- Email: [email protected]
The metabolic syndrome
Comment
neighbouring countries. However, the accomplishments [email protected] have certainly outweighed the difficulties. In 20 years, an JD is supported by a Fogarty AITRP grant. We declare that we have no conflicts of effective health-care system has replaced that left by the interest. 1 Anon. Czech senate rejects abolition of health care fees. Ceske Noviny country’s Communist rule. As one of the most successful June 18, 2009. http://www.ceskenoviny.cz/news/zpravy/czech-senaterejects-abolition-of-health-care-fees/383407 (accessed June 19, 2009) overhauls of a health-care system in history continues, (in Czechoslovakian). modern challenges must be properly dealt with in the 2 Anon. Health ministry wants to preserve patients’ fees. Prague Daily Monitor June 17, 2009. http://praguemonitor.com/2009/06/17/czechnext 20 years and beyond. health-ministry-wants-preserve-patients-fees (accessed June 19, 2009). 3
Petra Antonova, Daniel I Jacobs, Martin Bojar, Rudolf Černý, Katerina Ciharová, Melissa A Frick, Bara Fintel, Jack DeHovitz, *Charles L Bennett Cardiovascular Centre, University Hospital Motol, Prague, Czech Republic (PA); Robert H Lurie Comprehensive Cancer Center and the Buehler Center on Aging, Health & Society at the Northwestern University Feinberg School of Medicine, Chicago, IL, USA (DIJ, MAF, BF, CLB); Charles University Department of Neurology, Prague, Czech Republic (MB, RC); Innovation Leadership Advisors, Prague, Czech Republic (KC); School of Public Health, SUNY Downstate Medical Center, Brooklyn, NY, USA (JD); and Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA (CLB)
4 5 6
7
8
European Health For All Database. June, 2009. http://data.euro.who.int/ hfadb (accessed June 19, 2009). WHO Statistical Information System, Czech Republic. http://www.who.int/ countries/cze/en (accessed June 19, 2009). WHO Regional Office for Europe. Highlights on health. June, 2009. http:// www.euro.who.int/Document/E88735.pdf (accessed June 22, 2009). OECD. OECD factbook 2009. June, 2009. http://www.oecd.org/document/ 62/0,3343,en_21571361_34374092_34420734_1_1_1_1,00.html (accessed June 22, 2009). Institute of Health Information and Statistics of the Czech Republic. Health Care and Health Services in the Czech Republic 2007. July, 2008. http:// www.uzis.cz/news.php?mnu_id=1100&lng=en (accessed June 19, 2009) (in Czechoslovakian). Anon. New HIV cases increasing in Czech Republic; most cases reported among men. Medical News Today Jan 30, 2009. http://www. medicalnewstoday.com/articles/137282.php (accessed June 22, 2009).
The metabolic syndrome Although the metabolic syndrome has existed in various forms and definitions for more than eight decades, only in the past 5 years has real controversy about its definition and significance emerged.1 The main controversy was that the syndrome had had too many definitions and there was a lack of clarity about its role and value in clinical practice. And it is fair to say, with exception,2 that most of the published reports indicate that the syndrome does not predict cardiovascular events or disease progression any better than the sum of its components.3,4 The relative value in predicting type 2 diabetes remains uncertain.5 The controversy, however, drove the need for a single global definition. Thus came the initiative of the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), joined by the World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity1 to develop one unified definition, which has now been published (table).6 The main difference between the NCEP ATP III (National Cholesterol Education Program Expert Panel www.thelancet.com Vol 375 January 16, 2010
on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults)7 and the IDF definitions8 was that the IDF had a threshold value for waist circumference as obligatory. As a major step in consensus, this obligation has been reversed so that we now have a platform for standardised reporting in epidemiological and clinical research. Yet, because the relation between waist circumference and cardiovascular disease and diabetes risk differs globally, the definition for the expanded waist circumference remains unsettled. In the meantime, national or regional cutpoints for waist circumference can be used. Insulin resistance continues to explain most if not all of the metabolic syndrome. In fact, no other mechanisms have emerged that come close to justifying the individual components or their clustering. Evidence now indicates that the metabolic syndrome all begins with excess central adiposity.9 When β-cell function is responsive, hyperinsulinaemia results but fasting and postprandial glycaemia often remain normal for years. However, in those genetically predisposed, defects in insulin secretion and impaired fasting glucose and/or impaired glucose tolerance follow.10 181
