BRIEF REPORT

Metabolic Syndrome Risk Factors Drive Significantly Higher Health Care Costs

ScienceDaily (Sep. 17, 2009) — Risk factors for metabolic syndrome, such as obesity, high blood pressure, and elevated blood lipid levels, can increase a person's healthcare costs nearly 1.6-fold, or about $2,000 per year. For each additional risk factor those costs rise an average of 24%, according to an illuminating article in a recent issue of Metabolic Syndrome and Related Disorders, a peer-reviewed journal published by Mary Ann Liebert, Inc.


A two-year study that compared annual healthcare costs for people with and without diabetes found both higher healthcare utilization and significantly greater expenses ($5,732 versus $3,581 per year) for those who had risk factors for metabolic syndrome. A group of researchers from the Center for Health Studies (Seattle, WA); United BioSource Corp. (Bethesda, MD); University of Arizona, Tucson; Kaiser Permanente's Colorado Clinical Research Unit in Denver and Northwest Center for Health Research in Portland, Oregon; Genzyme (Cambridge, MA); and Sanofi-Aventis (Bridgewater, NJ), led by D.M. Boudreau, PhD, from United BioSource, evaluated healthcare utilization among more than 170,000 men and women, approximately 58% of whom had risk factors for metabolic syndrome.

The study, entitled "Health Care Utilization and Costs by Metabolic Syndrome Risk Factors," also compared the annual healthcare costs for subjects who had both diabetes and metabolic syndrome risk factors and found them to be nearly double the costs for people who did not have diabetes but had similar risk factors for metabolic syndrome ($8,067 vs. $4,638).

"This important study clearly brings home the enormous economic burden that the metabolic syndrome extracts in a very large sample. Future studies should be directed at targeting the dyslipidemia, hypertension, etc., to see what the savings would be with respect to complications and economic burden," says Ishwarlal (Kenny) Jialal, MD, PhD, Editor-in-Chief of the Journal and Robert E. Stowell Endowed Chair in Experimental Pathology, Director of the Laboratory for Atherosclerosis and Metabolic Research, and Professor of Internal Medicine at the University of California, Davis Medical Center, in Sacramento, CA.

Practice guideline
The Aim

Primary and secondary prevention of type 2 diabetes, cardiovascular disease (hypertension, coronary heart disease, stroke, intermittent claudication), and possibly also Alzheimer's disease

Definition of Metabolic Syndrome (MBS)

MBS is a clustering of risk factors for type 2 diabetes and cardiovascular diseases. The risk factors are associated with obesity, insulin resistance, endothelial dysfunction, and possibly with cellular membrane disruption (Reaven, 1988; Laakso, 1993).
The clustering of risk factors results in a higher risk of type 2 diabetes and cardiovascular disease than would be estimated if each individual factor were taken into account separately (Tuomilehto et al., 2001; McNeil et al., 2005) Insulin resistance associated with obesity, plays an important role in the accumulation of the components of MBS in any one individual.
In insulin resistance, the biological response to insulin is impaired in the adipose tissues, muscles, the liver, and possibly the brain. The core abnormality of the syndrome includes the clustering of insulin resistance, compensatory hyperinsulinaemia, and dyslipidaemia in an obese hypertensive.
MBS is usually evident from truncal obesity which can be detected in clinical practice by measuring the circumference of the waist. MBS is rare in slim individuals (Vanhala et al., 1998).
The presence of MBS may be detected through medical history, anthropometry, blood pressure readings and by measuring
Lipid values
Blood or plasma glucose (glucose tolerance test or postprandial glucose if fasting glucose is normal).

The Diagnosis of MBS

According to the International Diabetes Federation (IDF) consensus 2005, the diagnostic criteria of MBS are:
Central obesity, defined as waist circumference of >94 cm for Europid men and >80 cm for Europid women PLUS
At least two of the following factors:
Increased serum triglyceride level: fasting value >1.70 mmol/L, or specific treatment for this lipid abnormality
Reduced serum high-density lipoprotein (HDL)-cholesterol: fasting concentration <1.03>130 mmHg or diastolic BP >85 mmHg, or treatment of previously diagnosed hypertension
Increased fasting plasma glucose: >5.6 mmol/L, or previously diagnosed type 2 diabetes. If the value is above 5.6 mmol/L, oral glucose tolerance test is strongly recommended but is not necessary to define the presence of the syndrome.
Other important signs and clinical findings supporting the diagnosis include:
Familial component: first-degree relative with type 2 diabetes
Obesity: body-mass-index (BMI) >30 kg/m2. For calculation see programme 1 included in the original guideline document.
Abnormal glucose tolerance test result: impaired glucose tolerance (IGT) or type 2 diabetes (NIDDM= non-insulin-dependent diabetes mellitus) according to World Health Organization [WHO] criteria)
Hyperuricaemia: fasting serum urate >450 micromoles/L in men, >340 micromoles/L in women
Microalbuminuria: urine albumin >20 milligrams/24 hours
Hyperinsulinaemia: fasting plasma insulin >78 pmol/L (>13.0 mU/L)
Alzheimer's disease, depression, and sleep apnoea may also be associated with MBS.

Prevalence

According to the IDF criteria, the prevalence of MBS in a middle-aged population is 38% for men and 34% for women (Alexander et al., 2003).
About one half of hypertensive patients are hyperinsulinaemic and/or have insulin resistance (Reaven, Lithell, & Landsberg, 1989). In Finnish population, almost half of hypertensive patients fulfill the criteria for MBS (Vanhala et al., 1997).

Treatment

The treatment is principally non-pharmacological and based on lifestyle changes. This approach has been shown to have an excellent effect, for example in the prevention of diabetes (DPS Study) (Tuomilehto et al., 2001; Knowler et al., 2002) [A].
Lifestyle changes are the only treatment form which have an effect on all the components of MBS, and not employing this treatment should be considered ethically wrong.

Non-Pharmacological Treatment
Increasing physical activity
Weight reduction
Dietary changes: increased intake of fibre and decreased intake of fat (particularly saturated fat) and rapidly metabolised carbohydrates (highly refined); salt restriction
Cessation of smoking
Limit alcohol intake to a moderate level
Drug Treatment
Drug treatment encompassing the entire MBS does not exist, and treatment should therefore consist of the management of the individual components of the syndrome.
Unless contraindicated, all patients with MBS should be prescribed low dose aspirin.
The treatment of hypertension in a patient with MBS should not contain drugs that worsen insulin resistance, such as non-selective beta-blockers and high-dose diuretics, unless other reasons (secondary prevention of myocardial infarction) warrant their use. The first-line drugs for the treatment of hypertension are:
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin-II receptor antagonists (losartan, valsartan, eprosartan, candesartan)
Alpha1 receptor blockers
Calcium-channel blockers
Highly selective beta-blockers

Dyslipidaemia in a patient with MBS should principally be treated with statins bearing in mind that the patient has a high risk of coronary artery disease.

Hypertriglyceridaemia should be treated with fibrates if, in spite of non-pharmacological treatment, the triglyceride values are persistently >5.0 mmol/L. Hypertriglyceridaemia in a patient with MBS should be treated medically (statin or fibrate) if the level of triglycerides is >2.30 mmol/L and total-cholesterol/HDL-cholesterol ratio is higher than 5 or if HDL-cholesterol is lower than 0.9 mmol/L.

Dysglycaemia in a patient with MBS should be treated with metformin or thiazolidine derivatives (pioglitazone or rosiglitazone) since these will not only improve the dysglycaemia but will also have an effect on the other components of the MBS. Insulin may also be used for the treatment of dysglycaemia in a MBS patient to achieve good diabetic control.

Biguanides, acarbose, and guar gum may correct insulin resistance and are thus feasible as a first-line drug for an obese patient with type 2 diabetes.

Orlistat or sibutramine may be indicated in MBS if the BMI is >30 kg/m2. These are anti-obesity drugs that also reduce the amount of visceral fat, in particular. However, the new endocannabinoid-receptor blockers are likely to provide the best benefit among pharmacotherapeutic alternatives. Rimonabant is an example of these drugs, and it has a positive effect on almost all the components of MBS.

Rimonabant should not be prescribed if the patient is concurrently in severe depression. It should be prescribed with caution and the patient should be carefully followed up if he/she has a history of depression.

Follow-up of a Patient with MBS

Motivation and monitoring of lifestyle changes is of the utmost importance.

The monitoring of a patient who requires drug treatment is the responsibility of a doctor. Regular appointments may often act as an important motivator.

The monitoring of a patient who does not require drug treatment may be carried out by a practice nurse. The following should be included in the follow-up: motivation of lifestyle changes, weight and waist circumference measurements, blood pressure readings, and checking of blood lipids and fasting blood glucose. A doctor should be consulted if:
Blood pressure repeatedly >140 mmHg and/or >90 mmHg
Total cholesterol: HDL-cholesterol ratio >5
Triglyceride values repeatedly >2.30 mmol/L
Plasma glucose is >7.8 mmol/L (fasting plasma glucose is >6.7 mmol/L
The patient develops symptoms of another illness (gout, etc.)

reference
Finnish Medical Society Duodecim. Metabolic syndrome. In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki, Finland: Wiley Interscience. John Wiley & Sons; 2007 Dec 13 [Various].

