The Controversial Question of Metabolic Syndrome


The high prevalence of diabetes and cardiovascular disease (CVD) has tasked the medical community to not only treat but to better identify people at risk for these diseases. Risk factors for diabetes had been identified more than 90 years ago, and the term metabolic syndrome emerged in the late 1970s.1,2 In the late 1980s, a potential link had been identified—insulin resistance, which itself has been strongly associated with obesity.3 On the other hand, some believe that insulin resistance contributes to the development of the risk  actors but is not the underlying cause.4 Identifying a cluster of predictive risk factors would enable healthcare providers to identify and  treat patients with metabolic syndrome, thus reducing the risk for a progression to diabetes, CVD, or both.
 
 
The Controversy: What Is Metabolic Syndrome, and Is It a Treatable Disorder?
 
Metabolic syndrome (sometimes referred to as “syndrome X” or “insulin-resistance syndrome”) is defined as a grouping of several related risk factors,4 including:

• Abdominal fat
• Dyslipidemia
• Hyperglycemia
• Hypertension
 

Merriam-Webster defines the term syndrome as “a group of signs and symptoms that occur together and characterize a particular  abnormality.”5 What is truly more important to the final objective of preventing diabetes and CVD—identification of the underlying mechanism(s) for the syndrome, or identification of the risk factors that occur together and usually lead to diabetes and CVD?


This question defines the debate within the healthcare community: Is metabolic syndrome a cluster of risk factors or a syndrome? Proponents for  characterizing metabolic syndrome as a syndrome believe that the evidence linking the risk factors with the development of diabetes and CVD supports the view that it is a treatable entity. Detractors believe that metabolic syndrome is really just a clustering of risk factors, without any known underlying mechanism  that associates the maladies. Confounding the discussion is whether metabolic syndrome is a pre-morbid condition—whether metabolic syndrome can only  be recognized before a patient is given a diagnosis of diabetes or CVD, thus excluding the population with these highly prevalent chronic conditions. On the other hand, an actual diagnosis of diabetes or CVD does not affect the underlying mechanism (eg, insulin resistance or some other factor still exists).


Regardless of whether  professional organizations are supporters or skeptical of metabolic syndrome, the medical community as a whole believes that additional research is needed to better understand its etiology.


In 2005, the American Diabetes Association and the European Association for the Study of Diabetes published a statement underscoring their concerns regarding metabolic syndrome.6 Their concerns included the value of including diabetes in the definition, whether the criteria have accurate thresholds and are completely explanatory, and the omission of other cardiovascular disease risk factors. They worried that if the cardiovascular risk for metabolic  syndrome is the same as the sum of the individual risk factors, treatment of the syndrome would be the same as the treatment for each of the respective risk  factors. Furthermore, these professional societies were not convinced that insulin resistance is the unifying mechanism and whether there is overall value in  diagnosing the syndrome.


Yet, 2 American professional organizations and several international societies generally agree on the risk factors that should be included in the definition of  metabolic syndrome. Until this time, there were several different criteria discussed for metabolic syndrome, most notably from the World Health Organization, the National Cholesterol Education Program Adult Treatment Panel III, the International Diabetes Foundation, and the American Heart Association/National Heart, Lung, and Blood Institute. These organizations agreed on the risk factors that should be included in a definition of metabolic syndrome; however, they differed on the definition of the components and the number of risk factors that needed to be present to constitute the diagnosis. Members from these  organizations came together in 2009 to meld together consistent criteria for metabolic syndrome.4 Most disagreement involved whether body mass index or  waist circumference should be used as the indicator for central obesity. They concluded that waist circumference was a useful screening tool and should  correlate with specific country or population demographics, and that further research was required.


This coalition of professional societies did agree that having 3 of the abnormal findings from the cluster of 5 maladies would constitute a diagnosis of  metabolic syndrome (Table 1). They also agreed that people with any of the identified risk factors usually also present with a prothrombotic and proinflammatory state.


