Metabolic Syndrome: Available Evidence Urges to Action the Society and Each of Us

Teodoro Marotta, MD, PhD
Azienda Sanitaria Locale “Napoli 1”, Unità Operativa Assistenza Sanitaria di Base, Naples, Italy

A Risky Condition

Three new prospective, general-population-based studies published in the first months of this year [1-3], in which data of 24,800; 24,100; and 13,300 person-years, respectively, have been analyzed, highlight the link of metabolic syndrome (MS) with total [1,2] and cardiovascular [1-3] mortality. In the smallest of these studies [3], indeed, the association of cardiovascular mortality with MS was not stronger than that with the single components of the syndrome. However, just one year ago, in another wider population (46,300 person-years) an independent association between MS and cardiovascular mortality, beyond the effects of other well-established cardiovascular risk factors [4], was observed. Therefore, although the topic of the clinical relevance of MS is still debated [5,6], overall the last available data reinforce the conclusion of the recent meta-analysis by Gami et al. [7], i.e. that MS is a very risky condition. Analyzing data obtained from more than 170,000 persons, the authors found that the probability of cardiovascular events and death was increased by 78% in the presence of MS. The finding was statistically robust: 95% confidence interval (CI) of the relative risk was 1.58-2.00. When the usual cardiovascular risk factors were taken into account, the association was still highly significant (relative risk = 1.54, 95% CI = 1.32-1.79). Many recent studies have shown that incident cardiovascular disease is increased by MS [8-12], which is a predictor of cardiovascular events as good as the conventional coronary risk equations [13]. In a population-based study, the pooled risk of cardiovascular death, coronary heart disease, and stroke attributable to MS approximated that of low density lipoprotein (LDL) cholesterol [14].

A Condition to Which Some People Are More Susceptible Than Others

Women [7,15,16] and elderly people [9,17-20] appear particularly prone to the detrimental consequences of MS. Moreover, in old age the syndrome is more frequent [21,22] and is often underdiagnosed [23]. An association between low social status, as indicated by education, income, and work qualification, and MS prevalence has been observed in many countries, particularly in women [24-34]. This finding has been usually obtained across wide age ranges and very different social levels, or among active workers. However, it is present even in a low-level social context and among retired persons. In the 503 elderly, mostly retired, or never-employed outpatients (73% women) of the ICON study [35], attending two public clinics of the city of Naples, we have found that disparities in education level and in work qualification are associated with differences in blood pressure, body mass index, and serum lipid concentrations. Using the diagnostic criteria of the U.S. National Cholesterol and Education Program (ATP III) [36], odds ratio of MS in the highest of three education groups (just 8 years of school or more), as compared to the lowest one (not more than 4 years of school), was 0.28 (95% CI = 0.15-0.52). Odds ratio of MS in the highest of three work activity groups (craftsmen or more qualified jobs), with the lowest one as reference (mostly housewives), was 0.35 (95% CI = 0.20-0.62). Similar results were obtained using the International Diabetes Federation (IDF) diagnostic criteria [37]. Two separate multivariate logistic regressions where covariates were age, gender, and, alternatively, school education or work activity level, showed a highly significant association of MS with both these social indicators. Moreover, the least educated patients required a more intensive treatment than the others.

A Condition of Which Not Everybody Is Aware

Beside the increased prevalence of MS and, in general, the worse cardiovascular risk profile and clinical outcomes [28,38-41], people with a lower social position have often to face a worse medical assistance [42], which can increase the rate of missing diagnoses of cardiovascular risk factors and target organ damage. Elderly per se often implies social isolation and disadvantage and is frequently accompanied by reduced awareness and low compliance to treatment of cardiovascular disease [43-46]. In the ICON patients [35], we have made 462 new diagnoses, 156 of which concerning previously ignored cardiovascular risk factors (one every three patients) and 127 target organ diseases (one every four patients). Despite the fact that they were not spontaneously attending our clinics, but were referred by their general practitioners, 8% of hypertensives, 16% of diabetics, and 25% of dyslipidemics were not informed of their diseases. We cannot say if this incomplete awareness should be ascribed to an insufficient diagnostic workup or to communication problems, but the effect was that the impending risk for our patients was strongly increased. No wonder if none of them knew anything about MS; however, recent data indicate that even many doctors do not have adequate knowledge of the role of all its components as cardiovascular risk factors [47].

