For many years, scientists and clinicians have recognized the association between several relatively common conditions such as hypertension, abnormal glucose metabolism (diabetes and other milder forms of glucose intolerance), and obesity. The observed association has also included other factors such as abnormal lipids (cholesterol and triglycerides), elevated uric acid, and microscopic amounts of protein in the urine. This association has received many names, including insulin resistance syndrome, syndrome X, and the deadly quartet, and is now widely known as metabolic syndrome (MetSx).
The relevance of MetSx relies on its high prevalence in both developed and less developed countries and on its association with a high risk for developing cardiovascular disease and type 2 diabetes mellitus. This review will summarize the current data regarding the diagnosis and prevalence of MetSx worldwide, its risk factors, clinical relevance, and treatment. This review will also discuss some of the ongoing controversies related to MetSx that major medical organizations and recognized authorities have spurred, and how the lack of a global agreement can distract attention from an epidemic that affects all ages.
Although there is full agreement that several factors such as hypertension, abnormal glucose metabolism, abnormal lipids, and obesity are strongly associated and may indeed share one or more physiopathological pathways, there is significant variability in the way in which MetSx is defined. To illustrate this lack of consensus, Table 1 displays the three most commonly used definitions of MetSx, revealing major differences in the diagnostic criteria. For example, the World Health Organization (WHO) requires a measure of insulin resistance to make the diagnosis of MetSx and includes microalbuminuria as a possible criterion, while the International Diabetes Federation (IDF) requires the presence of central obesity but does not require the documentation of glucose intolerance or insulin resistance to determine the presence of MetSx. A more clinically oriented definition is provided by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) by using measurements that are commonly used in clinical practice.
This lack of a standard way to define the diagnosis of MetSx has caused some skepticism in the scientific community and even some quarrels among major medical organizations, as documented in the position statement of the American Diabetes Association (ADA), which minimizes the importance of diagnosing patients with this ‘new’ nomenclature. This lack of a unified diagnostic method also makes it difficult to compare or combine results of studies assessing the incidence and prevalence of MetSx and the effect of therapeutic interventions on MetSx.
The prevalence of MetSx has been estimated in multiple studies, showing that about one-quarter of the US population meet diagnostic criteria for MetSx. National surveys performed with similar methodology prove that the prevalence of MetSx has increased by 25% in only 10 years, parallel to the increase in the prevalence of obesity and diabetes.
The prevalence of MetSx is higher in Native Americans and Mexican- Americans than in Non-Hispanic Whites or African-Americans. Gender appears to affect the prevalence of MetSx depending on the country or ethnic group. For example, in France and the US, the prevalence of MetSx is lower in women than in men, while the opposite occurs among Native Americans and in Turkey, India, and other parts of the world. It is not clear why these country- or race-related differences exist, but they may be related to some genetic traits and to different levels of physical activity between men and women depending on the country of origin. The prevalence of MetSx also increases with age, as suggested by prevalence studies showing that MetSx is six times more common in people older than 50 years compared with young adults aged between 20 and 29 years. This increased prevalence with older age may reflect a more sedentary lifestyle in elderly groups, which is a major risk factor for MetSx, but also reflects the higher prevalence of several of the MetSx criteria—such as hypertension, diabetes, and obesity—compared with younger people.
Because of the well-documented genetic predisposition for diabetes/insulin resistance, hypertension, dyslipidemia, and obesity—all key components of MetSx—it is clear that MetSx also has some genetic cause. In addition, the genetic theory is supported by the fact that some ethnic groups, such as Asians and Latin people with Native American ancestors, are more likely to develop diabetes at milder degrees of abdominal obesity than Caucasians. However, the increased prevalence of MetSx in recent decades cannot be explained by genes alone, and environmental factors that lead to obesity can probably take most of the blame for the MetSx epidemic.
It has been extensively documented that obesity is arguably the most important risk factor for MetSx. Excess body fat is indeed a major risk factor for insulin resistance, a factor considered by many as the underlying disease mechanism of MetSx. When the deposits of fat in the body increase, the turnover of free fatty acids also increases, acting as a potent inhibitor of the insulin effect at the cellular level. The second mechanism to explain why obesity promotes insulin resistance is that the former induces a leptin-resistance state with subsequent increase in the levels of leptin, which is also a potential inhibitor of the insulin receptor.