Comment
Categorical cutpoints Increased waist circumference*
Population-specific and country-specific definitions
Increased triglycerides (drug treatment for elevated TG is alternate indicator†)
≥150 mg/dL (1·7mmol/L)
Reduced HDL cholesterol (drug treatment for reduced HDL cholesterol is alternate indicator†)
<40 mg/dL (1·0 mmol/L) in men; <50 mg/dL (1·3 mmol/L) in women
Increased blood pressure (antihypertensive drug treatment Systolic ≥130 and/or diastolic ≥85 mm Hg in patient with history of hypertension is alternate indicator) Increased fasting glucose‡ (drug treatment of increased glucose is alternate indicator)
> 100 mg/dL (5·5 mmol/L)
*It is recommended that the IDF cutpoints be used for non-Europeans and either the IDF or AHA/NHLBI cutpoints used for people of European origin until more data are available. †Most commonly used drugs for increased triglycerides and reduced HDL cholesterol are fibrates and nicotinic acid. A patient on one of these drugs can be presumed to have high triglycerides and low HDL. Use of high-dose ω-3 fatty acids presumes high triglycerides. ‡Most patients with type 2 diabetes will have the metabolic syndrome by the proposed criteria.
Table: Criteria for clinical diagnosis of metabolic syndrome
Most controversial has been the mechanism of hypertension under the tent of insulin resistance. However, not only are the effects of insulin on sodium reabsorption and sympathetic nervous system activation maintained despite insulin resistance, but increases in angiotensinogen, resistin, and leptin secretion from adipose tissue have also all been implicated in the pathophysiology of hypertension in the syndrome.11 Moreover, insulin resistance is closely associated with abnormalities in nitric oxide (NO) bioavailability and reduced PI3K/Akt signalling in the vascular wall, both of which have a crucial role in mobilisation of endothelial progenitor cells from bone marrow. And not only do higher levels of free fatty acids directly reduce NO-dependent vasodilatation, but insulin resistance itself also results in structural or functional damage to the endothelium and apoptosis. Reparative processes that regenerate injured endothelium might be increased by agents such as PPARγ agonists that enhance insulin sensitivity, an effect mediated by endothelial progenitor cells.12 Genetic predisposition also relates to the metabolic syndrome. A recent study found that a polymorphism in the multi-PDZ domain-containing adaptor protein (PDZK1), a protein that regulates the HDL-receptor scavenger-receptor type B class 1, was associated with the metabolic syndrome.13 Shift work, sleep deprivation, and bright-light exposure at night also relate to increased adiposity and prevalence of the metabolic syndrome; clock genes are expressed in adipose tissue, and both their levels of expression and their genetic variants correlate with different components of the syndrome.14 182
Another area of recent interest is vitamin D. Increasing evidence indicates that vitamin D deficiency is associated with risk of cardiovascular disease. Particularly relevant is a study that examined the association of serum vitamin D concentrations with risk factors for cardiovascular disease in US adolescents.15 In 3577 adolescents without diabetes who took part in the 2001–04 NHANES survey, low concentrations of vitamin D were strongly associated with overweight status and abdominal obesity. And after multiple adjustments, vitamin D concentrations were inversely associated with the metabolic syndrome (relative risk 3·88, 95% CI 1·57–9·58). The hypothesis that the metabolic syndrome is an outgrowth of insulin resistance provides a strategy for management. Weight loss often reduces insulin resistance; and caloric restriction, weight-loss drugs, and bariatric surgery are proven to be effective. Although long-term weight reduction through dietary and pharmacological means is theoretically possible, most dietary and weight-loss drug studies have only continued for a few years. By contrast, in one 10-year follow-up after bariatric surgery,16 weight loss of 25% and improvement in the metabolic syndrome were achieved; and total mortality was also reduced. Even in the absence of weight loss, long-term physical activity, as measured by cardiorespiratory fitness, prevents the metabolic syndrome,17 reduces cancer incidence and related mortality, and all-cause mortality.18 Finally, one class of drugs that reduces insulin resistance and many of the components of the syndrome is the thiazolidinediones. These drugs act mainly in adipose tissue