Free
Editor's Message  |   April 2007
Reducing the “Domino Effect” of the Metabolic Syndrome
Jeffrey S. Freeman, DO
Author Notes
  • Dr Freeman serves on the speakers bureaus of GlaxoSmithKline Inc, Novartis International AG, Novo Nordisk Inc, and sanofi-aventis US, and he has received grants and research support from AstraZeneca Pharmaceuticals LP and Bristol-Myers Squibb Company. 
  • Address correspondence to Jeffrey S. Freeman, DO, FACOI, Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, 4190 City Ave, Suite 324, Philadelphia, PA 19131-1626. E-mail: jeffreyfreemando@aol.com 
Article Information
Cardiovascular Disorders / Endocrinology / Preventive Medicine / Diabetes
Editor's Message   |   April 2007
Reducing the “Domino Effect” of the Metabolic Syndrome
The Journal of the American Osteopathic Association, April 2007, Vol. 107, Cov2-S3. doi:
The Journal of the American Osteopathic Association, April 2007, Vol. 107, Cov2-S3. doi:
The physiologic relationships between dyslipidemia, glucose intolerance, insulin resistance, obesity, and a procoagulant state are well established.1 The pathologic clustering of these conditions—which some researchers have likened to a chain-reaction “domino effect”2—is usually referred to as the metabolic syndrome. However, definitions of the metabolic syndrome vary, and several alternate names are ascribed to this condition, including the insulin resistance syndrome, syndrome X, and, most recently, the cardiometabolic syndrome.3-5 This confusing terminology has been criticized by healthcare professionals, some of whom have even questioned its clinical usefulness.6,7 
The definitions of metabolic syndrome endorsed by the World Health Organization (WHO) and European Group for the Study of Insulin Resistance (EGIR) are used predominantly for research purposes.8 By contrast, the definitions developed by the National Cholesterol Education Program (NCEP) and American Association of Clinical Endocrinologists (AACE) are typically used for clinical case-finding.9 The NCEP and AACE definitions are preferred for clinical case-finding because they allow the simple measurement of waist circumference to be used in place of the more complex waist-hip ratio, and they also allow a fasting glucose value to be used in place of a glucose tolerance test.9 
In 2005, the International Diabetes Federation (IDF) issued a new definition of metabolic syndrome in an attempt to unify the previous terminology.3 Based on all the various definitions, the estimated prevalence of metabolic syndrome in the European adult population ranges from 27% to 35.9% in men and from 19.7% to 34.1% in women.3 The IDF definition applies a diagnosis of metabolic syndrome at lower cut points of waist circumference than do the other definitions. Thus, the IDF estimates of metabolic syndrome are the highest estimates given for both sexes.3 
Cardiovascular Disease Risk and Cardiometabolic Syndrome
The different definitions of metabolic syndrome also lead to different interpretations of the association of cardiovascular disease (CVD) risk with sex differences. After adjustments by multivariant analyses, however, the definitions provide a strong correlation between metabolic syndrome and CVD mortality only in men.3 Only the WHO definition results in a correlation between metabolic syndrome and CVD mortality in women.3 
The cardiometabolic syndrome has been defined as an all-encompassing constellation of metabolic risk factors—including the metabolic syndrome—that culminates in increased cardiovascular risk.10 Researchers have estimated that as many as 70 million Americans (approximately 34% of the adult population) have cardiometabolic syndrome.10 The prevalence of this syndrome varies substantially throughout the world. For example, an analysis of patients in Mexico conducted from 1997 to 1999 revealed a cardiometabolic syndrome prevalence of 60% in men and 40% in women.10 These findings contrasted sharply with the findings of a 1996 study of patients in France, which indicated a cardiometabolic syndrome prevalence of 10% in men and 7% in women.11 Most likely, both lifestyle and genetic factors play a role in such population differences. 
