for an increase risk of myopathy or hepatic dysfunction when these agents are used concomitantly.2,3
In regard to elevated blood pressure, no single antihypertensive agent or class of agents has been identified as superior in the treatment of metabolic syndrome. It is recommended that treatment of hypertension be based on the seventh report of the Joint National Committee (JNC 7), which includes the use of one or more of the following classes of drugs: thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers.17 Lifestyle modifications recommended in the JNC 7 include those previously discussed, in addition to the Dietary Approaches to Stop Hypertension (DASH) diet. This plan consists of a diet rich in potassium, magnesium, calcium, protein, and fiber, as well as a reduction in dietary sodium and saturated/total fat, increased physical activity, and moderation of alcohol consumption.2,17
Elevated fasting glucose places patients at a greater risk for developing CVD. Implementation of proper nutritional therapy and increased physical activity will help reduce the complications of elevated fasting glucose. Standard therapy for all patients with diabetes is warranted, and goals of therapy should include target hemoglobin A1C levels of less than 7%.5 The use of antidiabetic agents for the prevention of diabetes has been proposed, but no evidence is available to support the potential benefit or cost-effectiveness in metabolic syndrome.5
Patients with metabolic syndrome also exhibit a prothrombotic state due to the abnormalities in coagulation factors, which are not routinely measured in clinical practice. The AHA recommends the initiation of low-dose aspirin in order to reduce CVD events in patients who have a 10-year risk for CHD of 10% or greater, as determined by the Framingham algorithm.5,18
The proinflammatory state that patients may exhibit when diagnosed with metabolic syndrome must also be considered. CRP is a general marker of inflammation and may identify a proinflammatory state; however, concentrations are not routinely drawn in clinical practice. Currently, no pharmacotherapeutic interventions have been recommended for the prevention or treatment of this proinflammatory state. However, reinforcement of therapeutic lifestyle changes may be of value in certain individuals.5
Although not currently approved for use in the U.S., it is noteworthy to mention an emerging class of agents with a potential role in the management of metabolic syndrome: the endocannabinoid receptor antagonists. These agents participate in various central and peripheral functions and can affect either the cannabinoid-1 (CB1) (expressed in the brain, hypothalamus, and pituitary gland) or the CB2 (expressed in immune cells) receptors. By selectively inhibiting CB1 receptors, these agents control food intake and energy expenditure, thereby reducing appetite.19 In 2006, the first CB1 endocannabinoid receptor antagonist (rimonabant [Acomplia]) was introduced in Europe for the treatment of obesity and associated cardiometabolic disorders, particularly in individuals with metabolic syndrome or type 2 diabetes. However, due to an increased risk of central nervous system and psychiatric adverse events (including suicidality) associated with this agent, the FDA denied the agent’s approval despite its promise in the treatment of obesity.20
Pharmacists play an important role in the management of metabolic syndrome. We have an integral part in patient education regarding the syndrome as well as in the management and monitoring of individualized treatment plans. Patients will undoubtedly benefit from information regarding metabolic syndrome and its various components and complications. Increasing awareness of the risks of this syndrome, in addition to providing guidance with lifestyle modifications and appropriate monitoring of medication regimens, will empower patients with the information needed to reduce their risks of CVD. Both the NCEP ATP III and the AHA offer educational materials to assist pharmacists in educating their patients, as well as themselves.2,3
Metabolic syndrome consists of a number of metabolic risk factors that increase the risk for atherosclerotic CVD. Six major components of this syndrome have been determined and include abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without the presence of glucose intolerance), a proinflammatory state, and a prothrombotic state. Careful identification, assessment, management, and monitoring of patients with or at risk of developing metabolic syndrome are essential for the prevention of subsequent cardiovascular complications.
Although the criteria for the diagnosis of metabolic syndrome have not been standardized, it is important to acknowledge the established risk factors. By identifying the various components, patients can be assessed and monitored carefully for the development of this syndrome and the ultimate risk of CVD.
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19. Pagotto U, Marsicano G, Cota D, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100.
20. Testimony before FDA advisory committee meeting on rimonabant (HRG publication #1815). June 13, 2007. www.fda.gov/ohrms/dockets/ac/ 07/slides2007-4306oph1-01-
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