The metabolic syndrome increases the risk for cardiovascular disease in individuals with and without diabetes.[1,2] Key features of the syndrome include obesity (in particular central obesity), dyslipidemia, hypertension, and insulin resistance. (These 4 major features will be discussed in detail below.) Although the risk associated with the metabolic syndrome is well documented, the definition of the syndrome is still in flux. Currently, the National Cholesterol Educational Program (NCEP) Adult Treatment Panel III (ATP III) guidelines are the most commonly used criteria, although other criteria, such as those of the World Health Organization, are also used.Table 1: WHO and NCEP ATP III Definitions of the Metabolic Syndrome
|Characteristics||WHO||NCEP ATP III|
|Hypertension||Current antihypertensive therapy and/or BP > 140/90||Blood pressure medication or BP > 130/85|
|Dyslipidemia||Plasma triglycerides > 1.7 mmol/L (150 mg/dL) and/or HDL < 0.9 mmol/L (35 mg/dL) in men and < 1.0 mmol/L (< 40 mg/dL) in women||Plasma triglycerides > 150 mg/dL, HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women.|
|Obesity||BMI > 30 and/or waist/hip ratio > 0.90 in men, > 0.85 in women||Waist circumference > 102 cm in men and > 88 cm in women|
|Glucose||Type 2 diabetes or IGT||Fasting blood sugar > 110 mg/dL|
|Other||Microalbuminuria = overnight urinary albumin excretion rate> 20 mcg/min (30 mg/g Cr)||
|Requirements for diagnosis||Type 2 diabetes or IGT and any 2 of the above criteria. If normal glucose tolerance, must demonstrate 3 other disorders.||Any 3 of the above disorders|
BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; IGT, impaired glucose tolerance; NCEP ATP III, National Cholesterol Education Program - Adult Treatment Panel III; WHO, World Health Organization
A recent report derived from the National Health and Nutrition Examination Survey database (NHANES-III)[6,7] assessed the prevalence of the increasingly common syndrome in the US population using the ATP-III guidelines. On the basis of these criteria, the age-adjusted prevalence of the metabolic syndrome among adults in the United States was estimated at 23.7%. Rates were similar in men and women and increased with age. Among specific population groups, Mexican Americans had the highest age-adjusted prevalence (31.9%). According to current census data, an estimated 47 million people living in the United States likely have the metabolic syndrome.Components of the Metabolic Syndrome Obesity
An elevated body mass index (BMI) is a risk factor for the metabolic syndrome, and a BMI greater than 30 mg/kg2 is considered obese. Obesity increases insulin resistance and thus raises circulating insulin levels. Obesity is due to an increase in both visceral and subcutaneous fat deposits, but the pattern of weight gain that is particularly problematic is visceral or central obesity.[8,9] Even lean individuals with central weight gain can have the metabolic syndrome.
Fat deposits were once considered to be a storage region for excess energy. However, fat cells have been found to secrete a number of different substances, and it is now thought that fat creates a metabolically active organ. Fat cells have afferent pathways to the central nervous system. Abdominal adipocytes exert effects on beta-cell function, hepatic glucose production, muscle glucose uptake, appetite regulation, and arterial inflammation through various adipocytokines such as leptin, resistin, TNF-alpha, and adiponectin.[11,12] Visceral fat has a higher rate of lipolysis, increasing the flux of free fatty acids to the liver, which increases insulin resistance and the production of abnormal (triglyceride-enriched) lipid particles. Visceral fat cells are more resistant to the suppressive effects of insulin on lipolysis than is subcutaneous fat.
Although visceral fat can be measured with computed tomography (CT) scans and magnetic resonance images (MRIs), central obesity is quantitated clinically with a measuring tape or simply through observation. Central obesity is considered present if the waist circumference is greater than 88 cm (35 in) in a woman or 102 cm (40 in) in a man (these numbers may be less accurate in Asians and adolescents). To measure waist circumference, measure around the abdomen at the level of the uppermost lateral border of the iliac crest. The measurement is made at the end of a normal expiration, and the tape measure should rest gently on the patient's skin without significant compression.Dyslipidemia
Insulin resistance results in specific abnormalities of lipid metabolism that tend not to be well understood by practitioners or patients (who are trained to know their cholesterol level as a risk factor for CVD). The dyslipidemia of insulin resistance is characterized by elevated levels of plasma triglycerides (> 150 mg/dL) and low levels of HDL cholesterol (< 40 mg/dL in men and < 50 mg/dL in women). Although total non-HDL cholesterol may be elevated in this syndrome, actual LDL cholesterol levels often are not significantly increased. However, if particle size is measured, the LDL particles tend to be smaller and denser, which increases their atherogenic potential.
