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

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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.

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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.

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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