A Condition That Should Be Faced From a Double Perspective

The three points outlined above (high impact of MS on public health, high prevalence in the old age and in the disadvantaged social classes, scarce awareness of the problem among lay people and many health professionals) underscore the importance of health policies addressed to improve knowledge, prevention, diagnosis, and treatment of all MS components. Although extensive studies on cost-effectiveness of MS treatment in the general population are lacking, available data about several of its components indicate that improving their control would lead to economic advantages for the health systems and the whole society [48,49]. In particular, some neglected MS elements (abdominal obesity, low high density lipoprotein [HDL] cholesterol levels, hypertriglyceridemia, suboptimal blood pressure levels, impaired fasting glucose, impaired glucose tolerance) deserve more attention by public authorities, in addition to the effort often performed to face other cardiovascular risk factors, such as diabetes, frank hypertension, and high LDL cholesterol. Moreover, risk factor clustering should be addressed by health institutions as an additional target, at variance of what is done in some countries. The Italian National Drug Agency (Agenzia Italiana del Farmaco, AIFA), for example, states in its last official directory to family doctors that, in the case of multiple cardiovascular risk factors, the physician should choose which ones to treat and which ones to leave untreated, since “it cannot be proposed to assume drugs for each of them” [50]. Moreover, for the prescription of lipid-lowering drugs, AIFA refers physicians to the risk charts produced by the National Health Institute (Istituto Superiore di Sanità, ISS) [51], which take into account ages between 40 and 69 years, gender, smoking status, diabetes, systolic blood pressure, and total cholesterol. Unfortunately, they ignore older ages, visceral adiposity, triglyceride levels, and prediabetic states, as well as signs of target organ damage. HDL cholesterol, too, is omitted in the charts, although it can be entered in the risk calculator available on the ISS website.
But in approaching the treatment of MS, as always in medicine, there is another level to be considered, besides that of health policy and resource allocation ─ it is the level of interaction between the individual physician and the individual patient. To obtain adequate compliance is a critical step of each therapy. Moreover, cardiovascular disease prevention, and MS control in particular, are strictly linked to the patient’s lifestyle [52,53] and changes in this field often require strong motivation. Several authorities recommend addressing the issue of doctor-patient interaction to improve cardiovascular risk profile [36,54,55]. The Seventh Report of the U.S. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) discusses the role of patients’ trust in their doctor as a potent motivator to follow drug and lifestyle prescriptions [55]. Empathy is essential to build trusting and join the patient in a therapeutic alliance [55,56], which in turn can improve clinical outcomes. Systematic revisions of the literature strongly suggest that a good patient-physician relationship and a warm, reassuring style of communication significantly affects important outcomes, such as patient and physician satisfaction, perceived quality of life, anxiety, glycemic control, and blood pressure [57,58]. This is specially true for the elderly and the low social level patients, where compliance problems are more pronounced [41,46]. In the ICON study, providing an empathetic approach and implementing JNC 7 recommendations to build an effective therapeutic alliance has led to a significantly improved control rate of several cardiovascular risk factors, including obesity, hypertension, glucose intolerance, dyslipidemias, and smoking habit. The number of patients fitting the ATP III criteria for MS decreased from 47% of the whole sample at baseline to 34% at the end of follow-up [35] (p < 0.05 at the χ2 test).
The political and the individual-patient/individual-doctor levels are not independent, but on the contrary are strictly interconnected. On one hand, politicians have the responsibility to shape health systems where physicians are not bound by excessive regulatory ties, which can “sterilize” the patient-physician relationship and lead to the deprofessionalization of medicine [59]. On the other hand, each doctor, in his/her profession, is committed to hold and, if necessary, revitalize ethical values which are essential in building social trust towards the medical profession [60,61].

