liftsiron
Owner/Admin
- Joined
- Nov 12, 2003
- Messages
- 19,024
metabolic syndrome
The clinical picture of metabolic syndrome
The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.
Preview: Metabolic syndrome has piqued the interest and concern of physicians and patients alike. The syndrome represents a commingling of several conditions and risk factors common in the United States and links accelerated cardiovascular disease with insulin resistance. As more details are uncovered about metabolic syndrome, new questions arise. Here, Dr Doelle reviews what is known and not yet known about metabolic syndrome, its etiology, and its treatment.
Doelle GC. The clinical picture of metabolic syndrome: an update on this complex of conditions and risk factors. Postgrad Med 2004;116(1):30-8
Metabolic syndrome is a clustering of disorders that has a major consequence: a marked increase in cardiovascular disease. The syndrome has had several names, including syndrome X and dysmetabolic syndrome, since its initial description by Reaven (1) in 1988. Greater awareness of metabolic syndrome has followed its recent definition by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) (2).
A role for insulin resistance is suggested by observations that link it to each of the metabolic criteria for diagnosis of metabolic syndrome as proposed by the ATP III (table 1). Plasma insulin concentration strongly correlates with blood pressure in different populations of both obese persons and persons who are not obese (3,4). Normotensive offspring of hypertensive parents are more insulin-resistant than offspring of normotensive parents (5). The dyslipidemia of metabolic syndrome may be causally related to the insulin-resistant state and to increased free fatty acid flux, which promotes production of triglyceride-rich very low-density lipoprotein cholesterol in the liver.
Insulin resistance is an obvious factor (although not the sole factor) in development of impaired fasting glucose, glucose intolerance, and type 2 diabetes. Known diabetes or impaired fasting glucose makes up only one of five criteria for diagnosis of metabolic syndrome, reinforcing the observation that insulin resistance and hyperinsulinemia, even in the absence of overt abnormalities of glucose tolerance, lead to increased cardiovascular disease.
The presence of any three of the five criteria listed in table 1 is sufficient for diagnosis of metabolic syndrome. According to age-adjusted estimates from the third National Health and Nutrition Examination Survey (1988-1994), 23.7% of US adults meet metabolic syndrome criteria, with age and ethnicity being key prevalence determinants (6). On the basis of census data from 2000, roughly 47 million people in the United States have metabolic syndrome.
The major clinical consequence of metabolic syndrome is atherosclerotic cardiovascular disease, and several components of metabolic syndrome are known risk factors for atherosclerosis. Increased awareness of the diagnosis of metabolic syndrome will lead to the identification of additional cardiovascular risk factors and, in turn, to improved identification of high-risk patients. The ATP III guidelines do not incorporate emerging cardiovascular risk factors (eg, highly sensitive C-reactive protein) in assessment of risk, but it seems likely that the definition of metabolic syndrome will expand as the characterization of these risk factors is further elucidated.
Here, each component of metabolic syndrome is considered individually, with the recognition that there is overlap between the criteria.
Obesity
Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. It also is an important component of metabolic syndrome, although in a minority of obese persons, insulin resistance does not develop. Insulin resistance may also develop in persons classified as lean by body mass index (BMI) standards, who could thus be considered "metabolically obese."
Visceral adipose tissue has been proposed as the major site of fat deposition associated with the metabolic consequences of obesity (7). It is thought that visceral, or central, adiposity is the initial physical event that results in insulin resistance, by an increase in free fatty acid flux in portal and systemic circulations. Visceral adipose tissue may also contribute to other causes of increased atherosclerotic risk, including inflammatory, prothrombotic, and fibrinolytic factors (table 2). Whether measurement of these markers of adipose tissue hormonal activity improves accuracy in assessment of cardiovascular risk remains to be seen.
