7 Metabolic Syndrome: Prevalence Increases with Age 47 million or 23% of US adults have the metabolic syndromeMetabolic Syndrome—Prevalent and Problematic in the USCurrently, approximately 1 in 4 adults in the United States, or 23%, have metabolic syndrome. The incidence of metabolic syndrome is comparable to that of hypertension, which is 24%. These statistics may reflect what physicians see in their own clinical practices. The similarity between metabolic syndrome and hypertension in terms of prevalence should lead one to consider an association between the 2 conditions.As the US population ages, the rate of metabolic syndrome steadily increases among men and women in almost all categories of age. The prevalence of metabolic syndrome among older segments of the population may approach 50%. At 70 years of age and thereafter, the syndrome plateaus in women and declines in men.In terms of race and ethnicity, Mexican Americans have the highest age-adjusted prevalence of the metabolic syndrome—nearly 32%. Significantly lower rates are seen among whites (24%), African Americans (22%), and people reporting an “other” race or ethnicity (20%).Given the prevalence of metabolic syndrome and its strong association with emerging cardiovascular disease and type 2 diabetes, the burden imposed by this syndrome on the US healthcare system is enormous and may seriously strain resources for delivering care as well as escalate cost.Ford ES, Giles WH, Dieta WH. Prevalence of the metabolic syndrome among US adults. Findings From the Third National Health and Nutrition Examination Survey. JAMA ;287:Adapted from: Ford ES, et al. JAMA 2002;287:
13 Metabolic Syndrome1920s: first noted that certain symptoms associated with diabetes1970s & 1980s: cluster of symptoms with increased heath risks for CVD & diabetes1988: Gerald Reaven labeled the cluster “Syndrome X” (史丹佛大學GM Reaven教授 將自八零年代後臨床觀察到的現象加以歸納，提出“胰島素阻抗性症候群”的概念)。 emphasizing the role of insulin resistance1990s: Health agencies around the world began writing their own definitions直到1999年左右，醫界為了方便醫師對病人解釋，才以較通俗的新陳代謝症候群定名。
14 The Emerging Threat of Cardiovascular Disease Cardiovascular disease will be the number one killer in the world in the 21st centuryIncrease due to rising prevalence of risk factorsCigarette smokingObesityMetabolic syndromeType 2 diabetes
15 Cardiovascular Risk Factors: An Evolving Landscape Adapted from J.P. Després Québec Heart Institute, Laval Hospital Research Center, Québec, Canada The metabolic syndrome is largely caused by our sedentary affluent environment where our population is exposed to a diet dense in calories (fat and/or refined sugar). This “toxic” environment produces a positive energy balance and weight gain, which explains the epidemic proportions reached by type 2 diabetes and obesity worldwide. In this context, the metabolic syndrome has become a major issue because of its impact on cardiovascular disease risk. Hyperglycaemia does not appear to be the main culprit responsible for the increased cardiovascular disease risk in this population. Rather, a cluster of metabolic abnormalities which includes an atherogenic dyslipidaemic state, an impaired glucose/insulin homeostasis, a prothrombotic/inflammatory profile as well as an endothelial dysfunction substantially increases the risk of coronary heart disease in type 2 diabetic patients independently from the level of glycaemic control. Furthermore, even non-diabetic patients with the features of the metabolic syndrome are at increased risk of coronary heart disease. The epidemic proportions reached by the metabolic syndrome will require integration of medical specialties for the proper evaluation and management of this condition.