to favourably modify secretions of products that contribute to the pathophysiology of the metabolic syndrome, including free fatty acids and adipocytokines. The major effect of thiazolidinediones is on dysglycaemia, which accounts for their use in the treatment of diabetes, yet the class as a whole has anti-inflammatory effects. At present, however, drug therapy for the metabolic syndrome largely requires separate agents for the treatment of dysglycaemia, dyslipidaemia, and hypertension.19 The metabolic syndrome is a widely accepted concept that identifies the centrally obese patient with increased risk for cardiovascular disease and diabetes. A global definition has now been proposed, insights into aetiology and mechanisms have been furthered, and, despite the controversies, lifestyle interventions remain the primary www.thelancet.com Vol 375 January 16, 2010
Comment
therapy. After lifestyle, residual risk for cardiovascular disease needs to be treated with appropriate drugs. *Robert H Eckel, K G M M Alberti, Scott M Grundy, Paul Z Zimmet University of Colorado Denver School of Medicine, Anschutz Medical Campus, Denver, CO 80045, USA (RHE); Imperial College, St Mary’s Campus, London, UK (KGMMA); University of Texas Southwestern Medical Center, Dallas, TX, USA (SMG); and Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (PZZ) [email protected] RHE has a research grant from and is a consultant or on an advisory board for Sanofi-Aventis; he is also on speakers’ bureau for or has received honoraria from INNOVIA (Sanofi-Aventis sponsored), Vindico (Merck sponsored), SciMed, and the Cardiometabolic Health Congress. KGMMA is a consultant or on an advisory board for AstraZeneca, Boehringer Ingelheim, and Servier. SMG has research grants from Merck Project and Abbott, and is a consultant or on an advisory board for Merck, Merck Schering Plough, AstraZeneca, Pfizer, and GlaxoSmithKline. PZZ is a consultant or on an advisory board for GlaxoSmithKline, Sanofi-Aventis, Roche, Lilly, Novartis, and the Institute for Diabetes Discovery. All authors received fees from the Metabolic Research Institute funded by Solvay and Abbott, and co-chaired an International Diabetes Federation Workshop on the Metabolic Syndrome jointly funded by an educational grant from AstraZeneca, Sanofi-Aventis, and the Metabolic Research Institute (Abbott and Solvay). 1
2
3
4
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. 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. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham risk score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005; 165: 2644–50. Koskinen J, Kahonen M, Viikari JS, et al. Conventional cardiovascular risk factors and metabolic syndrome in predicting carotid intima-media thickness progression in young adults: the cardiovascular risk in young Finns study. Circulation 2009; 120: 229–36. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31: 1898–904.
www.thelancet.com Vol 375 January 16, 2010
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7
8 9
10
11 12
13
14 15 16 17
18
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Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640–45. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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): final report. Circulation 2002; 106: 3143–421. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet 2005; 366: 1059–62. Cameron AJ, Boyko EJ, Sicree RA, et al. Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius. Obesity (Silver Spring) 2008; 16: 2707–16. Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 2009; 373: 2215–21. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev 2008; 29: 777–822. Cubbon RM, Kahn MB, Wheatcroft SB. Effects of insulin resistance on endothelial progenitor cells and vascular repair. Clin Sci (Lond) 2009; 117: 173–90. Junyent M, Arnett DK, Tsai MY, et al. Genetic variants at the PDZ-interacting domain of the scavenger receptor class B type I interact with diet to influence the risk of metabolic syndrome in obese men and women. J Nutr 2009; 139: 842–48. Garaulet M, Madrid JA. Chronobiology, genetics and metabolic syndrome. Curr Opin Lipidol 2009; 20: 127–34. Reis JP, von Mühlen D, Miller ER 3rd, Michos ED, Appel LJ. Vitamin D. Pediatrics 2009; 124: e371–79. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 741–52. LaMonte MJ, Barlow CE, Jurca R, Kampert JB, Church TS, Blair SN. Cardiorespiratory fitness is inversely associated with the incidence of metabolic syndrome: a prospective study of men and women. Circulation 2005; 112: 505–12. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009; 301: 2024–35. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006; 5: 295–309.