MetSx has been linked to a systemic inflammatory state. Obesity increases the production of proinflammatory cytokines by the adipose tissue and the liver. Animal models have shown that markers of inflammation such as C-reactive protein may cause insulin resistance, suggesting that systemic inflammation may be both a cause and a consequence of impaired insulin sensitivity. However, the way in which obesity predisposes to MetSx is not simple because, as mentioned before, some populations develop MetSx at lower levels of obesity and some people can indeed develop MetSx even with normal body weight.
Other documented risk factors for MetSx include a sedentary lifestyle and a diet high in refined carbohydrates and saturated fat. These factors are independent of the risk for MetSx attributed to obesity, even though a sedentary lifestyle and a poor diet predispose to obesity. This can be illustrated by the results of the Diabetes Prevention Program trial, where patients with impaired fasting glucose levels assigned to an exercise program that included nutritional counseling reduced the risk of developing diabetes mellitus by more than 50%, despite a quite modest weight loss of <5lb.
The strong association between lifestyle and MetSx has motivated some clinicians to call it the ‘lifestyle syndrome.’ Indeed, changes in the level of physical activity and improvements in the diet have shown to improve all of the components of MetSx in different trials.
Clinical Implications of the Metabolic Syndrome
Each of the components of MetSx has been independently associated with cardiovascular disease, including myocardial infarction, the need for coronary revascularization, and stroke. Therefore, it is not surprising that MetSx is also associated with a higher rate of cardiovascular disease and death. The presence of MetSx gives a two- to four-fold greater risk for cardiovascular death compared with those who have none of the MetSx components. This risk estimate is equivalent to having a total cholesterol >300mmHg or to the risk of smoking two packs of cigarettes a day. The risk is proportional to the number of positive criteria for MetSx and appears to be slightly higher in men than in women. The second major clinical implication of MetSx is an almost eight-fold greater risk of developing diabetes mellitus compared with those without MetSx. Diabetes mellitus represents a leading cause of death and disability in the world, even beyond the consequences of diabetes on the heart. Diabetes mellitus is the most common cause of end-stage renal disease and blindness in many countries and a leading cause of inferior limb amputation due to vascular insufficiency.
Because of the prevalence of MetSx and the strength of the association to cardiovascular disease and diabetes, MetSx represents a major public health threat. Indeed, recent data from the Inter-Heart study demonstrated that components of MetSx have the highest putative risk for ischemic heart disease in Latin America, meaning that more new cases of myocardial infarction in that region of the world can be attributed to components of MetSx than to any other cardiovascular risk factor.
Focus on Lifestyle
The cornerstone of the management of MetSx is lifestyle change. Because most patients with MetSx are sedentary and have poor dietary patterns, there is usually enormous room for improvement. Since changing behavior is not simple, healthcare providers should avoid a minimalist approach of simply telling the patient “You need to exercise and lose weight”—a recommendation that takes less than 20 seconds.
Significant and sustainable behavioral change requires the use of basic techniques mastered by psychologists and those working on the treatment of people with addictions. The basic principles for behavioral change include: motivation— fear, desire for a good health state, competitiveness, vanity, etc.; tools to facilitate the change—learning material, equipment, facilities, etc.; and tools to facilitate the maintenance of a healthy behavior.
Patients need to be informed of the risks related to MetSx. Few things surprise patients more when they are diagnosed with MetSx than realizing that they have a risk equivalent to smoking two packs of cigarettes a day. Unfortunately, most patients are completely unaware of their condition; this is not surprising, as it has been demonstrated that physicians tend to ignore risk factors such as obesity. Patients need to receive specific instructions about how to start an exercise program, with details of the type, duration, intensity, and frequency of the exercise they need. It is not uncommon for patients to overestimate the amount of exercise they do, especially when they consider low-intensity activities such as playing golf or walking the dog as moderately intense activities. A few supervised exercise sessions usually help patients to gain self-confidence in the way they can exercise. Some people benefit from joining a fitness center that provides convenience and motivation. Because about half of the general population declare that they hate exercise, it is also imperative that patients recognize lifestyle changes as an investment in their future health. In the same way that saving money for retirement is not an activity that people love and look forward to, behavioral changes should be recommended to patients as a valuable investment for a healthy (future) life and retirement.