Metabolic Syndrome X Definition and Recognition

Interview with Dr. Christie Ballantyne on Metabolic Syndrome

Christie M. Ballantyne, MD

Metabolic syndrome is a cluster of clinical and biochemical abnormalities associated with the onset and progression of atherosclerotic cardiovascular disease (CVD). Adults with metabolic syndrome experience significantly greater mortality from coronary artery disease (CAD), vascular disease, stroke, and other causes in comparison with those who do not have the disorder. An enormous population is at risk, with important implications for public health. Comprehensive treatment strategies that modify CVD risk factors can ameliorate many of the pathophysiologic markers of metabolic syndrome and contribute to improved patient outcome. APOLLO interviewed Dr. Christie Ballantyne of Baylor College of Medicine, Houston, TX, whose editorial focuses on the metabolic syndrome.



Dr. Ballantyne, perhaps you could first describe some of the background regarding the current epidemic of cardiovascular disease (CVD).


Dr. Ballantyne: We can take a look at what has happened in the United States over the last century. There was a substantial epidemic with regard to coronary heart disease mortality, myocardial infarction, cardiovascular disease, and stroke, and it led to the initiation of studies like the Framingham Heart Study, which identified the risk factors associated with this problem. We have since made phenomenal progress in this area, identifying major risk factors and setting up programs regarding cholesterol, cigarettes, and so on.

But there has been a demographic change in the population of patients with heart disease. For example, there are studies, including one from Iceland published in The New England Journal of Medicine last year,1 or one we are involved with in the United States called the Atherosclerosis Risk in Communities (ARIC) study,2 showing an association between heart disease and body mass index (BMI). In the Icelandic study, the average BMI of patients who had a heart attack was 26 kg/m2, and in the United States it was close to 29 kg/m2. Those BMI values reflect the patients’ body weight years before having the heart attack. Furthermore, these studies were done in the 1980s and early 1990s, and the average body weight of the US population has increased since then.

The other issue is a very large increase in the number of people who have diabetes, very many of whom will also develop coronary artery disease. It is very curious that, even though we have made great progress with regard to cardiovascular disease, we are now diagnosing diabetes increasingly in young people. We used to diagnose diabetes typically in people in their 60s or 70s; then we started seeing it in patients in their 40s and 50s, and now we are seeing it in young adults in their 20s and 30s and even in teenagers. So there is real concern that we are about to see a reversal of the favorable trend of recent years because of a shift in the epidemiology of one of the drivers for the development of cardiovascular disease—for that is what diabetes clearly is.

We now know that—as is very carefully stated by the “ticking clock” hypothesis of Haffner and colleagues3—long before the onset of diabetes, a number of characteristic precursor features are present, including insulin resistance, an adverse lipid profile with low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels, relatively high glucose levels, elevated blood pressure, and increased blood levels of various inflammatory markers. Clearly, these features provide a fertile common soil for the development of both diabetes and cardiovascular disease. We also know that central adiposity plays an important role driving this. So this cluster of abnormalities has been recognized as a distinct clinical entity, which is termed metabolic syndrome.



So when we talk about the background of the CVD epidemic, we're talking about metabolic syndrome?


Dr. Ballantyne: Yes, this was a position taken by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III),4 which has also been endorsed more recently by the American Heart Association and the National Heart, Lung, and Blood Institute.5 The purpose was to develop a simple set of tools to help physicians identify individuals who have increased risk for both cardiovascular disease and diabetes but might not be identified by our traditional risk factor algorithms. Having identified these at-risk patients, we can intervene with more aggressive lifestyle modification and specifically point out that weight loss, by both diet and exercise, has been shown to have profound benefit for these individuals.



What is the exact definition of metabolic syndrome?


Dr. Ballantyne: As always, the devil is in the details. The ATP III set up some criteria with regard to waist circumference, >40 inches for men, >35 inches for women; glucose—the criterion was ³110 mg/dL but has been reduced to ³100 mg/dL, because that is the recognized definition of impaired fasting glucose; triglycerides >150 mg/dL; HDL-C <40 mg/dL for men and <50 mg/dL for women; and blood pressure ³130/³85 mm Hg (Table). Notice that the defining blood pressure level for metabolic syndrome is lower than the level of 140/90 mm Hg or greater that is commonly used to define hypertension.

The problem is whether using these continuous variables and cut points is the best way to assess these patients. So, some questions were raised: 1) Are these really valid cut points? 2)When we talk about metabolic syndrome, are we talking about a disease? 3) And another issue that came up in the position paper by the American Diabetes Association (ADA): Does the metabolic syndrome definition really provide much additional benefit to us with regard to cardiovascular disease prediction?



So, does the diagnosis of metabolic syndrome really provide additional benefit in the prediction of CVD?


Dr. Ballantyne: The ADA paper reviewed the issue just in terms of disease prediction and found that in fact the diagnosis of metabolic syndrome does not add to the predictive power of the Framingham risk assessment equation. Studies have suggested that HDL-C and blood pressure are the major drivers of the cardiovascular risk associated with metabolic syndrome,7,8 and they are already factored into the Framingham risk equation. So the ADA’s position is that the diagnosis of metabolic syndrome is really not a better tool than the Framingham score for predicting cardiovascular events, that we are making too much of it and should instead assess risk factors individually.


Do you agree?


Dr. Ballantyne: I think we need to step back and look at the purpose of this definition. Even if we can't come to a consensus, all of us agree that there are many individuals who are overweight, who are on their way to developing heart disease or diabetes, either one or both. We know that we have an epidemic of diabetes and that people with diabetes have a greatly increased likelihood of developing cardiovascular disease. So clearly we are not doing very well with this. Despite a tremendous amount of education, and a simple tool for the Framingham risk equation, the majority of physicians are not routinely implementing Framingham risk assessment in their offices, when they see patients.




They are not assessing risk.


Dr. Ballantyne: They are not assessing risk quantitatively using the Framingham algorithm. Now, physicians do count risk factors: it's very simple; you don’t even need a pencil, a piece of paper, or a calculator, so that’s a practical part of the guidelines. I think that works fairly well and practitioners do implement it.

In addition, physicians find it pretty easy to recognize the metabolic syndrome. They routinely look at weight and height and take note of increased waist circumference, and if a patient also has a high triglyceride level, a low HDL-C level, and high blood pressure, they can make the diagnosis of metabolic syndrome.

So if in fact practitioners are not using the Framingham equation, then by looking at the metabolic syndrome they are picking up people who without any doubt have increased risk for cardiovascular events.



But it's not better than Framingham.


Dr. Ballantyne: It’s not better than Framingham for assessing cardiovascular risk, but these patients also have increased risk for the development of diabetes, and I think that is really a critical issue. We really do a terrible job of identifying people at high risk for diabetes, warning them that they are on the way to developing diabetes, and helping them make the lifestyle modifications that we know are effective in prevention.

If we are going to try to do that also, we have to use a second equation, to calculate risk for diabetes, and this has not been put into practice. We looked at this in the ARIC study,9 and found that you can use multiple terms and complicated equations or can just use the metabolic syndrome criteria, giving double weight to glucose. Peter Wilson and his coworkers, in a report that came out just after this, from the Framingham study,10 clearly show that metabolic syndrome is really a very powerful predictor of diabetes, with relative risk ratios exceeding 4 in both sexes.

What we are saying, then, is that this is a simple-to-use, practical tool to identify people with increased risk for diabetes and heart disease—and you needn’t use the term “metabolic syndrome” if you don’t like it; some people are saying “increased cardiometabolic risk.” We see many such individuals in our practices, and I think it is a useful concept to identify people whom we need to be working with more closely to reduce their risk.



How do you counsel and manage patients like these?


Dr. Ballantyne: One of the things that I like about this metabolic syndrome concept is that it's easy to explain to a patient. It’s not hard to ask patients if they’ve gained weight since they were in college. The answer is always yes. Where did they gain the weight? In the abdomen? I ask the patient to stand up and tighten the abdominal muscles. I press on the skin and say, “You know, I can feel the muscles right below the skin— where is the fat? Well, it's inside the abdomen. And what are the organs back in there? They’re the pancreas and the liver. Those are what controls insulin, glucose, and lipid metabolism.” And I explain, “It's not by chance that you end up having high triglyceride or high glucose levels, low HDL-C levels, or insulin resistance. These are linked metabolic abnormalities, and the link is your problem with this fat.”