183
neighbouring countries. However, the accomplishments [email protected] have certainly outweighed the difficulties. In 20 years, an JD is supported by a Fogarty AITRP grant. We declare that we have no conflicts of effective health-care system has replaced that left by the interest. 1 Anon. Czech senate rejects abolition of health care fees. Ceske Noviny country’s Communist rule. As one of the most successful June 18, 2009. http://www.ceskenoviny.cz/news/zpravy/czech-senaterejects-abolition-of-health-care-fees/383407 (accessed June 19, 2009) overhauls of a health-care system in history continues, (in Czechoslovakian). modern challenges must be properly dealt with in the 2 Anon. Health ministry wants to preserve patients’ fees. Prague Daily Monitor June 17, 2009. http://praguemonitor.com/2009/06/17/czechnext 20 years and beyond. health-ministry-wants-preserve-patients-fees (accessed June 19, 2009). 3
Petra Antonova, Daniel I Jacobs, Martin Bojar, Rudolf Černý, Katerina Ciharová, Melissa A Frick, Bara Fintel, Jack DeHovitz, *Charles L Bennett Cardiovascular Centre, University Hospital Motol, Prague, Czech Republic (PA); Robert H Lurie Comprehensive Cancer Center and the Buehler Center on Aging, Health & Society at the Northwestern University Feinberg School of Medicine, Chicago, IL, USA (DIJ, MAF, BF, CLB); Charles University Department of Neurology, Prague, Czech Republic (MB, RC); Innovation Leadership Advisors, Prague, Czech Republic (KC); School of Public Health, SUNY Downstate Medical Center, Brooklyn, NY, USA (JD); and Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA (CLB)
4 5 6
7
8
European Health For All Database. June, 2009. http://data.euro.who.int/ hfadb (accessed June 19, 2009). WHO Statistical Information System, Czech Republic. http://www.who.int/ countries/cze/en (accessed June 19, 2009). WHO Regional Office for Europe. Highlights on health. June, 2009. http:// www.euro.who.int/Document/E88735.pdf (accessed June 22, 2009). OECD. OECD factbook 2009. June, 2009. http://www.oecd.org/document/ 62/0,3343,en_21571361_34374092_34420734_1_1_1_1,00.html (accessed June 22, 2009). Institute of Health Information and Statistics of the Czech Republic. Health Care and Health Services in the Czech Republic 2007. July, 2008. http:// www.uzis.cz/news.php?mnu_id=1100&lng=en (accessed June 19, 2009) (in Czechoslovakian). Anon. New HIV cases increasing in Czech Republic; most cases reported among men. Medical News Today Jan 30, 2009. http://www. medicalnewstoday.com/articles/137282.php (accessed June 22, 2009).
The metabolic syndrome Although the metabolic syndrome has existed in various forms and definitions for more than eight decades, only in the past 5 years has real controversy about its definition and significance emerged.1 The main controversy was that the syndrome had had too many definitions and there was a lack of clarity about its role and value in clinical practice. And it is fair to say, with exception,2 that most of the published reports indicate that the syndrome does not predict cardiovascular events or disease progression any better than the sum of its components.3,4 The relative value in predicting type 2 diabetes remains uncertain.5 The controversy, however, drove the need for a single global definition. Thus came the initiative of the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), joined by the World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity1 to develop one unified definition, which has now been published (table).6 The main difference between the NCEP ATP III (National Cholesterol Education Program Expert Panel www.thelancet.com Vol 375 January 16, 2010
on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults)7 and the IDF definitions8 was that the IDF had a threshold value for waist circumference as obligatory. As a major step in consensus, this obligation has been reversed so that we now have a platform for standardised reporting in epidemiological and clinical research. Yet, because the relation between waist circumference and cardiovascular disease and diabetes risk differs globally, the definition for the expanded waist circumference remains unsettled. In the meantime, national or regional cutpoints for waist circumference can be used. Insulin resistance continues to explain most if not all of the metabolic syndrome. In fact, no other mechanisms have emerged that come close to justifying the individual components or their clustering. Evidence now indicates that the metabolic syndrome all begins with excess central adiposity.9 When β-cell function is responsive, hyperinsulinaemia results but fasting and postprandial glycaemia often remain normal for years. However, in those genetically predisposed, defects in insulin secretion and impaired fasting glucose and/or impaired glucose tolerance follow.10 181