Initial treatment of obesity associated with metabolic syndrome is lifestyle modification, followed by pharmacologic therapy. Pharmacologic agents available to treat obesity are of two classes, an appetite suppressant (sibutramine hydrochloride [Meridia]) and a drug that inhibits fat absorption (xenical [Orlistat]). Weight loss with these agents is modest, typically 5% to 10% of initial weight. Of considerable interest are newer agents that target endogenous cannabinoid receptors to inhibit both short- and long-term food intake. Rimonabant is currently in phase 3 clinical trials. Surgical therapies such as gastric banding and gastric bypass can be considered for patients who are severely obese (BMI >40 kg/m2) or for patients with a BMI of 35 kg/m2 or more who have comorbid conditions. This latter group includes the majority of persons with metabolic syndrome.
Dyslipidemia
Combined hyperlipidemia is a hallmark of metabolic syndrome. The characteristic lipid disorders seen in this syndrome are hypertriglyceridemia, low levels of high-density lipoprotein cholesterol (HDL-C) and, often, normal levels of low-density lipoprotein cholesterol (LDL-C), although the LDL-C particles are typically smaller and more dense than usual. Whether these small, dense LDL-C particles confer increased cardiovascular risk independent of that related to hypertriglyceridemia and low HDL-C levels is uncertain (8).
The diagnosis of dyslipidemia is best made when a patient is in a basal state without acute illness. Low HDL-C levels (<40 mg/dL [1.03 mmol/L] in men, <50 mg/dL [1.29 mmol/L] in women) are altered little by fasting. However, triglyceride concentration can rise substantially after food intake, and current diagnostic criteria are based on measurements obtained after 12 hours of fasting.
It is important that physicians be mindful of other conditions that result in low HDL-C levels and to screen for these disorders when appropriate. Hypothyroidism, glucocorticoid excess (endogenous and exogenous), and use of protease inhibitors can result in lipid abnormalities typical of those seen in metabolic syndrome.
Treatment of the dyslipidemia of metabolic syndrome should involve nonpharmacologic interventions, including weight loss, exercise, and a low-fat diet. Reducing LDL-C levels with use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") is also appropriate for patients with metabolic syndrome. The ATP III guidelines recommend that LDL-C be the primary target of lipid-lowering therapy when a patient's triglyceride level is below 500 mg/dL (5.65 mmol/L).
Metabolic syndrome can be considered a coronary artery disease (CAD) equivalent. Thus, it is appropriate to have target LDL-C levels that are below 100 mg/dL (2.59 mmol/L). Achieving this goal usually requires addition of a cholesterol-lowering agent, such as a statin. However, for many patients, statin therapy does not correct abnormalities of triglyceride and HDL-C concentrations.
Modifying triglyceride and HDL-C levels with drug therapy improves cardiovascular risk beyond the benefits achieved with statins alone. The Coronary Drug Project (9) and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VAHIT) (10) used drug interventions (niacin and gemfibrozil) designed to modify triglyceride and HDL-C levels, and these interventions were associated with a reduction in cardiovascular events in both studies. Caution should be exercised when using both a fibric acid derivative and a statin, because the risk of myositis is increased with combination therapy. In addition, creatine kinase levels should be monitored if symptoms such as myalgia develop, especially in the setting of combination therapy.
Hypertension
Hypertension is an important hallmark of metabolic syndrome. Weight gain in youth (11) and middle age (12) is positively correlated with blood pressure levels, and weight reduction can effectively lower blood pressure in overweight hypertensive patients (13). This scenario again demonstrates the overlap of individual components of metabolic syndrome.
The ATP III defines elevated blood pressure as a reading of 130/85 mm Hg or greater. This category includes patients taking antihypertensive medicines even if treatment achieves a blood pressure level that is within target range. As with dyslipidemia, the initial treatment of hypertension is nonpharmacologic therapy, including sodium restriction and weight loss through calorie restriction and exercise. However, pharmacologic therapy is required in many patients with hypertension.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (14) provides guidelines for intensive treatment of hypertension. Although use of thiazide diuretics and beta-blockers has been avoided in patients with glucose tolerance abnormalities, the safety and efficacy of such medications have been demonstrated in large clinical trials (15). Drugs of these classes can be used in treatment of hypertension in patients with metabolic syndrome.