References

1. Mancia G, Bombelli M, Corrao G, et al. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis. Hypertension 2007;49:40-47.
2. Thomas GN, Schooling CM, McGhee SM, et al., for the Hong Kong Cardiovascular Risk Factor Prevalence Study Steering Committee. Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong Cardiovascular Risk Factor Study. Clin Endocrinol (Oxf) 2007 March 23 [e-pub ahead of print].
3. Wang J, Ruotsalainen S, Moilanen L, Lepisto P, Laakso M, Kuusisto. J. The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J 2007;28:857-64.
4. Sundström J, Risérus U, Byberg L, Zethelius B, Lithell H, Lind L. Clinical value of the metabolic syndrome for long term prediction of total and cardiovascular mortality: prospective, population based cohort study. Br Med J 2006;332;878-82.
5. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-304.
6. Farmer A. Commentary: metabolic syndrome and mortality. Br Med J 2006;332:882.
7. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403-14.
8. Bataille V, Perret B, Dallongeville J, et al. Metabolic syndrome and coronary heart disease risk in a population-based study of middle-aged men from France and Northern Ireland. A nested case-control study from the PRIME cohort. Diabetes Metab 2006;32:475-79.
9. McNeill AM, Katz R, Girman CJ, et al. Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. J Am Geriatr Soc 2006;54:1317-24.
10. Kurl S, Laukkanen JA, Niskanen L, et al. Metabolic syndrome and the risk of stroke in middle-aged men. Stroke 2006;37:806-11.
11. Assmann G, Guerra R, Fox G, et al. Harmonizing the definition of the metabolic syndrome: comparison of the criteria of the Adult Treatment Panel III and the International Diabetes Federation in United States American and European populations. Am J Cardiol 2007;99:541-48.
12. Nilsson PM, Engstrom G, Hedblad B. The metabolic syndrome and incidence of cardiovascular disease in non-diabetic subjects – A population-based study comparing different definitions. Diabet Med 2007; March 22 [e-pub ahead of print].
13. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care 2007;30:8-13.
14. Jeppesen J, Hansen TW, Rasmussen S, Ibsen H, Torp-Pedersen C. Metabolic syndrome, low-density lipoprotein cholesterol, and risk of cardiovascular disease: a population-based study. Atherosclerosis 2006;89:369-74.
15. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K, for the DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004;164:1066-76.
16. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004;110:1251-57.
17. Maggi S, Noale M, Gallina P, et al., for the ILSA working group. Metabolic syndrome, diabetes, and cardiovascular disease in an elderly Caucasian cohort: the Italian Longitudinal Study on Aging. J Gerontol A Biol Sci Med Sci 2006;61:505-10.
18. Lao XQ, Thomas GN, Jiang CQ, et al. Association of the metabolic syndrome with vascular disease in an older Chinese population: Guangzhou Biobank Cohort Study. J Endocrinol Invest 2006;29:989-96.
19. Butler J, Rodondi N, Zhu Y, et al; Health ABC Study. Metabolic syndrome and the risk of cardiovascular disease in older adults. J Am Coll Cardiol 2006;47:1595-602.
20. Simons LA, Simons J, Friedlander Y, McCallum J. Does a diagnosis of the metabolic syndrome provide additional prediction of cardiovascular disease and total mortality in the elderly? The Dubbo Study. Med J Aust 2007;186:400-403.
21. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415-28.
22. Scuteri A, Najjar SS, Morrell CH, Lakatta EG, for the Cardiovascular Health Study. The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care 2005;28:882-87.
23. Gause-Nilsson I, Gherman S, Kumar Dey D, Kennerfalk A, Steen B. Prevalence of metabolic syndrome in an elderly Swedish population. Acta Diabetol 2006;43:120-26.
24. Wamala SP, Lynch J, Horsten M, Mittleman MA, Schenck-Gustaffson K, Orth-Gomér K. Education and the metabolic syndrome in women. Diabetes Care 1999;22:1999-2003.
25. Dallongeville J, Cottel D, Ferrières J, et al. Household income is associated with the risk of metabolic syndrome in a sex-specific manner. Diabetes Care 2005;28:409-15.
26. Alegrìa E, Cordero A, Laclaustra M, et al. Prevalence of metabolic syndrome in the Spanish working population: MESYAS registry. Rev Esp Cardiol 2005;58:797-806.
27. Carnethon MR, Loria CM, Hill JO, Sidney S, Savage PJ, Liu K. Risk factors for the metabolic syndrome. The Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985-2001. Diabetes Care 2004;27:2707-15.
28. Silventoinen K, Pankow J, Lousilahti P, Hu G, Tuomilehto J. Educational inequalities in the metabolic syndrome and coronary heart disease among middle-aged men and women. Int J Epidemiol 2005;34:327-34.
29. Stelmach W, Kaczmarczyk-Chalas K, Bielecki W, Drygas W. How education, income, control over life and life style contribute to risk factors for cardiovascular disease among adults in a post-communist country. Public Health 2005;119:498-508.
