|Understanding the Metabolic Syndrome and its Relationship to CHD|
Donald B. Hunninghake, MD
Departments of Medicine & Pharmacology
Heart Disease Prevention Clinic
University of Minnesota
In this article, renowned lipid specialist Donald Hunninghake, MD, of the University of Minnesota addresses the metabolic syndrome, a relatively new diagnostic term introduced by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines, which were released in 2001. The term is used to describe a cluster of cardiovascular risk factors that is associated with the development of coronary heart disease and type 2 diabetes mellitus, as well as an increased risk of mortality. Dr. Hunninghake has served as an NCEP expert committee member since its inception in 1985 and has been on the writing committees of ATP I, II, and III.
This article was supported by an educational grant from AstraZeneca.
Diagnosing the Metabolic Syndrome
The NCEP ATP III guidelines stipulate that the metabolic syndrome may be diagnosed when a patient has three or more of five clinically identifiable risk factors. These include abdominal obesity, a high triglyceride level, a low high-density lipoprotein (HDL) cholesterol level, hypertension, or an elevated fasting glucose level (Table 1) (The National Cholesterol Education Program Adult Treatment Panel III Report, 2001. Bethesda, MD: National Heart, Lung, and Blood Institute, NIH publication no. 02-5215, 2002).
The causes of the syndrome are multifactorial. The major contributing factors are environmental or lifestyle, such as being overweight or obese, getting little physical activity, or eating a poor diet. Insulin resistance is now believed to be causative of the metabolic syndrome, or at the very least closely associated with it, although the exact mechanistic connections are still unclear. Genetic factors may also be involved (Lakka H-M, et al. JAMA 2002;288:2709-2718. Reusch JE, et al. Am J Cardiol 2002;90(Suppl 5A):19G-26G).
The ATP III guidelines stress that the metabolic syndrome should be a clear target of therapy to achieve maximal benefit. Such therapy begins by focusing on the root causes of the syndrome: physical inactivity and being overweight or obese. This entails recommending weight reduction in overweight and obese people with an emphasis on a diet that favors fruits, vegetables, and whole grains over fats, animal products, and processed foods, and adoption of a regular exercise program.
In addition, drug therapy can be prescribed to improve lipid parameters, high blood pressure, and the prothrombotic state. Indeed, pharmacologic therapy is well established to lower the various CHD risk factors that patients with the metabolic syndrome exhibit.
Due to the epidemic of growing numbers of overweight and obese Americans who lead mostly sedentary lifestyles the metabolic syndrome is becoming increasingly common (Heart Disease and Stroke Statistics – 2003 Update. Dallas, TX: American Heart Association 2002).
Findings from the Third National Health and Nutrition Examination Survey (NHANES III) have been analyzed in the hope of shedding some light on how common the metabolic syndrome might be. This survey, conducted between 1988 and 1994, analyzed data from a cross section of 8814 U.S. men and women who were at least 20 years old. The survey analysis found that the overall unadjusted prevalence of the metabolic syndrome was an estimated 21.8% of the population. When adjusted for age, the prevalence was 23.7%. Prevalence differed little by gender, but did differ by age: Among 20- to 29-year-olds, the prevalence of the syndrome was 6.7%, whereas among 60- to 69-year-olds, it was 43.5%. Among those 70 or older, the prevalence was 42% (Ford ES, et al. JAMA 2002;287:356-359).
Application of these rates to the U.S. Census data from the year 2000 suggests that 47 million people in the United States have the metabolic syndrome. In terms of race, Mexican-Americans have the highest prevalence, followed by Caucasians, African-Americans, and other ethnic groups. Among Mexican-Americans and African-Americans, women have a higher prevalence of the syndrome than do men.
One of the primary features of the metabolic syndrome is atherogenic dyslipidemia or the so-called “lipid triad.” This triad consists of a high triglyceride level; small, dense low-density lipoprotein (LDL) particles; and low HDL-C.
A “normal” triglyceride level is defined as being <150 mg/dL. Patients with the metabolic syndrome typically have triglycerides that are above this level. Several factors conspire to raise triglyceride levels above normal in the patient with the metabolic syndrome.
When triglyceride levels are >200 mg/dL, the ATP III cautions that the presence of increased quantities of atherogenic remnant lipoproteins can raise the risk of CHD far beyond what an LDL-C level alone can predict. The atherogenic lipoproteins in question are likely to be small, dense LDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL), which are cholesterol-enriched particles that have many of the same properties as LDL-C, which ATP III recognizes as “the most abundant and clearly evident atherogenic lipoprotein.”