Obesity and physical inactivity have been found to be important contributors to metabolic syndrome.7 Other contributing factors include genetic and racial composition, aging, and the presence of other endocrine disorders. Patients with metabolic syndrome are usually susiceptible to additional problems as well, some that may be associated with its individual component risk factors:

• Fatty liver
• Cholesterol gallstones
• Obstructive sleep apnea
• Gout
• Depression
• Musculoskeletal disease
• Polycystic ovarian syndrome8


The Prevalence of Metabolic Syndrome

Assuming one accepts the definition of metabolic syndrome, it is unsurprising that its prevalence has increased over  time, perhaps reflecting the obesity  epidemic and predictions of greater incidence of diabetes.9 An analysis of the 2003 to 2006 National Health and Nutrition Examination Survey revealed  that, based on a waist circumference threshold of ≥102 cm for men and ≥88 cm for  women, the age-adjusted prevalence of metabolic syndrome in American adults was 34.3% (36.1% for men; 32.4% for women). This percentage increased to 38.5% for all adults when racial- or ethnic-specific criteria were used (41.9% for men; 35.0% for women). The prevalence increases with age, peaking in the 60- to 69-years group, which parallels a correlation with weight gain  with increasing age. Caucasian and Mexican-American men had a higher prevalence of metabolic syndrome than African American men, whereas the  prevalence for women was lower among Caucasian women than for African American or Mexican American women.10


Among the risk factors, abdominal obesity is observed in the majority (53.6% total [45.8% men; 61.2% women]) of the population with metabolic syndrome. The other risk factor components in the total population are, in descending order of prevalence, hyperglycemia, high triglyceride levels, elevated blood  pressure, and low concentrations of high-density lipoprotein cholesterol.


Although each of the components of metabolic syndrome increases the risk for CVD, the combination of the risk factors appears to increase it substantially. The presence of metabolic syndrome is associated with a 2-fold increased risk for CVD (and a 5-fold greater risk for the development of type 2 diabetes).8  Traditional risk algorithms for CVD, such as the Framingham Risk Score, may be more accurate in risk prediction.11


The Cost Implications of Metabolic Disease for Payers

Unsurprisingly, patients diagnosed with metabolic disease can be expected to utilize more health resources than those individuals without it. A study of  patients in 3 health plans confirmed this statement—members meeting at least 3 criteria for metabolic syndrome had 60% higher annual costs compared with patients without metabolic syndrome ($5732 vs $3581, respectively), and these costs increased incrementally by 24% when they met 4 or more risk  factors.12 When patients progressed to a diagnosis of diabetes, the healthcare costs were higher in patients with diabetes and metabolic syndrome than in  those patients with diabetes without metabolic syndrome ($7896 vs $6038, respectively). Patients with diabetes do not necessarily meet all of the criteria  required to be considered to have metabolic syndrome.12


Similar results were seen in a health plan that assessed the direct medical costs associated with patients who were overweight, obese, or met risk criteria for  metabolic syndrome using a cost model.13 Comparing patients who were overweight or obese with those who were not, direct costs were $4563 versus $4015, respectively. The highest annual costs (>$5000) were in the patients with risk factors meeting the requirements of metabolic syndrome. This cost was  $2061 higher than in those without the risk factors for metabolic syndrome.13 Both of the above studies support the hypothesis that there are increased costs associated with patients meeting the risk factor criteria for metabolic syndrome.


However, another study of health plan members concluded that the higher costs were associated with the individual risk factors rather than with a clustering of the risk factors. In this analysis, 5 years of health data were evaluated for adults with metabolic syndrome risk factors  and their impact on direct medical costs. They compared total annualized direct costs for all possible combinations of the metabolic syndrome risk components.Every risk factor except for impaired fasting glucose led to increased annual medical costs; however, the higher costs were independent of the other risk factors. The presence of each of the risk  factors was associated with higher future medical costs, which were mostly attributable to the development of diabetes or the need for hospitalization due to  cardiovascular disease.14


Current Approaches to Managing Metabolic Syndrome

Currently, there is no 1 specific treatment for treating patients meeting thecriteria for metabolic syndrome. Rather, lifestyle modification and weight  reduction, along with drug therapy for the respective risk factors (eg, hypertension, dyslipidemia, hyperglycemia, and weight reduction) are employed.  Pharmaceutical companies have found it challenging to develop medications, as they would need to address multiple aspects of metabolic syndrome in  order to be approved for the indication.15 As a result, clinicians utilize available tools to address these risk factors (and usually, on an individual basis).


From  the clinical and public health standpoint, however, the need for better tools to prevent and manage metabolic syndrome is urgent (Table 2).8 Until an  underlying mechanism is positively identified (or insulin resistance is finally recognized as the “smoking gun”), medications will be utilized that address the  respective components of metabolic syndrome.