The mechanism supporting the association between insulin resistance and hypertension is unclear. Insulin acts as a direct vasodilator when given as a short-term infusion (16) but also acts to increase both sympathetic outflow (17) and renal sodium reabsorption (18). These last two mechanisms may counter vasodilatory effects and result in elevations of blood pressure in the insulin-resistant state. Despite evidence that blood pressure control is critical for reducing cardiovascular risk in diabetic patients, clinical studies show that fewer diabetic patients than nondiabetic patients in a matched group have blood pressures under 140/90 mm Hg.
Abnormal glucose tolerance
Elevated fasting glucose levels are an important feature of metabolic syndrome, but neither impaired fasting glucose nor diabetes is an absolute criterion. Insulin resistance is associated with an increased risk of type 2 diabetes, and overt diabetes develops in many persons with metabolic syndrome. Measurement of fasting glucose is required in all patients with metabolic syndrome to identify comorbid conditions that warrant specific intervention. Currently, impaired fasting glucose is identified by a fasting blood glucose level of 100 to 126 mg/dL (5.6 to 7.0 mmol/L), a criterion recently reduced from a level of 110 to 126 mg/dL (6.1 to 7.0 mmol/L).
While NCEP guidelines suggest measurement of fasting glucose when a diagnosis of metabolic syndrome is being considered, the role of fasting insulin levels, postchallenge glucose levels, and more precise measures of insulin sensitivity is open to question. At this time, these measures are not part of the diagnostic criteria for metabolic syndrome and are often more useful for epidemiologic or research considerations (see article by Dr Sivitz).
Again, nonpharmacologic intervention is appropriate as initial therapy for patients with impaired fasting glucose or impaired glucose tolerance, but insulin-sensitizing drugs may be considered an early treatment option if lifestyle intervention is ineffective, even in the absence of overt diabetes. The Diabetes Prevention Program demonstrated the effectiveness of lifestyle change (weight loss of 7% and exercise level of 150 min/wk) in persons with impaired fasting glucose, but metformin hydrochloride (850 mg twice daily) was also effective in delaying progression to overt diabetes in patients with impaired fasting glucose (19).
Polycystic ovary syndrome
Polycystic ovary syndrome affects 5% to 10% of US women of reproductive age and has been increasing in incidence similarly to metabolic syndrome and type 2 diabetes. It is characterized by anovulation with irregular menses, infertility, and androgen excess leading to hirsutism and acne. Polycystic ovary syndrome, like metabolic syndrome, is associated with insulin resistance and an increased risk of type 2 diabetes and cardiovascular disease. By age 40, 40% of women with polycystic ovary syndrome have evidence of abnormal glucose tolerance (20).
Use of insulin-sensitizing drugs to treat the anovulation and infertility of polycystic ovary syndrome is of considerable interest. A meta-analysis of metformin use in polycystic ovary syndrome (21) demonstrated that 46% of subjects who received metformin monotherapy achieved ovulation, compared with 24% of those who received placebo. Therapy with metformin (Glucophage) also enhances the effectiveness of clomiphene citrate (Clomid, Milophene, Serophene) in inducing ovulation and fertility. However, similar to the Diabetes Prevention Program findings, equal or better ovulation rates with regular menses and decreased hair growth are achieved through lifestyle modification than through metformin monotherapy.
Atherosclerotic cardiovascular disease
There is no question that impaired fasting glucose and impaired glucose tolerance represent intermediate stages in the progression from metabolic syndrome to type 2 diabetes. The process is considered a continuum in which progressive defects in insulin action and insulin release lead to more overt abnormalities of glucose homeostasis (22). Impaired glucose tolerance has also been associated with CAD and stroke before it progresses to full-blown diabetes.
In the Funagata Diabetes Study (23), mortality rates for cardiovascular disease were significantly higher in subjects with impaired glucose tolerance than in those with normal glucose tolerance, although lesser degrees of glucose intolerance (impaired fasting glucose) were not associated with increased risk. In the Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) trial (24), 2-hour postchallenge glucose concentrations correlated more closely with carotid intima-media thickness than did fasting glucose concentrations in patients with a family history of type 2 diabetes.
Impaired fasting glucose and type 2 diabetes have insulin resistance in common, and insulin resistance has been shown to be an independent risk factor for atherosclerotic cardiovascular disease (25). It is not unexpected that in the natural history of type 2 diabetes, macrovascular complications may antedate--often by many years--the typical diagnosis of diabetes. Thus, the challenge is to identify and correct defects in glucose metabolism as early as possible.