It is common to find low HDL-C levels in patients who have triglyceride levels >200 mg/dL. In addition, these low levels often accompany insulin resistance. A low HDL-C level is considered an independent CHD risk factor and is clearly linked to increased CHD morbidity and mortality. In fact, various epidemiologic studies have shown that for every 1% decrease in HDL-C, there is a 2% to 3% increase in CHD risk.
In patients with the metabolic syndrome, as with others, an elevated LDL-C level is the primary target of lipid-lowering therapy. Non-HDL-C, which incorporates the “lipid triad,” is the secondary target. Non-HDL-C is basically total cholesterol minus HDL-C. It is an indirect measurement of all the apo B-containing lipoproteins, including LDL, IDL, VLDL and its remnants, and Lp(a). Apo B is the major apolipoprotein of all atherogenic lipoproteins and has been shown to be very predictive of the severity of coronary atherosclerosis and CHD events. The NCEP ATP III recommends calculating non-HDL-C to enhance risk prediction. In patients with the metabolic syndrome, non-HDL-C is an important marker to target and monitor. The target goal for non-HDL-C levels is 30 points higher than the corresponding LDL-C goal.
Relationship to CHD Risk & Diabetes
The metabolic syndrome has a direct link to CHD and mortality. According to ATP III, in aggregate, the risk factors comprising the metabolic syndrome enhance the risk for CHD at any given LDL-C level. However, despite its prevalence, there are few studies investigating the association between the metabolic syndrome and cardiovascular disease or overall mortality. Indeed, most of today’s understanding about the metabolic syndrome and its attendant CHD risk comes from data about the individual components of the syndrome. For instance, numerous studies have clearly shown that high blood pressure is a risk factor for CHD. Many other studies have associated obesity, particularly abdominal fat, with increased morbidity and mortality from CHD. Excess weight also predisposes patients to other cardiovascular risk factors, such as dyslipidemia, type 2 diabetes, hypertension, and stroke.
In aggregate, these risk factors increase CHD risk dramatically, although it’s difficult to ascertain the individual impact of each factor on total risk. Recently, though, a study of 1209 healthy men ages 42 to 60 in Finland, starting in 1984 and continuing through 1998, gave a glimpse of the metabolic syndrome’s impact, at least in the male population. The study found that men who were defined as having the metabolic syndrome – even in its earliest stages in patients without evidence of cardiovascular disease or type 2 diabetes – were 2.9 to 4.2 times more likely to die of CHD after adjustment for conventional cardiovascular risk factors (such as smoking, age, alcohol consumption, and LDL-C) (Lakka H-M, et al. JAMA 2002;288:2709-2718).
Besides increasing the risk of CHD, the metabolic syndrome also increases a person’s chances of developing type 2 diabetes mellitus, probably as a consequence of insulin resistance. Of course, two of the risk factors for the metabolic syndrome – an elevated or prediabetic fasting glucose level and obesity – are also risk factors for diabetes.
Type 2 diabetes is not an inevitable consequence of prediabetes, however. A landmark study called The Diabetes Prevention Program shows that improving diet and increasing exercise can prevent progression to outright diabetes. In this trial, 3234 patients with elevated fasting and post-load plasma glucose concentrations were randomized to placebo, metformin, or an exercise program of 30 minutes of moderate daily physical activity. The average follow-up was 2.8 years, during which time the lifestyle-only group showed a 5% to 10% decrease in body weight and a 58% reduction in progression to diabetes. Use of metformin, in contrast, reduced the incidence of diabetes by only 31% (Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403).
Therapeutic Lifestyle Changes
The ATP III guidelines acknowledge that the most successful approach in clinical practice is pharmacologic therapy. However, the panel believes optimal management actually lies in reversing the root causes, and endorses a lifestyle approach as the safest and most preferred way to reduce insulin resistance. This approach is called Therapeutic Lifestyle Changes (TLC).
The TLC diet, which is consistent with the recommendations in the Dietary Guidelines for Americans 2000, is a low-fat diet designed to reduce LDL-C. Importantly, for patients with the metabolic syndrome, in whom overconsumption of carbohydrates can fuel insulin resistance, raise triglyceride levels, and lower HDL-C levels, the diet stipulates that patients reduce carbohydrate consumption. Hence, patients with the metabolic syndrome should consume no more than 50% of their calories from carbohydrates.
Patients on the TLC diet should be instructed to choose more servings of high-fiber breads and cereals, vegetables, fruit, and low-fat or nonfat dairy products. They should also be encouraged to enjoy limited amounts and certain types of eggs, meats, fats, and oils. And the TLC diet gives the option of adding stanol/sterol-containing margarines and viscous fiber food sources to the diet. They should also be encouraged to engage in routine physical exercise.