They say, “Oh, I thought it was just bad luck”; and they start to get it. In 18 years of practice, I have asked every patient who has high triglycerides the same questions: What are triglycerides for? What are they? I explain that there are three things in the diet: fat, carbohydrates, and protein. Most people understand that—protein is the building blocks for muscle and other tissues, carbohydrates are for energy; and when I remind them that fats are for energy also and that you have 9 calories per gram of fat versus 4 calories per gram of carbohydrate, they remember that. Then I ask, how do you transport fat in your circulation? They almost always say, “I don’t know,” and then I say, “Well, that’s what triglycerides are, 3 fatty acids stuck to a glycerol molecule—it's the way you transport fat in your circulation. Now let's look at your problem. You have a high triglyceride level, you have a high glucose level, and you have all this extra fat in your abdomen. You've got a problem with energy metabolism.” It's as if a light bulb went on, and they say, “Oh, that’s what’s going on here. You know, it does seem as though I had some problems with my metabolism.” “Yes, you do,” I say, and I ask them how they think they would address that. “Well, I guess I would have to burn up more calories by exercise.” Then, if we go through the explanations of what's involved with their glucose and triglyceride problem, what they should watch in their diet—it's not too hard to figure out, sugars, carbohydrates and fat—it all takes about five minutes, and it usually at least gives people, in a simplified model, reasonably accurate information about why these factors are clustered. And it helps them understand that in fact their actions play a key role in their metabolic abnormalities.




What sort of intervention do you usually first recommend?


Dr. Ballantyne: Lifestyle modification. In particular the Diabetes Prevention Program11 showed that walking 30 minutes a day 6 days a week combined with dietary changes, with average weight loss of 5% or 7%, led to a reduction in diabetes of approximately 60%. Why are we not giving that information to our patients who need it most, the high-risk patients? When you tell them that 30 minutes of exercise 6 times a week is enough, and that they only have to lose 5% of body weight, and that reduces diabetes by 50%—for most people this is new, they've never heard of that, and they say, “Well, I think I can do that.” I find it's very motivational. I have a family history of diabetes on both my mother's and my father's side, and that motivates me to get my 180 minutes of exercise every week. So we start off with that, we really have to educate, emphasize it, give a prescription for exercise and set a target for their weight, and also discuss dietitians, Weight Watchers—there are lots of practical things for people to do. And beyond lifestyle modification alone, lifestyle modification and pharmacotherapy together have been shown to be successful in preventing cardiovascular disease and diabetes.



For whom and when do you consider pharmacologic therapy?


Dr. Ballantyne: I think that, particularly as patients become older, if someone develops, for example, hypertension that may not quite reach the 10% risk cutoff, we should consider pharmacologic therapy, particularly for those who are not successful with lifestyle modification. The ASCOT study,12 which enrolled hypertensive patients with multiple risk factors, clearly showed that a statin reduced events—the overall event rate in that study was actually a little less than 1% a year. The AFCAPS/TexCAPS study,13 which included patients with low HDL-C levels, who also tend to have these clusters of abnormalities, showed that statin therapy was beneficial. There have been some post-hoc analyses of data for patients with metabolic syndrome, but it is primarily data for patients with low HDL-C levels and hypertension that show benefit, and if we know that the main drivers of risk tend to be low HDL-C levels and hypertension, it's pretty clear in my mind that even though we haven't had a study enrolling patients specifically by metabolic syndrome criteria, statins will benefit these patients with regard to reduction of cardiovascular risk.

Beyond using statins, blood pressure should be well treated. We have some very interesting data from ASCOT,14 showing that the way hypertension is treated may also influence the risk for developing diabetes and the lipid response to treatment. That study used a calcium channel blocker, amlodipine, followed by an ACE inhibitor and then by a long-acting alpha blocker, and this regimen was clearly superior to the traditional approach using the beta blocker–diuretic combination. So we should give our attention to good blood pressure control and perhaps be more careful to use agents that do not adversely affect lipids, insulin, and glucose metabolism.

These are the two cornerstones. Furthermore, for a man at higher risk or an older woman, consider aspirin. Data for younger women do not currently support the use of aspirin.



How about pharmacologic therapy for the prevention of diabetes?


Dr. Ballantyne: Here we get to the controversy about pharmacologic therapy for the prevention of diabetes. We certainly have some data indicating that metformin was successful in this.15 There is some evidence that PPAR-? [peroxisome proliferator-activated receptor gamma] agonists should have benefit here,16 and there are some new therapies in development that may also be beneficial. But I think we perhaps need more data regarding the overall long-term outcomes with some of the PPAR-? agonists before we go beyond the current indications of lowering glucose in a patient with diabetes.



In summary, after all these recent position statements and controversy, what is, in your opinion, the bottom line for the clinician concerning the utility of the diagnosis of metabolic syndrome?


Dr. Ballantyne: It is a useful clinical tool for risk assessment, because it is simple and something everyone can do in the office, and we know that if we target these patients’ obesity rather than treating each risk factor individually, their cardiovascular risk will be reduced. I agree with certain points raised by the ADA about treating metabolic syndrome as a disease, and I am not saying that we should treat it as a disease, but we must use it as a simple means of identifying people with a clustering of abnormalities that increase their risk for cardiovascular disease and diabetes. When we talk about high ADA, for example, speaks about prediabetes. What is prediabetes? We don't talk about pre–heart attack. Rather than try to create a disease state, I would prefer to say simply that it is a useful construct to identify individuals with high cardiovascular risk. In their position paper, the ADA ignored this, as well as the utility for identifying people at risk for diabetes. I do agree with them that it could be misused, and would say that the target of therapy may not be metabolic syndrome itself so much as it is the high risk for cardiovascular events and diabetes that is associated with metabolic syndrome.



References

1. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004;350:1387-1397.

2. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837-842.

3. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;263:2893-2898.

4. 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;285:2486-2497.

5. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752.

6. Kahn R, Buse J, Ferrannini E, et al. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28:2289-2304.

7. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities study. Diabetes Care. 2005;28:385-390.

8. Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.

9. Duncan BB, Schmidt MI, Pankow JS, et al. Low-grade inflammation and the development of type 2 diabetes. The Atherosclerosis Risk in Communities study. Diabetes. 2003;52:1799-1805.

10. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112:3066-3072.

11. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25:2165-2171.

12. Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial—lipid-lowering arm (ASCOT-LLA). Diabetes Care. 2005;28:1151-1157.

13. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.

14. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906.

15. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

16. Plutzky J. Medicine. PPARs as therapeutic targets: reverse cardiology? Science. 2003;302:406-407

Metabolic Syndrome, Diabetes, and Cardiovascular Disease ... Metabolic Syndrome, Diabetes, and Cardiovascular Disease .

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Prevalence of the Metabolic Syndrome in Latin America and
its association with sub-clinical carotid atherosclerosis: the
CARMELA cross sectional study

Jorge Escobedo*1,2, Herman Schargrodsky3, Beatriz Champagne4,
Honorio Silva5, Carlos P Boissonnet6, Raul Vinueza7, Marta Torres8,
Rafael Hernandez9 and Elinor Wilson10

Address: 1Medical Research Unit on Clinical Epidemiology, Mexican Social Security Institute, Mexico City, Mexico, 2Gabriel Mancera 222m Col.
Del Valle, 03100 Mexico City, Mexico, 3Department of Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, 4InterAmerican
Heart Foundation, Dallas, Texas, USA, 5InterAmerican Foundation for Clinical Research, New York, New York, USA, 6Coronary Care Unit, Centro
de Educación Médica e Investigaciones Clínicas "Norberto Quirno," Buenos Aires, Argentina, 7Clinical Protocol Manager Canada/Latin America/
Africa/Middle East Region Worldwide Development Operations, Pfizer Inc., New York, New York, USA, 8Programa Buenos Aires de Control de
Calidad Externo-CEMIC, Buenos Aires, Argentina, 9Clinical Pharmacology Unit and Hypertension Clinic, School of Medicine, Universidad
Centroccidental "Lisandro Alvarado," Decanato de Medicina, Barquisimeto, Venezuela and 10Department of Community and Preventive Health,
School of Medicine & Dentistry, University of Rochester, Rochester, New York, USA
Email: Jorge Escobedo* - jorgeep@unam.mx; Herman Schargrodsky - bubyscha@fibertel.com.ar;
Beatriz Champagne - beatriz.champagne@interamericanheart.org; Honorio Silva - honorio.silva@globecpd.org;
Carlos P Boissonnet - pboisson@intramed.net.ar; Raul Vinueza - Raul.Vinueza@pfizer.com; Marta Torres - progba@cemic.edu.ar;
Rafael Hernandez - rahernandez001@msn.com; Elinor Wilson - elinor_wilson@ahrc-pac.gc.ca
* Corresponding author

Abstract
Background: Metabolic syndrome increases cardiovascular risk. Limited information on its
prevalence in Latin America is available. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study included assessment of metabolic syndrome in 7 urban Latin American populations.
Methods: CARMELA was a cross-sectional, population-based, observational study conducted in Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. The prevalence of metabolic syndrome, defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and associated carotid atherosclerosis were investigated in 11,502 participants aged 25 to 64 years.
Results: Across CARMELA cities, metabolic syndrome was most prevalent in Mexico City (27%) and Barquisimeto (26%), followed by Santiago (21%), Bogota (20%), Lima (18%), Buenos Aires (17%), and Quito (14%). In nondiabetic participants, prevalence was slightly lower but followed a comparable ranking. Overall, 59%, 59%, and 73% of women with high triglycerides, hypertension, or glucose abnormalities, respectively, and 64%, 48% and 71% of men with abdominal obesity, hypertension, or glucose abnormalities, respectively, had the full metabolic syndrome. Prevalence of metabolic syndrome increased with age, markedly so in women. Mean common carotid artery intima-media thickness (CCAIMT) and prevalence of carotid plaque increased steeply with increasing numbers of metabolic syndrome components; mean CCAIMT was higher and plaque more prevalent in participants with metabolic syndrome than without.
Conclusion: The prevalence of metabolic syndrome and its components by NCEP ATP III criteria was substantial across cities, ranging from 14% to 27%. CARMELA findings, including evidence of the association of metabolic syndrome and carotid atherosclerosis, should inform appropriate clinical and public health interventions.