Therapy
Current recommendations for therapy for metabolic syndrome focus on correction of the components (ie, hypertension, dyslipidemia, visceral adiposity, and abnormal glucose tolerance). It has been said many times and in many ways, but the fact remains that exercise, diet, and weight loss each independently improves insulin resistance and reduces progression to type 2 diabetes. Even though the success of lifestyle modification is limited, the importance of such therapy cannot be overemphasized.
Drug intervention focuses on treatment of the manifestations of metabolic syndrome with clearly defined targets for blood pressure, weight, and levels of triglycerides, HDL-C, and hemoglobin A1c. The success of metformin use in polycystic ovary syndrome and in the Diabetes Prevention Program suggests that one medication or drug class could be used to treat the entire syndrome. Use of medications in the thiazolidinedione class (pioglitazone hydrochloride [Actos] and rosiglitazone maleate [Avandia]) directly improves insulin resistance but has not yet been shown to reduce cardiovascular morbidity or mortality. Thus, the approach to treatment of metabolic syndrome is aggressive management of its individual components.
Conclusion
Metabolic syndrome represents a clustering of cardiovascular risk factors linked through their association with insulin resistance. Since insulin resistance is an independent risk factor for cardiovascular disease, its presence can lead to macrovascular complications long before other features of metabolic syndrome are evident.
Challenges remaining in the identification of high-risk persons include the introduction of clinical markers of insulin resistance, integration of postchallenge glucose and lipid concentrations, and better definition of the role of inflammatory, prothrombotic, and genetic factors. Improved understanding of the risk factors for metabolic syndrome is required, and clinical trials of therapeutic interventions specifically targeted to this syndrome need to be conducted.
References
Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607
Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97
Bonora E, Zavaroni I, Alpi O, et el. Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects. Diabetologia 1987;30(9):719-23
Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989;320(11):702-6
Beatty OL, Harper R, Sheridan B, et al. Insulin resistance in offspring of hypertensive parents. Br Med J 1993;307(6896):92-6
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287(3):356-9
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21(6):697-738
Sacks FM, Campos H. Low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 2003;88(10):4525-32
Natural history of myocardial infarction in the Coronary Drug Project: long-term prognostic importance of serum lipid levels. Coronary Drug Project Research Group. Am J Cardiol 1978;42(3):489-98
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Eng J Med 1999;341(6):410-8
Voors AW, Webber LS, Frerichs RR, et al. Body height and body mass as determinants of basal blood pressure in children--the Bogalusa Heart Study. Am J Epidemiol 1977;106(2):101-8
Havlik RJ, Hubert HB, Fabsitz RR, et al. Weight and hypertension. Ann Intern Med 1983;98(5 Pt 2):855-9
Reisin E, Abel R, Modan M, et al. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978;298(1):1-6
Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289(19):2560-72 [Erratum, JAMA 2003;290(2):197]
Pasternak RC. The ALLHAT lipid lowering trial--less is less. JAMA 2002;288(23):3042-4
Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994;94(3):1172-9
Anderson EA, Hoffman RP, Balon TW, et al. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991;87(6):2246-52
Skott P, Vaag A, Bruun NE, et al. Effect of insulin on renal sodium handling in hyperinsulinaemic type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance. Diabetologia 1991;34(4):275-81
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. N Eng J Med 2002;346(6):393-403
Legro RS. Diabetes prevalence and risk factors in polycystic ovary syndrome. Obstet Gynecol Clin North Am 2001;28(1):99-109
Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. Br Med J 2003;327(7421):951-3
Saad MF, Knowler WC, Pettitt DJ, et al. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 1988;319(23):1500-6
Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999;22(6):920-4
Hanefeld M, Koehler C, Henkel E, et al. Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes. Diabet Med 2000;17(12):835-40
Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25(7):1135-41
Dr Doelle is associate professor, department of internal medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City. Correspondence: Gregory C. Doelle, MD, Department of Internal Medicine, VA Medical Center, #3 East-17, Hwy 6, Iowa City, IA 55246. E-mail: [email protected].