Patient Management and Metabolic Syndrome

The most important benefit of using the term metabolic syndrome appears to be that it focuses attention on an important clustering of health problems. Each of the criteria, as well as the clustering of the criteria, increase the risk for future disease. Lifestyle modifications can address each of the criteria for metabolic syndrome; however, each component requires separate, focused treatment.


Use of the term metabolic syndrome has been educational for both healthcare professionals and patients.10 It has provided an easily understandable public health message, raised awareness of risk factor clustering as well as the need to identify additional risk factors among healthcare providers, and been an  impetus for healthcare professionals to look beyond only diagnosed diabetes and cardiovascular disease to risk factors that progress to these diseases.11


Finally, additional research should be conducted to fully understand and appreciate the clustering of risk factors identified as metabolic syndrome. Further investigation will be required to better understand if there is underlying  cause, such as a genetic defect. Finding an underlying mechanism would help settle  the controversy as to whether the syndrome is a treatable entity or metabolic syndrome is just a clustering of risk factors. Until that time, educational  endeavors need to continue to identify and reduce the modifiable risk factors for diabetes and CVD. Population-based strategies need to be further  developed and implemented because of the importance of these diseases.


Conclusions

Professional organizations and government agencies are not currently in agreement about whether metabolic syndrome is clinically relevant in predicting the development of diabetes or CVD. Fundamentally, there is disagreement whether metabolic syndrome even fits the criteria of a treatable entity. We do  know that the individual risk factors play an integral role in the development and advancement of these 2 important diseases. Until additional information is  available regarding the potential underlying mechanism of this syndrome, healthcare professionals need to address the rising incidence of obesity and a  sedentary lifestyle that are major contributors to the development of diabetes and heart disease. EBDM


Payer Perspective
Interview With Ross M. Miller, MD, MPH

 

EBDM: The term “metabolic syndrome” is fairly controversial. What’s your view on whether this classification is practical as a disease or entity?

Dr Miller: I believe it’s a legitimate entity. The guidelines issued jointly from the American Heart Association (AHA) and the National Heart, Lung, and Blood  Institute (NHLBI) in 20051 were a scientific, evidence-based approach to this multiple risk factor complex. It arises from a combination of insulin resistance,  abdominal obesity (abnormal fat disposition), dyslipidemia (high triglycerides and low high-density lipoprotein cholesterol levels), and high blood pressure. The science definitely supports the connection of metabolic disease to coronary heart disease and type 2 diabetes mellitus. According to these guidelines, if  you have at least 3 of the 5 risk factors, you’re at greater risk for these clinical consequences,1 and I totally buy into that.

I know it’s controversial, but where  there is some predictive value behind it, in terms of diabetes and cardiovascular events, I agree with it.


EBDM: Would a highly publicized scoring system of risk factors, similar to the risk score profiles produced by the Framingham Heart Study for heart disease,2 help bolster the case for recognizing and promoting metabolic syndrome within the healthcare community?

Dr Miller: I would love that. It would be similar to the “know your number concept” we have for diabetes and cholesterol. If we could quantify a number based  on the 5 risk factors, with some type of weighting of not only the risk factors themselves but within the 5 factors (ie, how far from the cut points one might be), where it can be calculated as a certain percentage risk over time, such as Framingham, or a certain numerical value that has been modeled with   real-world data, this would be the Holy Grail. Then, all patients need to know is their number and they can work collaboratively with their provider to address their risks through stratified interventions.


EBDM: Are disease management programs well equipped to address patients with metabolic syndrome?

Dr Miller: Yes. Previously, if we had a patient with hypertension, they were enrolled in a hypertension disease management program. If they had dyslipidemia, they were enrolled in a dyslipidemia disease management program, and so on. If they had more than 1 condition—and so many of them do  overlap—they should be in an integrated, coordinated multiple-condition management program. We have this capability today, mostly through use of   interoperable technology. In metabolic syndrome, where multiple conditions overlap, a singular program is more appropriate in order to provide better care coordination, continuity of care, and management in an integrated model.


EBDM: What is your perception of the proportion of patients already in diabetes disease management programs who would actually benefit from metabolic  disease management programs?