Background
The concept of the metabolic syndrome has developed in stages over the past 80 years; it is now recognized that the combination of abdominal obesity, glucose metabolism abnormalities, hypertension, and dyslipidemia, accompanied by prothrombotic and proinflammatory states, leads to type 2 diabetes and vascular diseases, including coronary heart disease and stroke [1,2]. Metabolic syndrome predicts total, cardiovascular, and coronary heart disease mortality; in fact, the presence of even 1 or 2 components of the metabolic syndrome increases overall mortality compared with the absence of any component of the metabolic syndrome [3-6]. A 65% excess risk has been estimated for cardiovascular disease in individuals with the metabolic syndrome [7]. Metabolic syndrome even predicts the occurrence of sudden death, independent of the presence of other cardiovascular risk factors [8]. Metabolic syndrome also predicts the incidence and progression of carotid atherosclerosis [9].
As reviewed recently, worldwide prevalence of metabolic syndrome ranges from <10%>to as much as 84%, depending on age, region, urban or rural environment, ethnicity, and the definition of metabolic syndrome used [10-12]. In the United States, between 1994 and 2000, prevalence
of metabolic syndrome in adults increased from 23% to 27% along with an increase in obesity and physical inactivity [13]. Developing regions like Latin America, undergoing
sea change in the lifestyle factors contributing to the metabolic syndrome, may see even greater increases in prevalence over a relatively short span of time. Local public health and clinical efforts to stem morbidity and mortality from the metabolic syndrome must be based on the
relevant local prevalence of its components. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study investigated risk factors for cardiovascular isease in 7 Latin American cities, as reported elsewhere [14]. With cardiovascular risk and clinical interventions in mind, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [2] were used to assess metabolic syndrome prevalence in CARMELA cities. The association of metabolic syndrome with mean common carotid artery intimamedia thickness (CCAIMT), as a marker of carotid atherosclerosis, was also investigated.
Methods
Study Design
CARMELA was a multistage, cross-sectional epidemiologic study conducted between September 2003 and August 2005, in Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. The study was conducted according to the Declaration of Helsinki and the Guides for Good Clinical Practice. Approximately 1,600 participants per city between the ages of 25 and 64 years were included, stratified by sex and age (10- year groups). The study was approved by an institutional review committee in all participating cities, and all subjects gave informed consent. Study methods are described in detail elsewhere [14].
Anthropometry
Waist circumference was measured at the midpoint between the last rib and the iliac crest with participants standing and wearing only undergarments.
Blood Glucose and Lipids
Participants were asked to refrain from using laxatives containing glycerin for 48 hours and from consuming glycerin-containing products and other sweets for 24 hours prior to blood sampling. Blood was drawn in the fasting state; only water, black coffee, or unsweetened tea and medications other than antidiabetic medications were permitted during the 12 hours prior to sampling. Following the sampling, participants were allowed to resume their usual antidiabetic medication. Plasma glucose was assayed within 6 hours. Serum was assayed for high density lipoprotein cholesterol and triglycerides.
Blood Pressure
Blood pressure (at rest) was measured with the participant seated. Two readings were taken 5 minutes apart; if different by >5 mm Hg, measurements were repeated until 2
concordant readings were obtained.
Measurement of CCAIMT
Far wall CCAIMT was evaluated according to the Mannheim intima-media thickness consensus [15]. Both common carotid arteries were examined by B-mode ultrasonography with participants in the supine position, using phased array 7.5 MHz transducers and ultrasound apparatus no older than 7 years. M'AthStd® software (Intelligence in Medical Technologies, Paris, France) automatically measured the CCAIMT; measurements were taken over a 10 mm length and averaged, and quality of acquisition was evaluated. Data were analyzed at a central
laboratory at Intelligence in Medical Technologies, Paris, France.
Definitions
Diabetes was defined as a fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dL) [16] or self-reported diabetes. Metabolic syndrome was defined by NCEP ATP III criteria as the presence of 3 or more of the following: waist >102 cm in men, >88 cm in women; triglycerides ≥ 1.70 mmol/
l (150 mg/dL); high density lipoprotein cholesterol (HDL-C) <1.03>Statistical Analysis
Statistical processing addressed the nonequal probability character of the sample and the structure of the design to generate data adjusted for the age and sex distribution of the population of each city. Means and prevalence along with their 95% confidence intervals were estimated by survey analysis procedures (SAS Software, Release 9.1, Cary, North Carolina, USA), taking into account the multistage stratified sampling design via CLUSTER and STRATA statements.

Results
A total of 11,550 participants between the ages of 25 and 64 years were enrolled in CARMELA between September 2003 and August 2005. Data for 11,502 participants were evaluable for metabolic syndrome: Barquisimeto, n = 1,836; Bogotá, n = 1,550; Buenos Aires, n = 1,476; Lima, n = 1,645; Mexico City, n = 1,720; Quito, n = 1,627; and Santiago, n = 1,648. Per the study design, age and sex distribution was relatively even for each city.
Prevalence of the Metabolic Syndrome in the Overall CARMELA Population
Metabolic syndrome was most prevalent in Mexico City (27%) and Barquisimeto (26%), followed by Santiago (21%) and Bogota (20%); lower prevalence was found in Lima (18%), Buenos Aires (17%), and Quito (14%). Overall, metabolic syndrome was more prevalent in women than men (22% vs 20%, respectively), with the exception of Buenos Aires and Barquisimeto where more men than women had metabolic syndrome. As expected, the prevalence of metabolic syndrome increased with age. In all cities, women showed markedly greater increase in metabolic syndrome with increasing age than men; in the oldest age group, female prevalence (range 25% to 49%) was greater than male prevalence (range 13% to 38%) in all cities except Buenos Aires (See Table 1 and Figure S1 in additional file 1). Of components of metabolic syndrome, the abdominal obesity was notably more prevalent in women than men, and the difference was accentuated in successively older age groups.
Prevalence of Specific Components of the Metabolic Syndrome
reports the prevalence of each component of the metabolic syndrome within the population of all participants with metabolic syndrome (with or without a history of diabetes mellitus). Overall, 86% had high triglycerides, 86% had low HDL-C, and 60% were hypertensive. Across cities, abdominal obesity was present in 81% to 93% of women, and in 46% to 73% of men with metabolic syndrome.
Prevalence of the Metabolic Syndrome in Participants With Specific Components
Prevalence of the metabolic syndrome in subsets of the overall population with specific components of the syndrome. Overall, approximately twothirds of men with abdominal obesity or glucose abnormalities, and approximately 60% to 70% of women with high triglycerides, hypertension, or glucose abnormalities had the full metabolic syndrome. In all cities except Mexico City, the prevalence of metabolic syndrome among participants with low HDL-C was fairly low. Prevalence of the syndrome among women with high triglycerides was notably higher than among men in all cities except Barquisimeto and Buenos Aires.
Prevalence of Metabolic Syndrome Among Participants Without Diabetes
reports the prevalence of the number of components of the metabolic syndrome among CARMELA participants without a history of diabetes mellitus. In all cities, >60% of the participants had at least 1 component of the metabolic syndrome. As in the overall CARMELA
population, the prevalence of metabolic syndrome in the nondiabetic population was higher in women than men, except in Barquisimeto and Buenos Aires.
Metabolic Syndrome and Carotid Atherosclerosis
In both men and women overall, mean CCAIMT increased steeply with increasing numbers of metabolic syndrome components . Similarly, the prevalence of carotid plaque
also increased with increasing numbers of components and overall, was approximately 50% more prevalent in both men and women with metabolic syndrome than those without. In all cities, mean CCAIMT and prevalence of plaque were higher in participants with metabolic syndrome than those without.