Comment
Categorical cutpoints Increased waist circumference*
Population-specific and country-specific definitions
Increased triglycerides (drug treatment for elevated TG is alternate indicator†)
≥150 mg/dL (1·7mmol/L)
Reduced HDL cholesterol (drug treatment for reduced HDL cholesterol is alternate indicator†)
<40 mg/dL (1·0 mmol/L) in men; <50 mg/dL (1·3 mmol/L) in women
Increased blood pressure (antihypertensive drug treatment Systolic ≥130 and/or diastolic ≥85 mm Hg in patient with history of hypertension is alternate indicator) Increased fasting glucose‡ (drug treatment of increased glucose is alternate indicator)
> 100 mg/dL (5·5 mmol/L)
*It is recommended that the IDF cutpoints be used for non-Europeans and either the IDF or AHA/NHLBI cutpoints used for people of European origin until more data are available. †Most commonly used drugs for increased triglycerides and reduced HDL cholesterol are fibrates and nicotinic acid. A patient on one of these drugs can be presumed to have high triglycerides and low HDL. Use of high-dose ω-3 fatty acids presumes high triglycerides. ‡Most patients with type 2 diabetes will have the metabolic syndrome by the proposed criteria.
Table: Criteria for clinical diagnosis of metabolic syndrome
Most controversial has been the mechanism of hypertension under the tent of insulin resistance. However, not only are the effects of insulin on sodium reabsorption and sympathetic nervous system activation maintained despite insulin resistance, but increases in angiotensinogen, resistin, and leptin secretion from adipose tissue have also all been implicated in the pathophysiology of hypertension in the syndrome.11 Moreover, insulin resistance is closely associated with abnormalities in nitric oxide (NO) bioavailability and reduced PI3K/Akt signalling in the vascular wall, both of which have a crucial role in mobilisation of endothelial progenitor cells from bone marrow. And not only do higher levels of free fatty acids directly reduce NO-dependent vasodilatation, but insulin resistance itself also results in structural or functional damage to the endothelium and apoptosis. Reparative processes that regenerate injured endothelium might be increased by agents such as PPARγ agonists that enhance insulin sensitivity, an effect mediated by endothelial progenitor cells.12 Genetic predisposition also relates to the metabolic syndrome. A recent study found that a polymorphism in the multi-PDZ domain-containing adaptor protein (PDZK1), a protein that regulates the HDL-receptor scavenger-receptor type B class 1, was associated with the metabolic syndrome.13 Shift work, sleep deprivation, and bright-light exposure at night also relate to increased adiposity and prevalence of the metabolic syndrome; clock genes are expressed in adipose tissue, and both their levels of expression and their genetic variants correlate with different components of the syndrome.14 182
Another area of recent interest is vitamin D. Increasing evidence indicates that vitamin D deficiency is associated with risk of cardiovascular disease. Particularly relevant is a study that examined the association of serum vitamin D concentrations with risk factors for cardiovascular disease in US adolescents.15 In 3577 adolescents without diabetes who took part in the 2001–04 NHANES survey, low concentrations of vitamin D were strongly associated with overweight status and abdominal obesity. And after multiple adjustments, vitamin D concentrations were inversely associated with the metabolic syndrome (relative risk 3·88, 95% CI 1·57–9·58). The hypothesis that the metabolic syndrome is an outgrowth of insulin resistance provides a strategy for management. Weight loss often reduces insulin resistance; and caloric restriction, weight-loss drugs, and bariatric surgery are proven to be effective. Although long-term weight reduction through dietary and pharmacological means is theoretically possible, most dietary and weight-loss drug studies have only continued for a few years. By contrast, in one 10-year follow-up after bariatric surgery,16 weight loss of 25% and improvement in the metabolic syndrome were achieved; and total mortality was also reduced. Even in the absence of weight loss, long-term physical activity, as measured by cardiorespiratory fitness, prevents the metabolic syndrome,17 reduces cancer incidence and related mortality, and all-cause mortality.18 Finally, one class of drugs that reduces insulin resistance and many of the components of the syndrome is the thiazolidinediones. These drugs act mainly in adipose tissue to favourably