There exist at least nine modifiable cardiometabolic factors that place a patient at risk for CVD, as well as for type 2 diabetes mellitus (T2DM). These factors include abdominal adiposity, depressed high-density lipoprotein (HDL) cholesterol, elevated low-density lipoprotein (LDL) cholesterol, elevated triglycerides, hyperglycemia, hypertension, increased inflammatory markers, insulin resistance, and smoking.12 Unfortunately, the definitions of cardiometabolic syndrome—like those of metabolic syndrome—can be confusing to physicians and patients. Nevertheless, the main component of cardiometabolic syndrome that physicians need to address in most patients is T2DM, which makes up approximately 90% of diabetes cases and is the sixth greatest cause of mortality in the United States.13 
Obesity is a major contributor to both T2DM and CVD, and it typically involves additional components of the metabolic syndrome, such as dyslipidemia and insulin resistance.14,15 Yet, components of metabolic syndrome do not necessarily confer short-term risk of CVD. Therefore, clinical translation to patients regarding information about these components should extend beyond short-term direction; patients need to understand how best to achieve the goals of long-term management. 
Integrating components of cardiometabolic syndrome into concepts of prediabetes and prehypertension is controversial for a number of reasons.6,16 For example, the risk imparted by the various components of cardiometabolic syndrome may be greater than the risk of the syndrome itself—raising the question as to whether the components act synergistically.6,7 
Diabetes, Cardiovascular Disease, and Obesity
Because the metabolic syndrome usually predates diabetes, it can be predictive of the onset of T2DM.1,4 
Ford1,4 calculated the population-attributable risk (PAR) for T2DM in patients with metabolic syndrome (as defined by WHO and NCEP), concluding that the PAR was between 30% and 52%. Wilson et al17 confirmed that the metabolic syndrome is a powerful predictor for T2DM, finding a PAR of 62% in men and 47% in women. In addition, an elevated blood glucose level (>100 mg/dL) has been associated with the highest risk for development of diabetes.1 The combination of abdominal obesity, elevated blood glucose level, and low HDL-cholesterol level is associated with a 12-fold risk of the development of T2DM.1 
Image not available
View Original  |  Slide (.ppt)
Image not available
View Original  |  Slide (.ppt)
Metabolic syndrome is also a precursor of CVD.1,17,18 Florez et al1 reported that based on the WHO and NCEP definitions of metabolic syndrome, the PAR for CVD ranged from 12% to 17%. This report1 found that the components of the metabolic syndrome that contributed most to cardiovascular outcomes were hypertension and low HDL-cholesterol level, with PAR estimates of 33% and 25%, respectively.1 
In the Insulin Resistance Atherosclerosis Study,1,19 the strongest predictor of metabolic syndrome was waist circumference. Because abdominal obesity may precede the development of components of metabolic syndrome, managing overweight and obesity is a high priority in addressing this syndrome. However, it is important to recognize that insulin resistance may be manifested in individuals who have visceral adiposity but are not overweight or obese.1,20 People of Asian descent are at particular risk for such visceral fat distribution and insulin resistance1,20 
Translation Into Patient Treatment
Several subclinical markers for metabolic syndrome may be difficult to translate into patient treatment, but these markers can be extremely important from a pathologic and physiologic perspective. They include increased levels of several adipokines and inflammatory cytokines, such as TNF-α and interleukin 6.5 High-sensitivity C-reactive protein, a widely known biomarker, is among the other subclinical markers that may correlate with the severity of metabolic syndrome and a patient's risk profile.1,21,22 
The primary goal of the management of metabolic syndrome should be the reduction of cardiovascular risk. Achieving this goal involves an understanding by both physician and patient of the individual components of metabolic syndrome. Emphasis should be placed by the physician on understanding these components, rather than on the confusing terminology of metabolic syndrome. Proactive involvement by the patient should involve lifestyle modification. 
During physician-patient clinical encounters, effective communication in an easy-to-understand format is imperative. Using such terminology as cardiovascular syndrome, insulin resistance syndrome, metabolic syndrome, or syndrome X may serve only to confuse the patient. That is why addressing the components of metabolic syndrome with the direction of therapeutic intent and intervention is much more salient. Discussing terms that represent a compilation of disease conditions will not emphasize the importance to the patient of the individual comorbidities. 