The clinical picture of metabolic syndrome
The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.
Preview: Metabolic syndrome has piqued the interest and concern of physicians and patients alike. The syndrome represents a commingling of several conditions and risk factors common in the United States and links accelerated cardiovascular disease with insulin resistance. As more details are uncovered about metabolic syndrome, new questions arise. Here, Dr Doelle reviews what is known and not yet known about metabolic syndrome, its etiology, and its treatment.
Doelle GC. The clinical picture of metabolic syndrome: an update on this complex of conditions and risk factors. Postgrad Med 2004;116(1):30-8
Metabolic syndrome is a clustering of disorders that has a major consequence: a marked increase in cardiovascular disease. The syndrome has had several names, including syndrome X and dysmetabolic syndrome, since its initial description by Reaven (1) in 1988. Greater awareness of metabolic syndrome has followed its recent definition by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) (2).
A role for insulin resistance is suggested by observations that link it to each of the metabolic criteria for diagnosis of metabolic syndrome as proposed by the ATP III (table 1). Plasma insulin concentration strongly correlates with blood pressure in different populations of both obese persons and persons who are not obese (3,4). Normotensive offspring of hypertensive parents are more insulin-resistant than offspring of normotensive parents (5). The dyslipidemia of metabolic syndrome may be causally related to the insulin-resistant state and to increased free fatty acid flux, which promotes production of triglyceride-rich very low-density lipoprotein cholesterol in the liver.
Insulin resistance is an obvious factor (although not the sole factor) in development of impaired fasting glucose, glucose intolerance, and type 2 diabetes. Known diabetes or impaired fasting glucose makes up only one of five criteria for diagnosis of metabolic syndrome, reinforcing the observation that insulin resistance and hyperinsulinemia, even in the absence of overt abnormalities of glucose tolerance, lead to increased cardiovascular disease.
The presence of any three of the five criteria listed in table 1 is sufficient for diagnosis of metabolic syndrome. According to age-adjusted estimates from the third National Health and Nutrition Examination Survey (1988-1994), 23.7% of US adults meet metabolic syndrome criteria, with age and ethnicity being key prevalence determinants (6). On the basis of census data from 2000, roughly 47 million people in the United States have metabolic syndrome.
The major clinical consequence of metabolic syndrome is atherosclerotic cardiovascular disease, and several components of metabolic syndrome are known risk factors for atherosclerosis. Increased awareness of the diagnosis of metabolic syndrome will lead to the identification of additional cardiovascular risk factors and, in turn, to improved identification of high-risk patients. The ATP III guidelines do not incorporate emerging cardiovascular risk factors (eg, highly sensitive C-reactive protein) in assessment of risk, but it seems likely that the definition of metabolic syndrome will expand as the characterization of these risk factors is further elucidated.
Here, each component of metabolic syndrome is considered individually, with the recognition that there is overlap between the criteria.
Obesity
Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. It also is an important component of metabolic syndrome, although in a minority of obese persons, insulin resistance does not develop. Insulin resistance may also develop in persons classified as lean by body mass index (BMI) standards, who could thus be considered "metabolically obese."
Visceral adipose tissue has been proposed as the major site of fat deposition associated with the metabolic consequences of obesity (7). It is thought that visceral, or central, adiposity is the initial physical event that results in insulin resistance, by an increase in free fatty acid flux in portal and systemic circulations. Visceral adipose tissue may also contribute to other causes of increased atherosclerotic risk, including inflammatory, prothrombotic, and fibrinolytic factors (table 2). Whether measurement of these markers of adipose tissue hormonal activity improves accuracy in assessment of cardiovascular risk remains to be seen.
Initial treatment of obesity associated with metabolic syndrome is lifestyle modification, followed by pharmacologic therapy. Pharmacologic agents available to treat obesity are of two classes, an appetite suppressant (sibutramine hydrochloride [Meridia]) and a drug that inhibits fat absorption (xenical [Orlistat]). Weight loss with these agents is modest, typically 5% to 10% of initial weight. Of considerable interest are newer agents that target endogenous cannabinoid receptors to inhibit both short- and long-term food intake. Rimonabant is currently in phase 3 clinical trials. Surgical therapies such as gastric banding and gastric bypass can be considered for patients who are severely obese (BMI >40 kg/m2) or for patients with a BMI of 35 kg/m2 or more who have comorbid conditions. This latter group includes the majority of persons with metabolic syndrome.