modify secretions of products that contribute to the pathophysiology of the metabolic syndrome, including free fatty acids and adipocytokines. The major effect of thiazolidinediones is on dysglycaemia, which accounts for their use in the treatment of diabetes, yet the class as a whole has anti-inflammatory effects. At present, however, drug therapy for the metabolic syndrome largely requires separate agents for the treatment of dysglycaemia, dyslipidaemia, and hypertension.19 The metabolic syndrome is a widely accepted concept that identifies the centrally obese patient with increased risk for cardiovascular disease and diabetes. A global definition has now been proposed, insights into aetiology and mechanisms have been furthered, and, despite the controversies, lifestyle interventions remain the primary www.thelancet.com Vol 375 January 16, 2010
Comment
therapy. After lifestyle, residual risk for cardiovascular disease needs to be treated with appropriate drugs. *Robert H Eckel, K G M M Alberti, Scott M Grundy, Paul Z Zimmet University of Colorado Denver School of Medicine, Anschutz Medical Campus, Denver, CO 80045, USA (RHE); Imperial College, St Mary’s Campus, London, UK (KGMMA); University of Texas Southwestern Medical Center, Dallas, TX, USA (SMG); and Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (PZZ) [email protected] RHE has a research grant from and is a consultant or on an advisory board for Sanofi-Aventis; he is also on speakers’ bureau for or has received honoraria from INNOVIA (Sanofi-Aventis sponsored), Vindico (Merck sponsored), SciMed, and the Cardiometabolic Health Congress. KGMMA is a consultant or on an advisory board for AstraZeneca, Boehringer Ingelheim, and Servier. SMG has research grants from Merck Project and Abbott, and is a consultant or on an advisory board for Merck, Merck Schering Plough, AstraZeneca, Pfizer, and GlaxoSmithKline. PZZ is a consultant or on an advisory board for GlaxoSmithKline, Sanofi-Aventis, Roche, Lilly, Novartis, and the Institute for Diabetes Discovery. All authors received fees from the Metabolic Research Institute funded by Solvay and Abbott, and co-chaired an International Diabetes Federation Workshop on the Metabolic Syndrome jointly funded by an educational grant from AstraZeneca, Sanofi-Aventis, and the Metabolic Research Institute (Abbott and Solvay). 1
2
3
4
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. 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. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham risk score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005; 165: 2644–50. Koskinen J, Kahonen M, Viikari JS, et al. Conventional cardiovascular risk factors and metabolic syndrome in predicting carotid intima-media thickness progression in young adults: the cardiovascular risk in young Finns study. Circulation 2009; 120: 229–36. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31: 1898–904.
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10
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13
14 15 16 17
18
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Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640–45. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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): final report. Circulation 2002; 106: 3143–421. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet 2005; 366: 1059–62. Cameron AJ, Boyko EJ, Sicree RA, et al. Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius. Obesity (Silver Spring) 2008; 16: 2707–16. Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 2009; 373: 2215–21. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev 2008; 29: 777–822. Cubbon RM, Kahn MB, Wheatcroft SB. Effects of insulin resistance on endothelial progenitor cells and vascular repair. Clin Sci (Lond) 2009; 117: 173–90. Junyent M, Arnett DK, Tsai MY, et al. Genetic variants at the PDZ-interacting domain of the scavenger receptor class B type I interact with diet to influence the risk of metabolic syndrome in obese men and women. J Nutr 2009; 139: 842–48. Garaulet M, Madrid JA. Chronobiology, genetics and metabolic syndrome. Curr Opin Lipidol 2009; 20: 127–34. Reis JP, von Mühlen D, Miller ER 3rd, Michos ED, Appel LJ. Vitamin D. Pediatrics 2009; 124: e371–79. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 741–52. LaMonte MJ, Barlow CE, Jurca R, Kampert JB, Church TS, Blair SN. Cardiorespiratory fitness is inversely associated with the incidence of metabolic syndrome: a prospective study of men and women. Circulation 2005; 112: 505–12. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009; 301: 2024–35. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006; 5: 295–309.
183