Discussion
The CARMELA study reports overall prevalence of 21% of metabolic syndrome by NCEP ATP III criteria in the 7 Latin American cities studied. Profiles of the metabolic syndrome according to sex varied among cities. Among the overall population and the nondiabetic population, the highest prevalence of metabolic syndrome was found in Barquisimeto and Mexico City. Women of Bogota, Lima, Quito, and Santiago had greater prevalence of metabolic syndrome than their male counterparts, while the opposite was true in Buenos Aires. Not surprisingly, prevalence
of metabolic syndrome increased with age, strikingly so in women. Participants with metabolic syndrome had higher mean CCAIMT and prevalence of carotid plaque than those without the syndrome.
The prevalence of metabolic syndrome found in CARMELA approximates prevalence estimates (23% to 27%) in the United States [6,13]. Direct comparison with other Latin America studies using NCEP ATP III criteria show CARMELA prevalence to be consistent with prevalence in
Mexico [17,18]. Also by NCEP ATP III criteria, 31% of a population of Zulia State, Venezuela [19], and 12% and 26% of men and women of Lima [18], respectively, were found to have metabolic syndrome. CARMELA reports lower prevalence in Barquisimeto than elsewhere in Venezuela, and prevalence that is less disparate between the sexes of Lima; however, CARMELA targeted a much broader population base than in the aforementioned
study in Lima. In the Peruvian Study of the Prevalence of Cardiovascular Risk Factors (PREVENCION) study in another urban region of Peru, 14% and 23% of men and women, respectively, were found to have the syndrome [20].
Whereas it has been suggested that the burden of metabolic syndrome is growing in younger populations, especially in developing regions [21], metabolic syndrome increases with age as CARMELA results confirm. Elevated body weight, waist circumference, and low HDL-C levels have been found to be more common contributors to metabolic syndrome in women, while blood pressure and apolipoprotein B have been found to be more common contributors in men [22]. Obesity in women is increasing faster than in men [23] and the metabolic syndrome
increases in a parallel manner. In many women, menopause is accompanied by the emergence of features of the metabolic syndrome and increased cardiovascular risk, whether as a direct result of ovarian failure or indirectly related to central adipose redistribution [23,24]. With this constellation of factors, it has even been suggested that the metabolic syndrome should be defined by different criteria in men and women [22]. CARMELA results illustrate the amplified increase in metabolic syndrome in women as opposed to men as women reach menopausal age. A study of post-menopausal Ecuadorian women [25] revealed an overall prevalence of metabolic syndrome of 42%, similar to that found in CARMELA, with prevalence of hypertension, abdominal obesity, and low HDL-C similar to that in women in the older 2 CARMELA age groups.
In a broader study of postmenopausal Latin American women, rates of metabolic syndrome in women of Bue-nos Aires were higher and those of Bogota, Lima, and Santiago, similar to those of women in the oldest 2 CARMELA age groups [26]. Although in all CARMELA cities, older
women showed strikingly higher abdominal obesity rates than men, high rates of abdominal obesity were found in women of all age groups. In designing targeted programs for detection and treatment of metabolic syndrome, CARMELA provides crucial data on the sensitivity and predictive value of each component. On the one hand, of the general population of men in CARMELA cities (except for Quito where lower prevalence of metabolic syndrome in men is noted), approximately 70% of those with glucose abnormalities, approximately two-thirds of those with abdominal obesity, and half with hypertension, will have the full syndrome. Of the general population of women in CARMELA cities, nearly three-quarters of those with glucose abnormalities, and approximately 50% to 60% with abdominal obesity, high triglycerides, or hypertension, will have the full metabolic syndrome. On the other hand,
once metabolic syndrome is diagnosed, the shape of the syndrome is characterized by predominance of hypertension, low HDL-C and high triglycerides in men, and predominance
of abdominal obesity, high triglycerides, and a remarkable predominance of low HDL-C in women. Thus, hypertension, low HDL-C, and high triglycerides in men and low HDL-C in particular, along with high triglycerides and abdominal obesity in women, are highly specific indicators of the syndrome. CARMELA provides data which confirms the likelihood of finding other specific components, once metabolic syndrome is diagnosed. Although the metabolic syndrome predicts diabetes along with cardiovascular risk, glucose abnormalities in and of themselves are not particularly specific to the full syndrome. This notion is confirmed by the similar prevalence of metabolic syndrome in CARMELA populations that both include and exclude diabetes. Since the metabolic syndrome is epitomized by the development of diabetes,
its presence in the nondiabetic population is of particular importance.
To our knowledge, this is the first study that provides evidence
of a relationship between the occurrence of the metabolic
syndrome and the presence of carotid
atherosclerosis in the Latin American population. A large study in Italy reported increased incidence of carotid plaques and stenosis over 5 years of follow-up in participants with metabolic syndrome [9]. Metabolic syndrome has also been associated with incident stroke in both
black and white populations in the United States [6] and with higher carotid intima-media thickness and prevalence of plaques in elderly French individuals [27]. Metabolic syndrome has also been associated with tissue characteristics of the intima-media complex in the carotid
artery [28], and the increasing number of components of the metabolic syndrome have also been related to higher carotid artery stiffness [29]. In other studies, the association between metabolic syndrome and carotid atherosclerosis has been reported to be stronger in women than men [30], however, in the CARMELA study it seems to be quite similar for men and women. Carotid intima-media thickening
as an indicator of atherosclerosis in other vascular beds [31] is a strong predictor of future cardiovascular events [32]. The relationship between metabolic syndrome
and carotid atherosclerosis noted in CARMELA enhances previous findings of metabolic syndrome as a cardiovascular disease predictor [3,7,9].
The value of CARMELA lies in its carefully constructed
sampling of populations by age and sex to elucidate prevalence of metabolic syndrome components. Urban vs rural and ethnic differences in prevalence of metabolic syndrome have been reported in a variety of Latin American settings [33] and should be investigated further.
Genetic predispositions to the metabolic syndrome [34], along with cultural and nutritional variations, also need investigation given Latin America's unique conglomeration of indigenous and immigrant populations. The obesity epidemic clearly affects the prevalence of metabolic
syndrome among women but also extends to the young; CARMELA's lowest age range (25 to 34 years) may not have fully encompassed populations at risk, nor did CARMELA include increasingly older populations, which until now have borne the brunt of chronic disease. Rigorous studies like CARMELA should aid in designing targeted solutions to increasing rates of metabolic syndrome and its consequences.
In the Shape of the Nations Survey, 39% of participants worldwide who visited primary care physicians were overweight or obese, but only 58% of primary care physicians recognized that abdominal obesity was a significant risk factor for cardiovascular disease, and 45% reported that
they never measured waist circumference [35]. As alarming as these statistics are, CARMELA findings reinforce the notion that metabolic syndrome is prevalent in urban Latin America and should be sought in the presence of even 1 component of the syndrome. Likewise, carotid
atherosclerosis in Latin American individuals should spur healthcare providers to seek evidence of metabolic syndrome components and effect appropriate interventions. Guidelines for treatment of specific components in the context of the full metabolic syndrome are being developed [2] and should be promoted by healthcare educators and providers. The chronic disease burden consequent to metabolic syndrome will be extensive and expensive in
Latin America if studies like CARMELA are ignored.

Conclusion
CARMELA reports high prevalence of metabolic syndrome in 7 Latin American cities. Although rates varied between cities, there was a striking increase in the prevalence of metabolic syndrome with age, especially in women. CARMELA provides evidence for the association
of metabolic syndrome with evidence of carotid atherosclerosis-- namely increasing mean CCAIMT and plaque with increasing numbers of components of the syndrome,
and overall higher mean CCAIMT and plaque in participants with the syndrome compared with those without. It is incumbent on government agencies and the medical community to address current prevalence of metabolic syndrome in order to prevent the dire consequences of
increased burden of disease.

Competing interests
RV is a permanent employee of Pfizer Inc, makers of a
cholesterol-regulating drug, and has shares in the company.
HS was an employee of Pfizer, Inc. during the conduct
of the study (now retired). All other authors declare
no competing interests.

Authors' contributions
JE participated in the design and coordination of the study
and drafted the manuscript. HSc conceived of the study,
and participated in its design and coordination and
helped to draft the manuscript. BC conceived of the study,
and participated in its design and coordination and
helped to draft the manuscript. HSi conceived of the
study, and participated in its design and coordination and
helped to draft the manuscript. CPB participated in the
design and coordination of the study and helped to draft
the manuscript. RV participated in the design and coordination
of the study and helped to draft the manuscript.
MT carried out the lab standardization. RH conceived of
the study, and participated in its design and coordination
and helped to draft the manuscript. EW conceived of the
study, and participated in its design and coordination and
helped to draft the manuscript.
All authors read and approved the final manuscript.