To understand these lipid changes in patients with insulin resistance, it is important to be aware of the regulatory role that insulin has on the metabolism of free fatty acids (FFAs) and the production of triglyceride-rich very low-density lipoprotein (VLDL) particles. In insulin resistance, there is an increase in free fatty acid (FFA) released from adipocytes. This increase causes circulating levels of FFA to rise, which stimulates synthesis of triglyceride-rich VLDL particles by the liver, leading to triglyceride-enriched high-density lipoprotein (HDL) and LDL particles (through cholesterol ester transfer protein). The increase in triglycerides in lipid particles changes their metabolism. Triglyceride-rich HDL particles are hydrolyzed more rapidly, and HDL levels fall. The triglyceride-enriched LDL particles are subject to further lipolysis, which gives rise to the formation of small, dense LDL particles. The resultant dyslipidemia is highly atherogenic and accounts for at least part of the increase in CVD risk in insulin-resistant individuals.[16,17]Hypertension
Hypertension occurs in up to one third of those with the metabolic syndrome. Insulin resistance has been directly tied to the development of hypertension and other abnormalities of vascular behavior, and may directly affect vascular signaling (through mediators such as nitric oxide) and endothelial cell function. Additionally, increased insulin levels may increase sympathetic nervous system activity and sodium retention. It is possible that treating insulin resistance primarily will help lower blood pressure, and there is some evidence that insulin sensitizers such as the glitazones pioglitazone and rosiglitazone reduce blood pressure.[19,20] However, standard treatment of hypertension -- ie, with angiotensin-converting enzyme (ACE) inhibitors, diuretics, beta-blockers, and calcium channel blockers -- is indicated to reach the blood pressure target of less than 130-135/80.Insulin Resistance
Insulin resistance is a condition in which increased amounts of insulin are required to produce a normal biological response. Although insulin resistance is present in virtually all cases of type 2 diabetes, it exists in many more individuals who do not yet have hyperglycemia but have the metabolic syndrome (and are at risk for developing type 2 diabetes). Prior to the overt development of diabetes, patients are able to hypersecrete insulin to maintain normal blood glucose levels. At some point, in individuals who develop type 2 diabetes, beta-cell failure occurs, insulin levels fall, and blood glucose levels rise. Unfortunately, it is only at this point (when fasting blood glucose levels increase) that we diagnose prediabetes. When patients with insulin resistance have normal blood glucose levels, fasting insulin levels are elevated but measurement of fasting insulin levels is not recommended in general practice (due to the variability seen with commercial assays). Therefore, insulin resistance is often the last part of the metabolic syndrome that is diagnosed in a clinical setting, even though it may be the underlying abnormality in patients with the condition.
Although impaired fasting glucose is defined by the American Diabetes Association as fasting blood glucose values in the range of 110-125 mg/dL, these levels may be too high. In a population-based study from the Framingham cohort, the metabolic risk factors for coronary heart disease, including obesity, hypertension, decreased HDL levels, elevated triglyceride levels, and hyperinsulinemia, demonstrated a continuous increase in CVD risk across the spectrum of glucose values in the nondiabetic range (90-125 mg/dL). This increase in risk was apparent even in the lowest quintiles of normal fasting glucose. The recent European Prospective Investigation into Cancer and Nutrition (EPIC) study also demonstrated a marked increase in cardiovascular events in men without diabetes when comparing hemoglobin A1C (A1C) levels in the highest quintile (5.0% to 5.4%) with those in the lowest quintile (< 5.0%). Therefore, fasting blood glucose levels that rise much above 90 mg/dL and certainly those that continue to increase over time are likely to be due to increasing insulin resistance.Clinical Management of the Metabolic Syndrome
Management of the metabolic syndrome requires treatment of many of the individual metabolic consequences present in each individual. Treatment is focused on improving abnormal glucose tolerance and reducing CVD risk. Ideally, both progression to diabetes as well as the development of clinically significant atherosclerosis can be prevented. Therapeutic lifestyle interventions, including weight management and increased physical activity, are the cornerstone for management and should be encouraged throughout a patient's care. Smoking cessation should be strongly encouraged. Most individuals will also need pharmacologic therapy, such as use of lipid-lowering drugs, ACE inhibitors and/or angiotensin receptor blockers (ARBs), daily aspirin, and perhaps treatment with medications such as metformin and/or a glitazone to reduce insulin resistance. Targets similar to those used for treating cardiovascular risk in individuals with diabetes should be applied (eg, LDL cholesterol < 100 mg/dL, BP < 130/80). Once a patient develops diabetes, glycemic targets (maintenance of A1C levels of < 7%) should be followed.Updates From the IDF 2003 Meeting Diagnosis
As recognition of insulin resistance gains prominence in clinical practice, and as consideration is given to earlier interventions to reduce cardiovascular complications, an accurate, easy method of diagnosis is important. In research, the gold standard of measurement is the hyperinsulinemic euglycemic clamp, a complicated method that is not practical in office-based practice.