Dyslipidemia
Combined hyperlipidemia is a hallmark of metabolic syndrome. The characteristic lipid disorders seen in this syndrome are hypertriglyceridemia, low levels of high-density lipoprotein cholesterol (HDL-C) and, often, normal levels of low-density lipoprotein cholesterol (LDL-C), although the LDL-C particles are typically smaller and more dense than usual. Whether these small, dense LDL-C particles confer increased cardiovascular risk independent of that related to hypertriglyceridemia and low HDL-C levels is uncertain (8).
The diagnosis of dyslipidemia is best made when a patient is in a basal state without acute illness. Low HDL-C levels (<40 mg/dL [1.03 mmol/L] in men, <50 mg/dL [1.29 mmol/L] in women) are altered little by fasting. However, triglyceride concentration can rise substantially after food intake, and current diagnostic criteria are based on measurements obtained after 12 hours of fasting.
It is important that physicians be mindful of other conditions that result in low HDL-C levels and to screen for these disorders when appropriate. Hypothyroidism, glucocorticoid excess (endogenous and exogenous), and use of protease inhibitors can result in lipid abnormalities typical of those seen in metabolic syndrome.
Treatment of the dyslipidemia of metabolic syndrome should involve nonpharmacologic interventions, including weight loss, exercise, and a low-fat diet. Reducing LDL-C levels with use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") is also appropriate for patients with metabolic syndrome. The ATP III guidelines recommend that LDL-C be the primary target of lipid-lowering therapy when a patient's triglyceride level is below 500 mg/dL (5.65 mmol/L).
Metabolic syndrome can be considered a coronary artery disease (CAD) equivalent. Thus, it is appropriate to have target LDL-C levels that are below 100 mg/dL (2.59 mmol/L). Achieving this goal usually requires addition of a cholesterol-lowering agent, such as a statin. However, for many patients, statin therapy does not correct abnormalities of triglyceride and HDL-C concentrations.
Modifying triglyceride and HDL-C levels with drug therapy improves cardiovascular risk beyond the benefits achieved with statins alone. The Coronary Drug Project (9) and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VAHIT) (10) used drug interventions (niacin and gemfibrozil) designed to modify triglyceride and HDL-C levels, and these interventions were associated with a reduction in cardiovascular events in both studies. Caution should be exercised when using both a fibric acid derivative and a statin, because the risk of myositis is increased with combination therapy. In addition, creatine kinase levels should be monitored if symptoms such as myalgia develop, especially in the setting of combination therapy.
Hypertension
Hypertension is an important hallmark of metabolic syndrome. Weight gain in youth (11) and middle age (12) is positively correlated with blood pressure levels, and weight reduction can effectively lower blood pressure in overweight hypertensive patients (13). This scenario again demonstrates the overlap of individual components of metabolic syndrome.
The ATP III defines elevated blood pressure as a reading of 130/85 mm Hg or greater. This category includes patients taking antihypertensive medicines even if treatment achieves a blood pressure level that is within target range. As with dyslipidemia, the initial treatment of hypertension is nonpharmacologic therapy, including sodium restriction and weight loss through calorie restriction and exercise. However, pharmacologic therapy is required in many patients with hypertension.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (14) provides guidelines for intensive treatment of hypertension. Although use of thiazide diuretics and beta-blockers has been avoided in patients with glucose tolerance abnormalities, the safety and efficacy of such medications have been demonstrated in large clinical trials (15). Drugs of these classes can be used in treatment of hypertension in patients with metabolic syndrome.
The mechanism supporting the association between insulin resistance and hypertension is unclear. Insulin acts as a direct vasodilator when given as a short-term infusion (16) but also acts to increase both sympathetic outflow (17) and renal sodium reabsorption (18). These last two mechanisms may counter vasodilatory effects and result in elevations of blood pressure in the insulin-resistant state. Despite evidence that blood pressure control is critical for reducing cardiovascular risk in diabetic patients, clinical studies show that fewer diabetic patients than nondiabetic patients in a matched group have blood pressures under 140/90 mm Hg.