Nutritional recommendations should include instructions for portion control, creating an understanding of the basic principle of thermodynamics that weight loss requires a negative balance between energy intake and expenditure. Without minimizing the importance of exercise, patients need to know that 30 minutes of exercise does not justify the extra muffin or the extra bagel with cream cheese. These latter two food choices have far more calories than a 190lb man can burn in 30 minutes of brisk walking.
Recent data show that diets rich in vegetables and protein with some restriction in carbohydrates—particularly refined carbohydrates—can improve insulin sensitivity regardless of changes in weight. Recommendations should always include limiting the intake of saturated fat, trans-fatty acids, and salt. Because dietary changes are also difficult, it is sometimes necessary for patients to see a nutritionist, attend a cooking demonstration class, or join a commercial program for weight loss with a good reputation. Patients need to understand that focusing on dietary changes and a more active lifestyle is more important than focusing on the amount of weight loss.
At Mayo Clinic Rochester, we have implemented the Cardiometabolic program, a six-week commitment that includes several of the key elements of behavioral change listed above. For example, patients watch a DVD about MetSx that emphasizes the risks associated to it and the role of the patient’s lifestyle for improving it. They receive an exercise prescription with detailed instructions on how to start a program and attend at least three supervised exercise sessions. They also attend a modified LEARN program with group-based sessions focused on sustainable weight loss. They attend a bi-monthly cooking demonstration class and learn about the incredibly high content of (added) sugar in common foods. They receive extensive patient education material with information about facilitating behavioral change, nutrition, and exercise. Although the commitment for such a program is high, most patients are able to attend two to three times a week for one to two hours each time. The feedback that participants provide has been extremely positive, and the majority of participants are able to maintain a more active life and a healthier diet.
Some components of MetSx may be completely out of control and require pharmacologic therapy. If blood pressure values exceed 140mmHg systolic or 90mmHg diastolic in more than one visit, they may need to start an antihypertensive medication or to add another one if they are already receiving one. The management of dyslipidemia should be guided by the underlying risk for or presence of cardiovascular disease, and the focus should be on maintaining low-density lipoprotein (LDL) cholesterol in target values. Attempts to increase high-density lipoprotein (HDL) levels or to reduce triglycerides with medications should be guided by the NCEP ATP III guidelines if there is little change in these two lipid parameters after lifestyle modification.
The evidence for the long-term efficacy of pharmacological intervention in weight loss is limited to three medications: sibutramine, orlistat, and rimonaban. Treatment with sibutramine produces significantly more maintained weight loss at two years than placebo, but the drug is contraindicated in patients with CHD. Orlistat, a medication that blocks the absorption of fat, causes weight loss of about 2.2kg greater than placebo at four years, with significantly more patients achieving >10% loss of initial body weight (26.2% and 15.6%, respectively).
Rimonaban, a canabinoid-receptor blocker with central anorexigenic properties, has been studied in several multicenter, randomized controlled trials. Rimonaban has shown excellent results in inducing weight loss and improving all of the components of MetSx. Side effects, which were mild and well tolerated, were mainly limited to dizziness, nausea, and diarrhea. Because the endocanabinoid system may also play a role in mood control, long-term safety data need to confirm that patients taking rimonaban do not develop higher rates of depression or suicide than controls. This drug is now available in several countries and is expected to be widely available in most of Europe and North America within two years.
Bariatric surgery has also been shown to improve the metabolic syndrome by causing major weight loss due to significant decrease in caloric intake. Typically, all of the elements of MetSx improve after surgery, although the most dramatic improvement occurs to glucose intolerance/insulin resistance. One year after the surgery, almost 70% of patients with a previous diagnosis of diabetes mellitus will have normal fasting glucose levels without insulin or other kind of pharmacological therapy for diabetes.
MetSx is a common and deadly disease whose prevalence has increased in recent years. Despite the lack of a unified definition, there is global consensus on the importance and consequences of this condition. The cornerstone in the management of MetSx is lifestyle change. Patients may need professional support to achieve their individualized goals of regular exercise and diet. Other modes of treatment are also helpful, but should be considered auxiliary methods and should be attempted only when lifestyle changes have not yielded the expected results.