The IRIS II algorithm, which determines an insulin resistance score by ranking measurements of BMI, blood glucose, fasting triglycerides, and HDL cholesterol in a stepwise multiple regression analysis, was evaluated in 4265 type 2 diabetes patients. Results compared favorably with other determinants of insulin resistance such as the homeostasis assessment model (HOMA) index and an intravenous glucose tolerance test with minimal model analysis in terms of prediction of vascular complications. The 13 C-glucose breath test, which requires a baseline and 90-minute breath sample, was evaluated in 26 subjects. Results demonstrated it to be better than HOMA when compared with the hyperinsulinemic euglycemic clamp technique. Since breath samples can be stored for up to 3 months and blood samples are not required, it is envisioned that this test may eventually be used for patients at home.Genetic Determinants
In order to ultimately develop effective treatment strategies for insulin resistance, a greater understanding of genetic and environmental influences is needed. Much information has been advanced regarding the roles of central obesity and physical inactivity. Several papers at the 18th International Diabetes Federation Congress (IDF) addressed genetic factors. The Pro12Ala polymorphism of the peroxisome proliferator activated receptor gamma 2 gene was associated with improved insulin sensitivity in Czech adults. The receptor for advanced glycation end products (RAGE) has been associated with proinflammatory events involved in diabetic complications. In the Leeds Family study from the United Kingdom, an association was established between the RAGE gene and the development of insulin resistance. A study that evaluated 130 Italian children from a pediatric obesity center revealed that the A allele at position 11391 of the adiponectin gene was associated with higher fasting glucose levels, higher BMI, and lower HDL cholesterol than those negative for the allele. Thus, the authors concluded that the adiponectin gene may be a "novel susceptibility gene for obesity and obesity-correlated traits in the Italian population."Cardiovascular Risk
A growing recognition and concern has arisen about cardiovascular risk before the onset of overt hyperglycemia in the insulin-resistant and/or prediabetic state. Steven Haffner, MD, from The University of Texas Health Science Center in San Antonio, summarized some of these data. In his investigations, heterogeneity was discovered among prediabetics, as those that were more insulin resistant were found to have more cardiovascular risk factors (eg, hypertriglyceridemia, low HDL-C) at the same glucose levels. He also presented data (in press) from The Insulin Resistance and Atherosclerosis Study showing that insulin resistant prediabetic persons had higher markers of subclinical inflammation, such as plasminogen activator inhibitor-1 (PAI-1) and C-reactive protein (CRP).
In a German study of 592 patients at high risk for macrovascular disease followed for 5 years (53.2% with diabetes), CRP was found to be the strongest risk factor predictive of mortality and cardiovascular death, even when compared with traditional risk factors among the diabetic subgroup and the total cohort. In a population-based cohort study among 70-year-olds (at baseline) from Sweden with a follow-up of 7.5 years, proinsulin (as a marker of insulin resistance) predicted CHD independent of traditional risk factors such as total cholesterol, smoking, and hypertension. In data compiled from 11 prospective European cohort studies that enrolled 6156 men and 5356 women aged 30 to 89 years without diabetes, the prevalence of metabolic syndrome in men was 15.7% and in women 14.2%. The overall hazard ratio for all-cause mortality in those with the metabolic syndrome compared with those without was 2.03 in men and 2.48 in women after adjustment for confounding factors.