Perspectives on the Metabolic Syndrome
In this month's supplement to JAOA—The Journal of the American Osteopathic Association, Thomas B. Repas, DO, discusses several aspects of the metabolic syndrome, with emphasis on the obesity link (2007;107[suppl 2]:S4-S11). The following comments are directed to current thoughts and controversies regarding the metabolic syndrome as they relate to Dr Repas's article. 
Current estimates of the prevalence of obesity in the United States are based on analyses from the National Health and Nutrition Examination Survey (NHANES) 1999-2002.23 According to this information, an estimated 30.5% of American adults are obese and 64.5% are overweight.23 Among American children and adolescents, 31% are overweight or obese based on the NHANES 1999-2002 data.23 Obesity is an independent risk factor for CVD and is associated with chronic inflammation, as well as being a key component of cardiometabolic syndrome.24-27 
Providing a greater amount of effective options for both pharmacologic and nonpharmacologic intervention is certainly of interest in cases involving cardiometabolic risk. However, it must be remembered that cannabinoid receptors are found in many tissues, including adipose tissue and tissues of the central nervous system and liver.24,25 Thus, the endocannabinoid system is a ubiquitous system in which there may be various unwanted effects that could affect drug safety, including effects that have yet to be identified. 
Joseph L. Lillo, DO, addresses the relationship of the endocannabinoid system to obesity management in this JAOA supplement issue (2007;107[suppl 2]:S12-S20). Dr Lillo reviews the principles of the Rimonabant in Obesity (RIO) clinical trials.28-31 The RIO trials were international studies of the effect of rimonabant on individuals with various cultural and psychosocial backgrounds. Analyses of such a diverse group may be quite challenging. 
In the RIO trials, patients without T2DM who received 20 mg of rimonabant per day achieved an average weight loss of between 6.3 and 6.9 kg after 1 year of treatment, while patients with T2DM lost an average of 5.3 kg.28-31 Unfortunately, durability data for rimonabant beyond 2 years was not available. Thus, one is left to wonder if the weight loss would continue, plateau, or increase over additional time. The decrease in waist circumference observed in the RIO trials ranged from 3.3 to 4.7 cm with a dosage of 20 mg of rimonabant per day, compared with placebo.28-31 Left unanswered was whether certain populations in this diverse sample were more susceptible to weight loss and reductions in waist circumference. 
The beneficial effects of rimonabant on triglyceride concentrations and HDL cholesterol were also demonstrated during the RIO trials.28-31 These results were impressive, but lipid parameters were not necessarily controlled as a primary clinical end point. This is an important point, because if patients were exercising or taking fibric acid, fish oil, neutraceuticals, niacin, or statins, the results could have been influenced. 
When introducing a new class of medication into the therapeutic paradigm, it is essential to compare the new agent with existing modes of therapy. Noninferiority—and preferably superiority—compared with existing medications must be clearly demonstrated to indicate the usefulness of any new drug. The RIO trials, however, compared rimonabant with only placebo in patients on reduced-calorie diets. Direct comparisons of rimonabant with other weight-loss medications, such as glucagonlike peptide-1 agonists or analogs, would be of great interest. 
Comment
The new drug class of cannabinoid receptor 1 antagonists is an exciting addition to the therapeutic paradigm for patients with obesity, but the long-term safety and durability of these medications remain of concern. Longer-term clinical trials, including analyses of combinations with other medications, are needed to assess safety, looking at such issues as exacerbation of depression. 
Florez HJ, Goldberg RB. Metabolic syndrome—a useful clinical marker of increased risk for type 2 diabetes and cardiovascular disease. Lipid Spin. 2006;4:1-7.
Itoh H. What is `metabolic domino effect'?—new concept in lifestyle-related diseases [review; in Japanese]. Nippon Rinsho. 2003;61:1837-1843.
The DECODE Study Group; Qiao Q. Comparison of different definitions of the metabolic syndrome in relation to cardiovascular mortality in European men and women. Diabetologia. 2006;49:2837-2846. Epub 2006 Oct 5.
Ford ES. Insulin resistance syndrome: the public health challenge. Endocr Pract. 2003;9(suppl 2):23-25.
Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;40:1286-1292.