Acknowledgements
The authors would like to thank participating institutions, coordinators, and
investigators: Asociación Cardiovascular Centro Occidental (Barquisimeto)
- Lic. Elizabeth Infante, Luis Rocha; Pontificia Universidad Javeriana
de Bogota (Bogota) - Álvaro Ruíz Morales, Esperanza Peña, Felipe Uriza;
Centro de Educación Medica e Investigaciones Clinicas "Norberto
Quirno"(Buenos Aires) - Carlos Boissonnet, Juan Fuselli, Víctor Torres;
Universidad Cayetano Heredia (Lima) - Raúl Gamboa-Aboado, Carlos
Kiyán, Mario Vargas; Instituto Mexicano del Seguro Social (Mexico City) -
Jorge Escobedo-de la Peña, Luisa Virginia Buitrón, Jesús Ramírez-Martínez;
Hospital Metropolitano de Quito (Quito) - Francisco Benítez, María
Velasco, Luis Falcóni; Pontificia Universidad Católica de Santiago de Chile
(Santiago) - Ximena Berrios-Carrasola, Beatriz Guzmán, Mónica Acevedo.

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editorial
Calcific Aortic Stenosis — Time to Look More Closely at the Valve

Catherine M. Otto, M.D.

Calcific aortic stenosis is a progressive disease that results in stiff valve leaflets with eventual obstruction to left ventricular outflow. Once symptoms occur, valve replacement is the only effective treatment, and there are no known therapies to prevent disease progression. However, several lines of evidence suggest that calcific valve disease is not simply due to age-related degeneration but, rather, is an active disease process with identifiable initiating factors, clinical and genetic risk factors, and cellular and molecular pathways that mediate disease progression.
The key initiating factor in the development of calcific aortic stenosis appears to be mechanical
stress. Specifically, a congenitally bicuspid valve, which is present in about 0.5 to 0.8% of
the population, is the underlying anatomy in the majority of valve replacements for aortic stenosis. [1] Blood-flow dynamics may also play a role, since early lesions are located on the aortic side of the valve in regions with low shear stress.
Clinical factors that are associated with the presence of calcific valve disease include older
age, male sex, elevated serum levels of low-density lipoprotein and lipoprotein(a), smoking, hypertension, diabetes, and the metabolic syndrome.[2]
The presence of mild valve changes, even in the absence of obstruction to blood flow, is associated with an increase of 50% in the risk of myocardial infarction and death from cardiovascular causes during the next 5 years. Genetic factors are difficult to study in a disease that often is not evident until the sixth or seventh decade of life. However, in a subgroup of families, a bicuspid valve appears to be inherited in an autosomal dominant pattern. In one study in France, familial clustering of calcific disease in trileaflet valves also was shown. Mutations in the signaling and transcriptional regulator NOTCH1 gene have been
identified in families with bicuspid aortic valves and leaflet calcification.[3] Case–control studies
have suggested an association between calcific aortic stenosis and genetic polymorphisms in
the vitamin D receptor, estrogen receptor, apolipoprotein E4, and interleukin-10 alleles.
Our understanding of disease progression at the tissue level is based on human valve studies
of either early lesions or end-stage disease, with the assumption that these processes represent
the ends of a disease spectrum .[4,5] Experimental models support this assumption, with
the demonstration that valve lesions occur in the presence of hypercholesterolemia, resulting in
leaflet calcification and valve obstruction.[6] Taken together, the association of calcific aortic stenosis with elevated serum lipid levels, the presence of lipid accumulation in the leaflets, and the increased risk of atherosclerotic clinical end points all lead to the hypothesis that lipid lowering therapy might slow or prevent disease progression. This hypothesis was supported by several retrospective clinical studies indicating slower hemodynamic progression or leaflet calcification in patients who were receiving lipid-lowering medications than in control subjects and by experimental models showing that lipid-lowering therapy blocks the development of valve lesions.[7]
Thus, the results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study (ClinicalTrials. gov number, NCT00092677) that are reported in this issue of the Journal8 are disappointing. In this large, randomized, prospective clinical trial, Rossebø et al. convincingly show that aggressive lipid lowering does not affect either hemodynamic progression or the time to valve replacement in adults with aortic stenosis.[8] Although it is possible that treatment even earlier in the disease process might have some benefit, the study patients
had only mild-to-moderate disease. Other than those with a bicuspid valve or specific genetic
markers, earlier identification of patients at risk would be problematic. The reduction in
atherosclerotic clinical end points in this study is encouraging. However, the clinical effect was
small, given that benefit was primarily due to a reduced rate of coronary bypass grafting at the
time of valve replacement.
If intensive lipid-lowering therapy is not the answer to the prevention of aortic stenosis progression, where do we go from here? Many adults with calcific valve disease meet current indications for lipid-lowering therapy, and the SEAS study certainly supports the evaluation and reduction of risk factors in patients with aortic stenosis, as recommended for all adults by established guidelines. However, we can no longer reassure ourselves that either the lipid-lowering or pleiotropic effects of potent agents such as statins and ezetimibe might change the disease process in the valve leaflets. We need to explore other potential therapeutic targets, especially the pathways that lead to tissue calcification. Calcific aortic stenosis is not atherosclerosis. Although there is overlap in clinical risk factors, in tissue characteristics, and in the association between the presence of calcific valve disease and atherosclerotic clinical events, there also are major differences. In aortic valve stenosis, tissue calcification is more severe; the mechanism of clinical events is increased leaflet stiffness, not plaque rupture; and the severity of coronary and valve disease in an individual patient often is discordant.
Demonstrating clinical benefit of potential therapies for calcific aortic stenosis will be challenging.
The evaluation of clinical end points requires a large study group, and enrollment in prospective, randomized trials is slow, given the relatively low prevalence of valve disease. Calcific valve disease progresses slowly over decades, whereas clinical trials usually follow patients for
only a few years. Clinical end points often are difficult to assess because indications for valve
replacement remain somewhat subjective and because therapy may affect other cardiovascular
end points, which limits our understanding of the mechanism of benefit. Doppler echocardiography allows assessment of the effect of therapy on the degree of stenosis, but it is not perfect, because hemodynamic obstruction occurs only with a substantial amount of leaflet thickening. The ideal end point for measuring the effect of therapy would be direct evaluation of tissue changes in the valve leaflets. Such analysis is possible in experimental models but in humans is limited to the examination of leaflets removed at the time of valve surgery.[9] Computed tomographic imaging allows measurement of leaflet calcification but not of other tissue components. In the future, molecular imaging approaches may provide sensitive measures of tissue changes sequentially over time, allowing detection of significant differences between small study groups.[10]
It is time to integrate and expand our understanding of the interactions between initiating
factors, genetic and clinical cofactors, and the mechanisms of progression from an early inflammatory lesion to phenotypic transformation of valve myofibroblasts and then to the end stage of severe valve calcification. Discovery of an effective medical therapy for calcific aortic stenosis will require innovative approaches to disease prevention and ingenuity in proving the mechanism of benefit.
From the Division of Cardiology, Department of Medicine, University
of Washington, Seattle.
1. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid,
and tricuspid aortic valves in adults having isolated aortic
valve replacement for aortic stenosis, with or without associated
aortic regurgitation. Circulation 2005;111:920-5.
2. Katz R, Wong ND, Kronmal R, et al. Features of the metabolic
syndrome and diabetes mellitus as predictors of aortic
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Diet, Exercise and the Metabolic Syndrome

Christos Pitsavos1, Demosthenes Panagiotakos2, Michael Weinem3 and Christodoulos Stefanadis1

1 First Cardiology Clinic, School of Medicine, University of Athens, Athens, Greece. 2 Department of Nutrition and Dietetics,
Harokopio University, Athens, Greece. 3 Society for Biomedical Diabetes Research, Duisburg, Germany. Address correspondence to: Demosthenes B. Panagiotakos, e-mail: d.b.panagiotakos@usa.net

■ Abstract
The metabolic syndrome is a combination of metabolic disorders, such as dyslipidemia, hypertension, impaired glucose tolerance, compensatory hyperinsulinemia and the tendency
to develop fat around the abdomen. Individuals with the metabolic syndrome are at high risk for atherosclerosis and, consequently, cardiovascular disease. However, as a result of several epidemiologic studies and some clinical trials, it has been suggested that people with the metabolic syndrome may benefit from intensive lifestyle modifications including dietary changes and adopting a physically more active lifestyle. In this review we summarize the effects of diet and physical activity on the development of the metabolic syndrome.
Keywords: metabolic syndrome · diet · exercise · lifestyle