In the Study of Osteoporotic Fractures (SOF) from the United States, the presence of metabolic syndrome in elderly women (> 65 years) and its effects on mortality were evaluated. The results revealed a 2- to 3-fold increased mortality and greater than 3-fold CVD mortality in those with the metabolic syndrome. Finally, a study from the Ukraine found that in patients with known coronary artery disease confirmed with angiography, the prevalence of metabolic syndrome based on at least 3 of the criteria from ATP-III was 49.2% vs 23.7% without coronary artery disease. Thus, it appears that recognition of insulin resistance and intervention at an earlier stage will be crucial in decreasing cardiovascular complications. Identification of novel markers such as CRP, which can be easily examined, will be very important.The Adipocyte
Adiponectin, a collagen-like protein produced exclusively in differentiated adipose tissue, has been shown to be decreased in several insulin-resistant states such as type 2 diabetes, obesity, and dyslipidemia.[37,38] It has thus been proposed that adiponectin is insulin-sensitizing and that increased levels are cardioprotective. Thus, interventions that increase adiponectin are beneficial.
In a Japanese study, adiponectin correlated with the heart-rate corrected QT interval (QTc), which is a marker of subclinical atherosclerosis and has been demonstrated to predict cardiac mortality and correlate with carotid intimal thickness. The authors purport that this significant inverse relationship "strongly suggests that adiponectin possesses a direct cardioprotective effect in man." Another study revealed that weight loss after gastric banding surgery resulted in significant elevations in adiponectin.
Clinicians who treat patients with type 2 diabetes and metabolic syndrome often make the observation that many of these patients appear Cushingoid. Yet if they are evaluated for excess cortisol, invariably no biochemical abnormalities come forth. The enzyme 11-beta hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone to the active compound cortisol, and, if overexpressed, may cause increases in local cortisol concentrations. Investigators from Australia confirmed that omental (visceral) adipose tissue produces a greater amount of cortisol compared with subcutaneous tissue, with greater activity of 11-beta HSD type 1 in omental tissue.Glitazones
While studies involving clinical cardiovascular outcomes with thiazolidinediones (TZDs) are in progress, a wealth of knowledge has accumulated demonstrating beneficial effects of this class of drug on surrogate markers of cardiovascular disease. Several more studies at IDF added to this base for the currently available agents rosiglitazone and pioglitazone.
Pioglitazone increased adiponectin 3-fold and decreased hepatic fat content, while rosiglitazone increased adiponectin and decreased FFA and PAI-1 in type 2 diabetes patients. In a large study of 3700 patients from 28 European countries, the effects of pioglitazone, metformin, and the sulfonylurea agent gliclazide on LDL particle size were studied. In monotherapy and combination therapy trials, pioglitazone demonstrated a favorable increase in LDL size.
Further insights into the potential benefit of TZDs with regard to effects on the vascular endothelium were presented by representatives of the Baker Heart Research Institute in Melbourne, Australia. Negatively charged glycosaminoglycans (GAGs) or proteoglycans (PGs) can trap lipoproteins in the vessel wall, leading to atherosclerosis. This group evaluated the effects on PG and GAG chain synthesis in human vascular smooth muscle cells (VSMC). TZDs (troglitazone, rosiglitazone, and pioglitazone) inhibited PG synthesis, and all had antiproliferative effects on VSMC. It is thought that the reduction in PG size results in less binding ability of atherogenic lipoproteins, leading to reduced atherosclerosis.
In a study from the Walter Reed Medical Center, Washington, DC, the effects of rosiglitazone and metformin were compared on high-sensitivity C-reactive protein (hs-CRP), homocysteine, and lipids independent of glycemic control in 51 patients with suboptimally controlled type 2 diabetes over 26 weeks. The group treated with rosiglitazone experienced a decrease in hs-CRP as early as 2 weeks (before any improvement in glycemia). This improvement persisted at the end of the study. The rosiglitazone group also sustained an improvement in homocysteine compared with the metformin group. No significant changes in lipids between the groups were demonstrated.
In a Japanese study, the effects of pioglitazone on cardiovascular surrogate markers (hs-CRP, adiponectin, and pulse wave velocity) in type 2 diabetes patients were studied for 3 months. Interestingly, both responders and nonresponders (those having a decrease in HbA1c < 1%) demonstrated improvements in these markers. Thus, the promise of this class of drugs in terms of potential cardiovascular disease reduction perhaps lies in their nonglycemic, pleiotropic effects.