Abnormal glucose tolerance
Elevated fasting glucose levels are an important feature of metabolic syndrome, but neither impaired fasting glucose nor diabetes is an absolute criterion. Insulin resistance is associated with an increased risk of type 2 diabetes, and overt diabetes develops in many persons with metabolic syndrome. Measurement of fasting glucose is required in all patients with metabolic syndrome to identify comorbid conditions that warrant specific intervention. Currently, impaired fasting glucose is identified by a fasting blood glucose level of 100 to 126 mg/dL (5.6 to 7.0 mmol/L), a criterion recently reduced from a level of 110 to 126 mg/dL (6.1 to 7.0 mmol/L).
While NCEP guidelines suggest measurement of fasting glucose when a diagnosis of metabolic syndrome is being considered, the role of fasting insulin levels, postchallenge glucose levels, and more precise measures of insulin sensitivity is open to question. At this time, these measures are not part of the diagnostic criteria for metabolic syndrome and are often more useful for epidemiologic or research considerations (see article by Dr Sivitz).
Again, nonpharmacologic intervention is appropriate as initial therapy for patients with impaired fasting glucose or impaired glucose tolerance, but insulin-sensitizing drugs may be considered an early treatment option if lifestyle intervention is ineffective, even in the absence of overt diabetes. The Diabetes Prevention Program demonstrated the effectiveness of lifestyle change (weight loss of 7% and exercise level of 150 min/wk) in persons with impaired fasting glucose, but metformin hydrochloride (850 mg twice daily) was also effective in delaying progression to overt diabetes in patients with impaired fasting glucose (19).
Polycystic ovary syndrome
Polycystic ovary syndrome affects 5% to 10% of US women of reproductive age and has been increasing in incidence similarly to metabolic syndrome and type 2 diabetes. It is characterized by anovulation with irregular menses, infertility, and androgen excess leading to hirsutism and acne. Polycystic ovary syndrome, like metabolic syndrome, is associated with insulin resistance and an increased risk of type 2 diabetes and cardiovascular disease. By age 40, 40% of women with polycystic ovary syndrome have evidence of abnormal glucose tolerance (20).
Use of insulin-sensitizing drugs to treat the anovulation and infertility of polycystic ovary syndrome is of considerable interest. A meta-analysis of metformin use in polycystic ovary syndrome (21) demonstrated that 46% of subjects who received metformin monotherapy achieved ovulation, compared with 24% of those who received placebo. Therapy with metformin (Glucophage) also enhances the effectiveness of clomiphene citrate (Clomid, Milophene, Serophene) in inducing ovulation and fertility. However, similar to the Diabetes Prevention Program findings, equal or better ovulation rates with regular menses and decreased hair growth are achieved through lifestyle modification than through metformin monotherapy.
Atherosclerotic cardiovascular disease
There is no question that impaired fasting glucose and impaired glucose tolerance represent intermediate stages in the progression from metabolic syndrome to type 2 diabetes. The process is considered a continuum in which progressive defects in insulin action and insulin release lead to more overt abnormalities of glucose homeostasis (22). Impaired glucose tolerance has also been associated with CAD and stroke before it progresses to full-blown diabetes.
In the Funagata Diabetes Study (23), mortality rates for cardiovascular disease were significantly higher in subjects with impaired glucose tolerance than in those with normal glucose tolerance, although lesser degrees of glucose intolerance (impaired fasting glucose) were not associated with increased risk. In the Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) trial (24), 2-hour postchallenge glucose concentrations correlated more closely with carotid intima-media thickness than did fasting glucose concentrations in patients with a family history of type 2 diabetes.
Impaired fasting glucose and type 2 diabetes have insulin resistance in common, and insulin resistance has been shown to be an independent risk factor for atherosclerotic cardiovascular disease (25). It is not unexpected that in the natural history of type 2 diabetes, macrovascular complications may antedate--often by many years--the typical diagnosis of diabetes. Thus, the challenge is to identify and correct defects in glucose metabolism as early as possible.