Defining the metabolic syndrome
he metabolic syndrome is a collection of conditions associated with metabolic disorder and increased risk of developing cardiovascular disease. Conditions such as dyslipidemia, high blood pressure, impaired glucose tolerance and abdominal fat accumulation
fall into this category [1-5]. Investigations were aimed at the establishment of a quantitative definition for the associated conditions. However, these efforts led to multiple definitions that are partly inconsistent and disputed.
The metabolic syndrome was first described in the 1940s by Jean Vague, who linked abdominal obesity to metabolic abnormalities. Three decades later, in the 1970s, Gerald Phillips, suggested that aging, obesity and sex hormone-associated clinical manifestations, now referred to as the metabolic syndrome, are associated with heart disease [1]. More recently, in 1988, Gerald
Reaven proposed insulin resistance, and not obesity, as the critical factor and named the constellation of abnormalities Syndrome-X [2]. However, the most widely used definitions were established by the World Health Organization (WHO) and the National Cholesterol
Education Program Adult Treatment Panel III (NCEP ATPIII). These organizations regarded the metabolic syndrome as a cardiovascular risk factor beside elevated low-density lipoprotein (LDL) cholesterol [6, 7]. Atherogenic dyslipidemia (a prothrombotic state), insulin resistance, hypertension, abdominal obesity and elevated levels of various inflammatory markers were then regarded as the prominent characteristics of the metabolic syndrome [8]. Kim and Reaven
claimed that although WHO and NCEP ATPIII use the same term to define this condition (i.e., metabolic syndrome), both pursue different diagnostic aims and use different criteria to identify individuals, which relate to their different institutional goals [9]. In contrast to the WHO definition, the NCEP ATPIII does not include the measurement of insulin and therefore may
fail to detect insulin resistance. Nevertheless, the NCEP ATPIII definition appears to be more predictive regarding the risk of developing the syndrome than the WHO definition, i.e. failure to detect insulin resistance need not be a disadvantage.
In 2005, the International Diabetes Federation (IDF) Epidemiology Task Force suggested a new definition for the metabolic syndrome, focusing on central obesity [10]. Comparing the three definitions with respect to their areas of use, the WHO criteria appear to be more suitable for research purposes, while the NCEP ATPIII and IDF criteria seem to be more useful for clinical practice. The latter require only fasting assessments of blood samples, while WHO criteria require oral glucose tolerance tests, which can meaningfully confirm insulin resistance but are less practical in epidemiological or clinical studies. In general, the NCEP ATPIII and IDF definitions give more weight to obesity and sedentary lifestyle, whereas the WHO emphasizes the importance of insulin resistance as an underlying etiology of the metabolic syndrome. The
common feature of all three definitions is that the definition of the metabolic syndrome should include characteristics of atherogenic dyslipidemia, insulin resistance, hypertension and obesity. However, only the IDF definition considers obesity as a prerequisite and takes into account that obesity in Asian and other populations differs in its definition from obesity in Europeans [10]. Nevertheless, each of the defining abnormalities may promote atherosclerosis independently,
but when clustered together, these metabolic disorders, beside elevated LDL cholesterol, are increasingly atherogenic and may substantially enhance the risk of cardiovascular disease. Because each independent factor of the metabolic syndrome can increase the individual’s cardiovascular risk, an integrated and comprehensive approach is necessary for people afflicted
with the syndrome.
It is now widely accepted that the treatment of hypertension, obesity and dyslipidemia should be primarily based on weight-loss diets and exercise programs to increase physical activity and to ameliorate progress of the symptoms. In this review we present a summary and assessment of the existing research regarding interventions in the metabolic syndrome and of epidemiologic
studies on diet and exercise in relation to the prevalence of the metabolic syndrome (or diabetes, which may lead to the development of the syndrome).

Epidemiology of the metabolic syndrome
In this section, we review studies on lifestyle changes and metabolic syndrome. However, first we examine the prevalence of this condition at the population level. It is supposed that a substantial proportion of individuals living in Western nations are afflicted with multiple metabolic abnormalities [3]. A recently published report by the NCEP ATPIII estimates that
at least 47 million Americans are afflicted with this condition and projects the number of US citizens with metabolic syndrome to be between 50 to 75 million in 2010 [11]. Considering Europe, Hu et al. from the DECODE Study group reported that the agestandardized
prevalence of the metabolic syndrome was 15.7% in men and 14.2% in women [12]. For the
Mediterranean region, Ferrannini et al. estimated that more than 70% of adults have at least one of the major characteristics of the metabolic syndrome [13]. In this context, the ATTICA Study, comprising 1,500 women and men from Greece, estimated the prevalence of the
metabolic syndrome at 25% in men and 15% in women [14]. Recently, Athyros et al., who considered a Northern Greek population, reported that the ageadjusted prevalence of the NCEP ATP III-defined metabolic syndrome was 25% whereas the IDFdefined prevalence was 43% [15]. Furthermore, the prevalence of the metabolic syndrome in a Portuguese population was 27% in women and 19% in men [16]. A very similar result was derived from an examination
of a Korean population, where the prevalence of the metabolic syndrome was 29% in men and 17% in women [17], while in another study of the same population the prevalence of the syndrome was only 13% in both men and women [18]. Differences in genetic background, dietary habits, levels of physical activity, population age and sex structure and levels of overand
under-nutrition may influence the prevalence of both the metabolic syndrome and its components worldwide. Nevertheless, all these epidemiologic studies
suggest that the prevalence of the syndrome is high worldwide. This could be due to increasing obesity and sedentary lifestyles and reflect the growing necessity for therapeutic intervention.

The role of diet in the treatment of the metabolic syndrome
The NCEP ATPIII suggested therapeutic lifestyle changes (TLC) in order to reduce the prevalence of the metabolic syndrome [11]. Among several factors related to lifestyle habits the beneficial effect of diet has already been highlighted in many clinical and epidemiological studies [19-29]. During the last decades increasing scientific evidence has emerged that protective
health effects can be obtained from diets that are rich in fruits, vegetables, legumes and whole grains, and which include fish, nuts, and low-fat dairy products. Such diets need not be restricted in total fat in take as long as energy intake does not exceed caloric expenditure and if they emphasize predominantly vegetable oils that have a low content of saturated fats
and partially hydrogenated oils. As the intake of specific nutrients may have different effects on the development of metabolic syndrome characteristics the following sections focus on separate nutrient groups in order to clarify their roles in disease and treatment.

Nutrients and the metabolic syndrome
Carbohydrate consumption has been a critical factor blamed for weight gain, obesity, diabetes, and a number of other diseases. It is important to recognize that such problems may be associated with the excess consumption of the wrong carbohydrates such as simple sugars (i.e., table sugar), but not with complex carbohydrates. Large proportions of complex carbohydrates
(such as potatoes, breads, corn, etc.) in the diet are recommended.
High-fiber diets have received considerable attention in recent years due to their association with decreased incidence of several metabolic disorders such as hypertension, diabetes, obesity, as well as heart disease and colon cancer.
Fat is a general term used to refer to oils, fats and waxes. Usually the daily energy intake consists of 30% fat, but no more than 10% of these calories should come from saturated (animal) fats. The residual energy should be obtained from polyunsaturated or monounsaturated
oils [27]. Saturated fats promote dyslipidemias and, consequently atherogenesis. The consumption of unsaturated fats, derived mostly from vegetable oils such as safflower, corn,
olive and soybean oil, may be able to prevent serious disorders, such as atherogenesis,
hypertension and consequently the metabolic syndrome.
Nutritional studies suggest that we only need relatively small amounts of protein for
good health. The requirements for adults are 0.8 grams per kilogram of body weight. Increased protein intake may be detrimental for obese persons and those with kidney disease [30].

Dietary patterns
Diets should include a balanced intake of nutrient elements [27]. During the past two decades a large body of evidence has related balanced dietary patterns, such as the Mediterranean, to lower mortality rates, decreased prevalence of some metabolic disorders (obesity, high blood pressure), as well as lower incidence of coronary heart disease and various types of cancer.
The Mediterranean dietary pattern has received much attention in the last ten years [22, 24-29, 31]. It is characterized by the use of olive oil, which is important not only because it has several beneficial properties, but also because it allows the consumption of large quantities of vegetables in the form of salads and equally large quantities of legumes in the form of cooked foods. Other essential components of the Mediterranean diet are wheat, olives and grapes, and their various derivative products. Total lipid intake may be high - around or in excess of 40% of total energy intake - however, the ratio of monounsaturated to saturated fats is much higher in the Mediterranean regions than in other places of the world. A potential explanation for the beneficial effect of this dietary pattern on human health is that it is low in saturated fat,
high in monounsaturated fat, mainly from olive oil, high in complex carbohydrates from legumes, and high in fiber, mostly from vegetables and fruits. The high content of vegetables, fresh fruits, cereals and olive oil guarantees a high intake of beta-carotene, vitamins C and E, polyphenols and various important minerals. These key elements have been suggested to be responsible
for the beneficial effect of this diet on human health [22]. Interestingly, during the last years, several researchers have associated the Mediterranean diet with improvements in the blood lipid profile (in particular HDL cholesterol and oxidized LDL), decreased risk of thrombosis (i.e., fibrinogen levels), improvements in endothelial function and insulin resistance, reduction in plasma homocysteine concentrations, and a decrease in body fat [24-29, 31].
Furthermore, antioxidants represent a common element in the Mediterranean diet and antioxidant action provides a plausible explanation for its apparent benefits [27]. It is known that wild edible greens frequently eaten in the form of salads and pies contain very high quantities of flavonoids. Although there is no direct evidence that these antioxidants are central to the benefits of the Mediterranean diet, indirect evidence from epidemiological data and an increasing understanding of their mechanisms of action suggest that antioxidants may play a major role. Recently, the ATTICA Study investigators showed that adherence to
the Mediterranean diet was associated with 20% lower odds of having the metabolic syndrome, irrespective of age, sex, physical activity, lipids and blood pressure levels [14].