Dr Miller: I believe that most of the folks with metabolic syndrome are probably prediabetic anyway. However, patients with diagnosed diabetes may also meet some of the other 5 risk factors. Through diet and exercise, patients with type 2 diabetes can actually improve their glycemic levels and reduce the need for diabetes medications.3


EBDM: Do you think a metabolic disease management program could be effective at preventing full-blown diabetes in those patients with insulin resistance?

Dr Miller: A study by the Centers for Disease Control and Prevention found that approximately 34% of adult Americans may have metabolic syndrome.4 It  has somewhat paralleled the rise of the obesity epidemic in this country. The prevalence of metabolic syndrome is about double the rate for diabetes, so the  idea is to prevent or reverse impaired glucose tolerance in these individuals by employing weight loss through diet and exercise.5


EBDM: You probably remember, in the middle part of the past decade, when sanofi-aventis was trying to bring rimonabant to market with a metabolic syndrome indication. It was primarily a weight-loss agent. The US Food and Drug Administration (FDA) has still not approved any medication with a metabolic syndrome indication. Why do you think that is the case, based on the size of the potential market?

Dr Miller: That’s a difficult and complicated question. I believe that to obtain FDA approval, the manufacturer might have to show improvements to several of the outcome measures across the syndrome (eg, lower blood sugar levels, weight loss, lower blood pressure, improved lipid profiles). This would be  extremely difficult to do in the context of a single, large clinical study. Today, pharmacologic management is related to treating the individual components  of metabolic syndrome, such as statins for dyslipidemia or metformin for elevated blood glucose levels. Most interventions targeting the entire syndrome are   focused on lifestyle modifications—changes in diet and exercise, for instance. Many experts believe that if you focus on weight loss (through diet and  exercise), everything else follows—waist circumference goes down, impaired glucose tolerance improves, hypertension resolves.

I don’t know if the 2 recently approved weight loss products are undergoing clinical studies (or subpopulation analyses) for their effects on these other components of the metabolic  syndrome.

(Editor’s Note: A review of the www.clinicaltrials.gov website revealed a total of 597 interventional clinical trials [phase II or III] for metabolic syndrome,  testing everything from bloodletting and the use of walnuts to rosiglitazone and chloroquine, but not the new weight loss products lorcaserin or the  phentermine/topiramate combination.)


EBDM: Even if the use of the term metabolic syndrome has not been fully accepted, do you believe more physicians today are aware of the inter-relationships among the various risk factors and their management?

Dr Miller: Absolutely. I’m not sure whether it’s because of the coverage of obesity and diabetes epidemics in the lay press or because of the release of the  AHA/NHLBI guidelines, but I definitely think there’s increased awareness. I actually don’t remember even hearing the term metabolic syndrome 15 or 20 years ago in primary care.


EBD: From the standpoint of the Medicaid program in California, what types of public health education are emphasized with regard to the insulin  resistance–cardiovascular–obesity axis of symptoms? Is Medi-Cal formally packaging thisinformation?

Dr Miller: Not that I am aware of as metabolic syndrome per se. A good deal of information has been disseminated on the individual components—there is tons of public education on obesity, including website information, posters geared to consumers, and fax blasts to providers. Some websites, such as WebMD  and Mayo Clinic, which are frequently accessed by the public, provide educational materials on metabolic syndrome and its criteria, but I have not been   involved in packaging it as such for Medicaid recipients and providers. Medicaid has patient messaging that says that if you are overweight and/or have other  risk issues you may have a higher likelihood of developing diabetes. That is “packaging” the message to some respect, but maybe only “soft”   packaging. Employer-sponsored wellness programs are also addressing this condition indirectly because health risk appraisals and biometric lab screenings  commonly identify the components of metabolic syndrome.


Dr Miller is a medical director consultant and physician executive at Cerner Corporation in Los Angeles, CA.


References

1. Grundy SM, Cleeman JI, Daniels SR, et al. AHA/NHLBI scientific statement: diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112:2735-2752.

2. Framingham Study Risk Score Profiles. Framingham Heart Study. www.framinghamheartstudy.org/risk/index.html. Accessed December 5, 2012.

3. Kumar AA, Palamaner Subash Shantha G, Kahan S, et al. Intentional weight loss and dose reductions of anti-diabetic medications—a retrospective cohort study. PLoS One. 2012;7(2):e32395.

4. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. National Health Statistics Reports; no 13. Hyattsville, MD: National Center for Health Statistics, 2009.

5. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.Lancet. 2009;374:1677-1686.
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