Recently, attention has focused on TZDs and their potential benefits on beta-cell function, perhaps through amelioration of insulin resistance and lipotoxicity. Thomas Buchanan, MD, from the Keck School of Medicine, University of Southern California, Los Angeles, presented data from the Troglitazone in Prevention of Diabetes (TRIPOD) study, in which the risk of developing type 2 diabetes in a high-risk, previously gestational diabetic population was markedly curtailed by troglitazone. Those who had the most benefit experienced "beta cell rest" with improved endogenous insulin production after troglitazone treatment. Some preliminary data presented by Dr. Buchanan from the Pioglitazone in Prevention of Diabetes (PIOPOD) study after 1 year are revealing a similar trend.
In a study by David Bell, MD, from the University of Alabama at Birmingham, the addition of rosiglitazone to patients failing metformin and sulfonylurea therapy was studied (initially, troglitazone was used, but rosiglitazone was substituted after troglitazone's withdrawal from the market). After 5 years, 63% of patients were well controlled with an average A1C of 7.1% (± 0.4%). In the group that remained well controlled on triple therapy, an increase in stimulated C-peptide was demonstrated, while there was a decrease in the failure group. Thus, evidence is pointing to a protective effect on beta-cell function with these agents, which may explain some of the significant durability on glycemic control.Other Treatments
The biguanide metformin was shown in a rat model to exert improvements on insulin resistance via phosphorylation of target molecules by AMP-activated protein kinase. In the same study, a distinct mechanism of the TZD rosiglitazone (increased adiponectin) was demonstrated. Thus, the authors concluded that the effects of metformin and rosiglitazone were complementary, and a rationale exists for their use in combination to treat insulin resistance.
The fibrate agent fenofibrate (a PPAR-alpha agonist) was beneficial in reducing CRP, fibrinogen, and uric acid in diabetic and nondiabetic subjects. Thus, this agent may have a role in the treatment of insulin resistance, especially in those with dyslipidemia. Two studies with statins also demonstrated benefits in patients with the metabolic syndrome. In a posthoc subgroup analysis from the Scandinavian Simvastatin Survival Study (4S), those with metabolic syndrome realized a 37% reduction in LDL-C and had reduced cardiovascular endpoints. Furthermore, the addition of ezetimibe to ongoing statin therapy resulted in further reductions in LDL-C in metabolic syndrome patients.
With the results of trials such as the Diabetes Prevention Program demonstrating the benefits of lifestyle interventions in reducing the risk of the development of type 2 diabetes, many have focused on this aspect of patient care to also improve insulin sensitivity. One study from Bulgaria evaluated the effects of dietary fat on patients with newly diagnosed type 2 diabetes vs age- and gender-matched controls without diabetes. It was determined that the amount of animal fat -- but not total dietary fat -- was positively correlated with type 2 diabetes. A study from Italy demonstrated the beneficial effects of moderate alcohol intake (sipping 40 g of vodka) on reducing FFAs and improving insulin sensitivity. Not surprisingly, a Canadian study showed that exercise training improved endothelial function in women with type 2 diabetes.Future Directions
Several agents currently in development hold promise in the treatment of insulin resistance, and, ultimately, cardiovascular disease. The dual PPAR-alpha/gamma agonists are currently the farthest along in development. Tesaglitazar was evaluated in a 12- week study in 390 nondiabetic subjects with insulin resistance. Dose-dependent reductions in triglycerides, total cholesterol, and FFA were seen with tesaglitazar administration. There was an increase in HDL-C and LDL-C particle size in 79% of patients who received tesaglitazar 1 mg and had mean particle diameter less than 20.5 nm at baseline. A dose-dependent decrease in fasting insulin and glucose was demonstrated.
In a presentation by Jim McCormack, MD, novel agents in development that may target insulin resistance at more downstream points, such as direct tyrosine kinase activators, protein tyrosine phosphatase 1 B inhibitors, and inhibitors of 11 BHSD-1, were discussed. None of these agents are ready for prime time, but the hope is that targeting insulin resistance at more specific sites will lead to more efficacious treatment with fewer adverse effects.References
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McGavock J, Mandic S, Lewanczuk RZ. Exercise training improves cardiorespiratory fitness and endothelial function in women with type 2 diabetes. Presented at the 18th International Diabetes Federation Congress; August 24-29, 2003; Paris, France. Abstract 767.
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Cite this: Daniel N Berger, Anne Peters Harmel. Clinical Implications of the Metabolic Syndrome - Medscape - Oct 13, 2003.