The role of exercise
In the late 1970s several observational studies suggested that mortality or morbidity caused by atherosclerotic disease was inversely related to the individual’s physical activity status [32-40]. Even though exercise is considered a cornerstone in the treatment of diabetes, a condition that is strongly related to metabolic syndrome, only a few studies have investigated its relationship with cardiovascular disease risk in diabetic persons. In a sample of 492 diabetic men and women
from the National Health and Nutrition Examination Survey, followed-up for 2 years, Ford and DeStefano [36] found that inactivity in non-leisure time was significantly associated with higher rates of coronary death. Data from an average 8.2-year, prospective, follow- up of 8,715 men in a preventive medicine clinic in the USA demonstrated a higher risk of all-cause mortality
for unfit compared to fit persons, within each of three glycemic status levels [37]. See Table 2 for a summary of studies evaluating physical activity in relation to the metabolic syndrome or associated conditions.
In a sample of 1,263 diabetic men, followed-up for 12 years in the Aerobics Center Longitudinal Study, participants who reported being sedentary had an adjusted risk for mortality of 1.7 compared to those who were physically active [38]. In another sample of 5,125 diabetic nurses from the Nurses Health Study, after 14 years of follow-up, the investigators found a 45% multivariate- adjusted reduction in cardiovascular disease risk with moderate to vigorous activity compared to sedentary [39]. The Whitehall Cohort Study investigated the relation of two indices of physical activity - walking pace and leisure activity - to total mortality,
coronary heart disease and other cardiovascular diseases, in a 25-years follow-up of 6,408 male British civil servants [40]. Among 352 diabetic men and 6,056 non-diabetics at study entry, the investigators found that the two indices of physical activity were inversely related to all-cause, coronary heart disease and other cardiovascular disease mortalities in both normoglycemic
men and men with diabetes/impaired glucose tolerance.
More recently, Tanasescu et al. [41] from the Health Professionals’ Study, during a 14-year follow-up of 2803 men, observed a 42% multivariate-adjusted reduction of total mortality and a 33% multivariateadjusted reduction of cardiovascular disease incidence in the highest quintile of physical activity compared with the lowest.
The Finish Diabetes Prevention Study (DPS), a randomized clinical trial including 522 men and
women with impaired glucose tolerance, intended to investigate if leisure-time physical activity is associated with the prevalence of type 2 diabetes [42]. The goal for physical activity in leisure times was an exercise of ≥ 30 min/day. The study showed that people with increased moderate-to-vigorous leisure time physical activity were 65% less likely to develop diabetes after various adjustments for changes in diet and body weight. In a similar study, the Diabetes Prevention
Program (DPP) included 3,234 obese subjects with impaired glucose tolerance but not diabetes and randomized them to metformin, lifestyle changes (diet and exercise) and placebo [43]. The investigators introduced a lifestyle-modification program with the goals of at least a 7 percent weight loss and a physical activity of ≥ 150 min/wk. It could be observed that both treatments, lifestyle changes and metformin, were significantly different to placebo. However, lifestyle
changes were more effective than metformin with a reduced incidence of diabetes of 58% (lifestyle) compared to 31% (metformin) [43].
In contrast to the number of studies that investigated the association of exercise with the development of diabetes or cardiovascular disease, data considering specifically the metabolic syndrome are sparse in the literature. One of the epidemiologic studies that evaluated
the association between physical activity and the prevalence of the metabolic syndrome was the ATTICA Study [14]. The results showed that even lightto- moderate leisure time physical activity (<7 kcal/min expended) was associated with a considerable reduction in the prevalence of the metabolic syndrome in 3042 men and women from the general population. Regular, intensive exercise was associated with a much greater decrease [14]. In addition, the ATTICA Study investigators demonstrated that the adoption of the Mediterranean diet by physically active people was associated with greater reduction in the odds of having the syndrome than diet or exercise alone, after adjusting for several potential confounders. Thus, the combination
of beneficial health factors in terms of nutrition and exercise explained at least a part of the reduction in the prevalence of the metabolic syndrome; and this effect still remained beneficial when considering differences in lipids as well as inflammation and coagulation factors [44].
The level of physical activity needed for a beneficial impact on coronary risk remains controversial. The Center for Disease Control and Prevention and the American College of Sports Medicine recommend the accumulation of at least 30 minutes of moderateintensity
physical activity (equivalent to brisk walking at 3-4 mph), on most, preferably all, days of the week on the basis of documented improvements in fitness, for the general population [45]. This level of activity is well tolerated by most middle-aged or older individuals. However, people who are initially unfit or sedentary should start at lower intensity. Nevertheless, it could be strongly suggested that even low levels of physical activity may modify the status of the clinical and biochemical components of the metabolic syndrome and, therefore reduce its prevalence in the
population [45].
The protective role of physical activity has been attributed to various mechanisms. On the one hand, physical exercise has favorable effects on traditional cardiovascular risk factors; on the other, the positive effect can be attributed to a direct action of physical activity on the heart itself leading to increased myocardial oxygen supply, decreased myocardial oxygen demands,
formation of collateral coronary circulation, improved myocardial contraction and electrical stability of the heart [45].
The theoretical mechanism for chronic exercise promoting a reduction in body fat involves increased total daily energy expenditure without a corresponding increase in energy intake. It is generally accepted that long-term physical activity of sufficient intensity, duration and frequency has a favorable effect on weight reduction and body fat distribution. Evidence supports the hypothesis that the effectiveness of exercise to induce weight loss is directly related to the initial degree of obesity and the total amount of energy expenditure [46].
The beneficial effect of physical activity on blood pressure levels has also been shown [47-49]. In particular, it is now accepted that moderate levels of exercise can significantly decrease blood pressure in patients with mild to moderate essential hypertension.
Although physical activity has an insignificant effect on blood lipid levels, some investigators have shown the overall benefit of physical activity in modifying blood lipid profiles. The Pawtucket Heart Study group reported that physical activity was significantly associated
with higher HDL-cholesterol levels [49]. Moreover, among 3,000 adult Japanese men the frequency of physical activity was independently and positively related to HDL-cholesterol [50]. Similarly, a pooled analysis among three European cohorts consisting of elderly men demonstrated a significant relation between physical activity and HDL-cholesterol [51]. Reports
by Ford [52], and King [53] studying approximately 14,000 adult participants in the National Health and Nutrition Examination Survey III (1988-1994) showed that the time devoted to physical activity was inversely associated with some inflammatory marker levels, such as C-reactive protein, plasma fibrinogen concentration and the number of white blood cells, after
adjusting for several potential confounders. Similarly, Abramson et al. [54] reported that physical activity was independently associated with a lower probability of having elevated inflammatory marker levels among healthy US adults aged 40 years and older, independent
of several confounding factors. An inverse relation between plasma fibrinogen levels and leisure time physical activity has also been reported by several others [55-58].
Lifestyle approaches to treating and preventing the metabolic syndrome vary, but nearly all experts agree that parameters involved in the syndrome are greatly improved by reducing body weight and increasing the level of physical activity . Recently, Roberts et al. [59] and Stone et al. [60] revealed by an extensive review of the literature that lifestyle modifications mitigated disease progression and reversed existing disease. Small changes can lead to great improvements, not for achieving a perfect lifestyle but for working towards a better and healthier one. However, it should be noted that although lifestyle changes can provide
many benefits for human health, and especially for the management of the metabolic syndrome, sometimes these changes are difficult to implement and maintain. Therefore, drug treatment including statins, ACE inhibitors, angiotensin-II receptor blockers, and oral antidiabetic agents can be considered. It has been shown that these drugs are able to reduce effectively
the levels of underlying risk factors for the metabolic syndrome such as dyslipidemia, hypertension, hyperglycemia and the risk of developing diabetes [61].

Concluding remarks
The metabolic syndrome seems to be an emerging epidemic that affects roughly one out of five persons in Western industrialized countries. Similar to other chronic diseases, the metabolic syndrome is a complex, lifestyle-dependent illness. Its solution is not difficult to achieve: eat less, exercise more. These solutions must become part of everyday life and be woven into our social life to be effective. Health care professionals need to help people to understand the potential benefits that may result from the introduction of dietary patterns and exercise, and support them in adopting and adhering to these behavioral patterns. Actually, society as a whole needs to acquire a profound consciousness of the relevance for health of lifestyle factors such as nutrition and activity.

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