Although reducing weight and increasing physical activity are the first-line treatments for the metabolic syndrome because they help to modify many risk factors for CHD and lower insulin resistance, many patients will also require pharmacotherapy. Clinical trials show that using pharmacologic agents to modify the lipid triad, hypertension, and the prothrombotic state can reduce CHD risk for the patient with the metabolic syndrome.
In the area of lipid-lowering, the first target is LDL-C. In general, the goal in patients with the metabolic syndrome – who typically have two or more CHD risk factors and a 10-year CHD risk of <20% – is to reduce LDL-C to <130 mg/dL. However, the optimal LDL goal, for all patients, remains <100 mg/dL (Table 2).
The second target of pharmacologic treatment is the atherogenic dyslipidemia associated with the metabolic syndrome. This includes elevated triglycerides (levels >200 mg/dL), non-HDL-C, and a low HDL-C level. Clinical trials have not yet pinpointed specific HDL-C and triglyceride levels as being optimal. Because of that, ATP III does not offer a specific triglyceride goal. Instead, the panel recommends focusing on the goal of bringing non-HDL-C to 30 mg/dL above the LDL-C goal, since that will offer more flexibility in therapy than would focusing on a triglyceride goal. In addition, the panel does not offer a specific HDL-C goal but encourages use of lifestyle changes and drug therapies that will raise HDL-C levels.
When lipid-lowering medication is indicated, an HMG-CoA reductase inhibitor (“statin”) should generally be the first line of therapy. Frequently, statins alone can achieve the LDL-C and non-HDL-C goals in many patients. This class of agents, which is well tolerated, can reduce LDL-C by approximately 18% to 55% and triglycerides by 7% to 30%. Choosing a statin that can raise HDL-C is also an important consideration. All of the statins currently on the market raise HDL-C levels to a modest extent, by approximately 5% to 15%.
An important new study suggests that statins may play a role in reducing CHD mortality in hypertensive patients with normal total cholesterol levels. This trial – the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) – enrolled 19,342 hypertensive men and women between the ages of 40 and 79. Patients had a total cholesterol level of <250 mg/dL and were randomly assigned to receive atorvastatin (Lipitor®) 10 mg or placebo. The trial was supposed to last 5 years, but the results were so dramatic in favor of the statin that it was stopped after a median follow-up of 3.3 years. Indeed, it was found at that time that only 100 primary CHD events had occurred in the atorvastatin group compared with 154 events in the placebo group. Specifically, the statin significantly lowered the risk of nonfatal myocardial infarction and fatal CHD by 36% compared with the placebo group (Sever PS, et al. Lancet 2003;361:1149-1158).
A novel agent, ezetimibe (Zetia®), launched in 2002, is the first cholesterol-absorption inhibitor. It can be used as an adjunct to statin therapy or as monotherapy and has been shown to reduce LDL-C by up to approximately 18% when given in 10 mg doses once per day (Bayes HE, et al. Clin Ther 2001;23:1209-1230).
Non-HDL-C, which should be targeted if triglyceride levels are >200 mg/dL and only after the LDL-C goal level has been achieved, can often be managed with nicotinic acid or a fibrate either alone or in combination with a statin. Nicotinic acid, for instance, can raise HDL-C by 15% to 35% and reduce triglycerides by 20% to 50%. It also transforms small, dense LDL into the more normal-sized LDL and is considered to be the most effective HDL-C-raising drug available. Fibrates can raise HDL-C by 10% to 35% and lower triglycerides by 20% to 50%. They can also lower LDL-C by 5% to 20% in patients with normal levels of triglycerides. However, they can raise LDL-C in patients with hypertriglyceridemia. Bile acid sequestrants are not recommended in patients with atherogenic dyslipidemia as they can raise triglyceride levels.
Rosuvastatin (CrestorTM), a statin recently approved for use in Europe and awaiting approval in the United States, appears to be effective in reducing triglycerides and non-HDL-C. In a comparison analysis of trials with rosuvastatin, atorvastatin, pravastatin (Pravachol®), and simvastatin (Zocor®), 71% of patients who had triglyceride levels above 200 mg/dL were able to meet their LDL-C and non-HDL-C ATP III goals while taking rosuvastatin, an increase over the other statins (Rader DJ, et al. Am J Cardiol 2003;91:20C-23C). Another recent analysis of data from five studies of rosuvastatin in patients with the metabolic syndrome found that 10 mg daily reduced LDL-C by 47%, non-HDL-C by 43%, and triglycerides by 23%. Rosuvastatin also increased HDL-C by 10%. The drug also improved various lipidemic ratios, and allowed 64% of subjects to meet their ATP III non-HDL goals (Ballantyne CM, et al. Am J Cardiol 2003;91:25-27).
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