Therapy
Current recommendations for therapy for metabolic syndrome focus on correction of the components (ie, hypertension, dyslipidemia, visceral adiposity, and abnormal glucose tolerance). It has been said many times and in many ways, but the fact remains that exercise, diet, and weight loss each independently improves insulin resistance and reduces progression to type 2 diabetes. Even though the success of lifestyle modification is limited, the importance of such therapy cannot be overemphasized.
Drug intervention focuses on treatment of the manifestations of metabolic syndrome with clearly defined targets for blood pressure, weight, and levels of triglycerides, HDL-C, and hemoglobin A1c. The success of metformin use in polycystic ovary syndrome and in the Diabetes Prevention Program suggests that one medication or drug class could be used to treat the entire syndrome. Use of medications in the thiazolidinedione class (pioglitazone hydrochloride [Actos] and rosiglitazone maleate [Avandia]) directly improves insulin resistance but has not yet been shown to reduce cardiovascular morbidity or mortality. Thus, the approach to treatment of metabolic syndrome is aggressive management of its individual components.
Conclusion
Metabolic syndrome represents a clustering of cardiovascular risk factors linked through their association with insulin resistance. Since insulin resistance is an independent risk factor for cardiovascular disease, its presence can lead to macrovascular complications long before other features of metabolic syndrome are evident.
Challenges remaining in the identification of high-risk persons include the introduction of clinical markers of insulin resistance, integration of postchallenge glucose and lipid concentrations, and better definition of the role of inflammatory, prothrombotic, and genetic factors. Improved understanding of the risk factors for metabolic syndrome is required, and clinical trials of therapeutic interventions specifically targeted to this syndrome need to be conducted.
References
Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607
Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97
Bonora E, Zavaroni I, Alpi O, et el. Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects. Diabetologia 1987;30(9):719-23
Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989;320(11):702-6
Beatty OL, Harper R, Sheridan B, et al. Insulin resistance in offspring of hypertensive parents. Br Med J 1993;307(6896):92-6
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287(3):356-9
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21(6):697-738
Sacks FM, Campos H. Low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 2003;88(10):4525-32
Natural history of myocardial infarction in the Coronary Drug Project: long-term prognostic importance of serum lipid levels. Coronary Drug Project Research Group. Am J Cardiol 1978;42(3):489-98
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Eng J Med 1999;341(6):410-8
Voors AW, Webber LS, Frerichs RR, et al. Body height and body mass as determinants of basal blood pressure in children--the Bogalusa Heart Study. Am J Epidemiol 1977;106(2):101-8
Havlik RJ, Hubert HB, Fabsitz RR, et al. Weight and hypertension. Ann Intern Med 1983;98(5 Pt 2):855-9
Reisin E, Abel R, Modan M, et al. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978;298(1):1-6
Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289(19):2560-72 [Erratum, JAMA 2003;290(2):197]
Pasternak RC. The ALLHAT lipid lowering trial--less is less. JAMA 2002;288(23):3042-4
Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994;94(3):1172-9
Anderson EA, Hoffman RP, Balon TW, et al. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991;87(6):2246-52
Skott P, Vaag A, Bruun NE, et al. Effect of insulin on renal sodium handling in hyperinsulinaemic type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance. Diabetologia 1991;34(4):275-81
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Diabetes Prevention Program Research Group. N Eng J Med 2002;346(6):393-403
Legro RS. Diabetes prevalence and risk factors in polycystic ovary syndrome. Obstet Gynecol Clin North Am 2001;28(1):99-109
Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. Br Med J 2003;327(7421):951-3
Saad MF, Knowler WC, Pettitt DJ, et al. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 1988;319(23):1500-6
Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999;22(6):920-4
Hanefeld M, Koehler C, Henkel E, et al. Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes. Diabet Med 2000;17(12):835-40
Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002;25(7):1135-41
Dr Doelle is associate professor, department of internal medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City. Correspondence: Gregory C. Doelle, MD, Department of Internal Medicine, VA Medical Center, #3 East-17, Hwy 6, Iowa City, IA 55246. E-mail: [email protected].