Kahn R. The Metabolic syndrome (emperor) wears no clothes [commentary]. Diabetes Care. 2006;29:1693-1696. Available at: http://care.diabetesjournals.org/cgi/content/full/29/7/1693. Accessed April 23, 2007.
Grundy SM. Does the metabolic syndrome exist? Diabetes Care. 2006;29:1689-1692.
Balkau B, Charles MA, European Group for the Study of Insulin Resistance (EGIR). Comment on the provisional report from the WHO consultation. Diabet Med. 1999;16:442-443.
Alberti KG, Zimmet PS. Definition, diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539-553.
Lorenzo C, Williams K, Gonzalez-Villalpando C, Haffner SM. The prevalence of the metabolic syndrome did not increase in Mexico City between 1990-1992 and 1997-1999 despite more central obesity. Diabetes Care. 2005;28:2480-2485.
Balkau B, Vernay M, Mhamdi L, Novak M, Arondel D, Vol S, et al: The French D.E.S.I.R. Study Group. The incidence and persistence of the NCEP (National Cholesterold Education Program) metabolic syndrome. The French D.E.S.I.R. study. Diabetes Metab. 2003;29:526-532.
Watson K, ed. Managing Cardiometabolic Risk: An Evolving Approach to Patient Care. sanofiaventis US.
Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2005. Available at: http://ndep.nih.gov/diabetes/pubs/2005_National_Diabetes_Fact_Sheet.pdf. Accessed April 23, 2007.
Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation. 2004;110:2952-2967. Epub 2004 Oct 27. Available at: http://circ.ahajournals.org/cgi/content/full/110/18/2952. Accessed April 23, 2007.
Aronne LJ. Classification of obesity and assessment of obesity-related health risks [review]. Obesity Res. 2002;10(suppl 1):105S-115S. Available at: http://www.obesityresearch.org/cgi/content/full/10/suppl_2/105S. Accessed April 23, 2007.
Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47:1093-1100. Epub 2006 Feb 23.
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. Available at: http://circ.ahajournals.org/cgi/content/full/112/20/3066. Accessed April 23, 2007.
Kahn R, Buse J, Ferrannini E, Stern M; American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes [review]. Diabetes Care. 2005;28:2289-2304. Available at: http://care.diabetesjournals.org/cgi/content/full/28/9/2289. Accessed April 23, 2007.
Palaniappan L, Carnethon MR, Wang Y, Hanley AJ, Fortmann SP, Haffner SM, et al. Predictors of the incident metabolic syndrome in adults: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 2004;27:788-93. Available at: http://care.diabetesjournals.org/cgi/content/full/27/3/788. Accessed April 23, 2007.
Tan CE, Ma S, Wai D, Chew SK, Tai ES. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care. 2004;27:1182-1186. Available at: http://care.diabetesjournals.org/cgi/content/full/27/5/1182. Accessed April 23, 2007.
Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996;312:1061-1065. Available at: http://www.bmj.com/cgi/content/full/312/7038/1061. Accessed April 23, 2007.
Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17(6):1121-1127. Available at: http://atvb.ahajournals.org/cgi/content/full/17/6/1121. Accessed April 23, 2007.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295:1549-1555.
Woods SC, Sakai RR. The endocannabinoid system: what is it? Baylor College of Medicine Reports on Cardiometabolic Disorders. 2006;1:1-10.
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity and Metabolism. Circulation. 2006;113:898-918. Available at: http://circ.ahajournals.org/cgi/content/full/113/6/898. Accessed April 23, 2007.
Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation. 2004;110:2952-2967. Epub 2004 Oct 27. Available at: http://circ.ahajournals.org/cgi/content/full/110/18/2952. Accessed April 23, 2007.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76-79.
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; for the RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial [published correction appears in JAMA. 2006;295:1252]. JAMA. 2006;295:761-775.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S; for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study [published correction appears in Lancet. 2005;366:370]. Lancet. 2005;365:1389-1397.
Despres JP, Golay A, Sjostrom L; for the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
Scheen, AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF; for the RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study [published correction appears in Lancet. 2006;368:1650]. Lancet. 2006;368:1660-1672.
Image not available
View Original  |  Slide (.ppt)
Image not available
View Original  |  Slide (.ppt)