30. Langenberg C, Kuh D, Wadsworth ME, Brunner E, Hardy R. Social circumstances and education: life course origins of social inequalities in metabolic risk in a prospective national birth cohort. Am J Public Health 2006;96:2216-21.
31. Perel P, Langenberg C, Ferrie J, Moser K, Brunner E, Marmot M. Household wealth and the metabolic syndrome in the Whitehall II Study. Diabetes Care2006;29:2694-2700.
32. Loucks EB, Rehkopf DH, Thurston RC, Kawachi. Socioeconomic disparities in metabolic syndrome differ by gender: evidence from NHANES III. Ann Epidemiol 2007;17:19-26.
33. Chiu YH, Lin WY, Wang PE, et al. Population-based family case-control proband study on familial aggregation of metabolic syndrome: finding from Taiwanese people involved in Keelung community-based integrated screening (KCIS no. 5). Diabetes Res Clin Pract 2007;75: 348-56.
34. Park MJ, Yun KE, Lee GE, Cho HJ, Park HS. A cross-sectional study of socioeconomic status and the metabolic syndrome in Korean adults. Ann Epidemiol 2007 February 12; [e-pub ahead of print].
35. Marotta T, Viola S, Ferrara F, Ferrara LA. Improvement of cardiovascular risk profile in an elderly population of low social level: the ICON (Improving Cardiovascular risk profile in Older Neapolitans) study. J Hum Hypertension 2007;21:76-85.
36. 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;285:2486-97.
37. Alberti KGMM, Zimmet P, Shaw J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005;366:1059-62.
38. Kunst AE, Groenhof F, Mackenbach JP. Health EW. Occupational class and cause specific mortality in middle aged men in 11 European countries: comparison of population based studies. EU Working Group on Socioeconomic Inequalities in Health. BMJ 1998;316:1636-42.
39. Bachmann MO, Eachus J, Hopper CD, et al. Socio-economic inequalities in diabetes complications, control, attitudes and health service use: a cross-sectional study. Diabetic Medicine 2003;20:921-29.
40. Rutledge T, Reis SE, Olson M, et al. Socioeconomic status variables predict cardiovascular disease risk factors and prospective mortality risk among women with chest pain. The Wise Study. Behav Modif 2003;27:54-67.
41. Mayer O Jr, Šimon J, Heidrich J, Cokkinos DV, De Bacquer D. Educational level and risk profile in the EUROASPIRE II substudy. J Epidemiol Community Health 2004;58:47-52.
42. de Koning JS, Klazinga N, Koudstaal PJ, et al. Deprivation and systematic stroke prevention in general practice: an audit among general practitioners in the Rotterdam region, The Netherlands. Eur J Public Health 2003;13:340-46.
43. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med 2001;345:479-86.
44. Shah S, Cook DG. Inequalities in the treatment and control of hypertension: age, social isolation and lifestyle are more important than economic circumstances. J Hypertens 2001;19:1333-40.
45. Boden-Albala B, Litwak E, Elkind MS, Rundek T, Sacco RL. Social isolation and outcomes post stroke. Neurology 2005 June 14;64(11):1888-92.
46. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005;165:1147-52.
47. Smith SC Jr, Haslam D. Abdominal obesity, waist circumference and cardio-metabolic risk: awareness among primary care physicians, the general population and patients at risk-the Shape of the Nations survey. Curr Med Res Opin 2007;23:29-47.
48. Hay JW, Sterling KL. Cost effectiveness of treating low HDL-cholesterol in the primary prevention of coronary heart disease. Pharmacoeconomics 2005;23:133-41.
49. Kouris-Blazos A, Wahlqvist ML. Health economics and weight management: evidence and cost. Asia Pac J Clin Nutr 2007;16 Suppl:329-38.
50. Agenzia Italiana del Farmaco. Le note AIFA 2007 per l’appropriato uso dei farmaci. In: Bollettino d’Informazione sui Farmaci 2006, anno XIII, n. 6.
51. Progetto Cuore. http://www.cuore.iss.it/, accessed on 16 April 2007.
52. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Impact of lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study. Am Heart J 2004;147:106-12.
53. Rennie KL, McCarthy N, Yazdgerdi S, Marmot M, Brunner E. Association of the metabolic syndrome with both vigorous and moderate physical activity. Int J Epidemiol 2003;32:600-606.
54. Wood D, DeBacker G, Faergeman O, Graham I, Mancia G, Pyöralä K, for the Task Force. Prevention of Coronary Heart Disease in Clinical Practice: recommendations of the second joint Task Force of European and Other Societies on coronary prevention. Atherosclerosis 1998;140:199-270.
55. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
56. Neuwirth ZE. Physician empathy - Should we care? Lancet 1997;350:606.
57. Stewart MA. Effective physician-patient communication and health outcomes: a review. CMAJ 1995;152:1423-33.
58. Di Blasi Z, et al. Influence of context effects on health outcomes: a systematic review. Lancet 2001;357:757-62.
59. Kaissi A. Manager-physician relationships: an organizational theory perspective. Health Care Manag (Frederick) 2005;24:165-76.
60. Medical Professionalism Project. Medical professionalism in the new millennium: a physicians’ charter. Lancet 2002;359:520-22.
61. Horton R. Medicine: the prosperity of virtue. Lancet 2005;366:1985-87.