16 The Metabolic Syndrome: An Evolving Concept Scott M. Grundy MD, PhD. University of Texas Southwestern Medical Center, Dallas, TexasThe metabolic syndrome represents a constellation of metabolic risk factors for atherosclerotic cardiovascular disease (ASCVD) occurring in a single individual. There are five metabolic risk factors that accompany the metabolic syndrome: atherogenic dyslipidaemia (elevated apolipoprotein B, elevated triglyceride, small LDL particles, and low HDL-cholesterol), elevated blood pressure, elevated glucose, a prothrombotic state, and a proinflammatory state. The major underlying risk factors for the metabolic syndrome are obesity and insulin resistance. Other factors that can worsen the syndrome are lack of physical activity, advancing age, and hormonal factors (e.g. androgens and corticosteroids). Several different criteria have been proposed for clinical diagnosis of the metabolic syndrome. There is a large amount of overlap among these different criteria, but emphasis is different. For example, the World Health Organization criteria emphasis insulin resistance as the major underlying risk factor, whereas the USA National Cholesterol Education Program places more emphasis on obesity. Most organisations however are in agreement that ASCVD is the major clinical outcome of metabolic syndrome. There is further agreement that metabolic syndrome is a major risk factor for type 2 diabetes. In fact, a significant portion of the ASCVD that develops in patients with the metabolic syndrome occurs in persons after they have developed type 2 diabetes. The underlying risk factors, prevalence and clinical manifestations of the metabolic syndrome vary among different populations. These differences likely represent variations in genetic susceptibilities of the different populations. Regardless, the rising prevalence of obesity in the world heralds a marked increase in the prevalence of metabolic syndrome along with its major outcomes ASCVD and type 2 diabetes. More recently, the IDF has proposed a new definition of the syndrome (derived from the ATP III) with a lower threshold for impaired fasting glucose and ethnic specific cut-points for waist circumference.
17 1998年WHO代謝性症候群的定義 Insulin resistance (必要條件) type 2 diabetes, IFG>110, IGT*Plus any 2 of the followingElevated BPBP >140/90 or drug RxPlasma TGTG > 150 mg/dlHDL-CHDL <35 mg/dl (men); <39mg/dl (women)ObesityBMI >30 and/or W/H >0.9 (men), >0.85 (women)MicroproteinuiraUrinary albumin >20 mg/min; Alb/Cr >30 mg/g(*Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR. )
18 2005 Revised ATP III Clinical Screening Criteria to Identify Metabolic Syndrome (AHA and NHLBI) Measure (any 3 of 5 constitute diagnosis of metabolic syndrome)Categorical cutpointsElevated waist circumference≥102 cm in men ≥88 cm in womenElevated triglycerides≥150 mg/dl (1.7 mmol/l) oron drug treatment for elevated triglyceridesReduced HDL-cholesterol<40 mg/dl (0.9 mmol/l) in men<50 mg/dl (1.1 mmol/l) in womenOr on drug treatment for reduced HDL-CElevated blood pressure≥130 mmHg systolic blood pressure or≥85 mmHg diastolic blood pressureor on antihypertensive drug treatment in a patient with a history of hypertensionElevated fasting glucose≥100 mg/dl oron drug treatment for elevated glucose
19 Diagnosis of The Metabolic Syndrome IDF CRITERIA (2005) Central obesitywaist circumference94 cm for Europid men80 cm for Europid womenethnicity specific values for other groupsPlus any two of the following four factorsTG 150 mg/dlHDL <40 mg/l in males and <50 mg/l in femalesSystolic BP 130 or diastolic BP 85 mmHgFasting plasma glucose 100 mg/dlIf above 100 mg/dl, OGTT is strongly recommended but is not necessary to define presence of the syndrome
20 Diagnosis of The Metabolic Syndrome IDF CRITERIA (2005) Ethnic-specific cut-points for waist circumferenceCountry/Ethnic groupWaist circumference (as measure of central obesity)EuropidsMaleFemale94 cm80 cmSouth Asians90 cmChineseJapanese85 cm
30 Obesity and Type 2 Diabetes are Interrelated Epidemics Global epidemic of overweight, obesity and diabetesThe generalisation of modern urban lifestyle has resulted in inadequate changes in diet and physical activity:Overconsumption of energy-dense foods: increased calorie intakeSedentary habits: reduced energy expenditureThe combination of the two is the recipe for generating more and more obese individualsMokdad, et al. Diabetes Care. 2000;23(9):Mokdad, et al. JAMA. 2000;286(10):
31 The Global Menace of The Metabolic Syndrome The metabolic syndrome is a predictor of type 2 diabetesThe metabolic syndrome is a risk factor for cardiovascular disease (CVD)
32 Consequences of metabolic syndrome Non-diabetic subjects4-fold increased risk for type 2 diabetes30% increased risk for CVDDiabetic patients40-70% increased risk for CVDExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:
33 Metabolic Syndrome And Risk of Type 2 Diabetes Incident diabetes after stratification by age or BMI, IGT, and the metabolic syndrome (San Antonio Heart Study)This slide examines the risk of the NCEP metabolic syndrome for the development of type 2 diabetes in the San Antonio Heart Study over a 7 year period of follow up. Overall, the metabolic syndrome is associated with a 3.5 fold increased risk of type 2 diabetes. Among subjects with normal glucose tolerance (NGT) subjects with the metabolic syndrome have a 4 fold increased risk of type 2 diabetes. Among subjects with impaired glucose tolerance, subjects with the NCEP metabolic syndrome have about a 2.5 fold risk of diabetes. Note that subjects who have both impaired glucose tolerance and the NCEP metabolic syndrome have almost a 60% chance of developing type 2 diabetes. In such a high-risk group for type 2 diabetes, the clinician may consider pharmacological interventions as well as behavioral interventions to delay/prevent the onset of type 2 diabetes (Steven M. Haffner).Lorenzo, et al. Diabetes Care. 2003;26:
34 Metabolic Syndrome And Risk of Type 2 Diabetes Risk of type 2 diabetes per unit change in risk trait levels San Antonio Heart StudyIn the San Antonio Heart Study, obesity and fasting glucose were the strongest predictors of the development of type 2 diabetes, in contrast to a previous slide showing predictors of CHD. Thus, it is difficult to answer the question "which components of the metabolic syndrome are most important?" without specifying the particular endpoints being studied (Steven M. Haffner).Stern MP, et al. Ann Intern Med 2002;136:
35 Metabolic Syndrome and Cardiovascular Risk Individuals without diabetes or CVD, but with the metabolic syndrome are at increased risk for long-term CV outcomesIn the Atherosis Risk In Communities (ARIC) study, individuals (mean age 54 5.7 years) had an average of 11 years of follow-up. 31.4% of men and 32.0% of women had the metabolic syndrome at baseline as defined with revised NCEP/ATP III criteria (inferior limit for impaired fasting glucose 100 mg/dL).Among the male participants without diabetes or CVD at baseline, the crude incidence rate of Coronary Heart Disease (CHD) during follow-up was 138.4/10 000/year for those with metabolic syndrome and 92.3/10 000/year for those without metabolic syndrome. The equivalent crude incidence for women was 57.5 versus 22.7.Among the male participants without diabetes or CVD at baseline, the crude incidence rate of stroke during follow-up was 24.6 /10 000/year for those with metabolic syndrome and 18.1/10 000/year for those without metabolic syndrome. The equivalent crude incidence for women was 19.0 versus 8.5.As shown on this slide, the relative risk of CHD or stroke in the participants was 50% more in men and twice in women. In both sexes, the risk increases with the increase of the number from 1 to 4 of the components of the metabolic syndrome (figure not shown).Among the component of the metabolic syndrome, high blood pressure and low HDL-cholesterol exhibited the strongest association with the risk of CHD.Schmidt MI, et al. (ARIC study) Diabetes Care 2005;28:
36 Metabolic Syndrome and CHD Risk Prevalence of CHD in patients with the metabolic syndrome (Botnia Study)This study shows data on the prevalence of coronary heart disease in subjects in the Botnia Study which was done in Western Finland. The prevalence of the metabolic syndrome is higher in subjects with the metabolic syndrome, and increases as glucose tolerance worsens from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to diabetes (DM).(Steven M. Haffner, MD)Adapted from Isomaa B, et al. Diabetes Care. 2001;24:
37 Increased CVD and All-cause Mortality 1209 Finnish men(See previous info.)Lakka H, et al. JAMA 2002;288;
38 Association Between The Number of Metabolic Syndrome Components and Incident CVD In this population-based study, subjects without diabetes were evaluated first in and again 5 years later. The WHO definition was used to identify subjects with metabolic syndrome.On this slide, the risk of incident cardiovascular disease (angina, heart attack or stroke) is presented as a function of the number of components of the metabolic syndrome. It clearly shows that the risk of subsequent cardiovascular disease progressively increases with the number of components at baseline.Klein BEK, et al. (Beaver Dam Study). Diabetes Care 2002;25:
39 The Association of Microalbuminuria/CKD and Metabolic Syndrome Cardiorenal syndromeThe Association of Microalbuminuria/CKD and Metabolic SyndromeIs Metabolic Syndrome a Risk Factor for CKD ?
40 Odds Ratios (95% CI) of MA Associated with Individual and Several Components of the MetS Ann Intern Med Feb 3;140(3):167-74
41 Odds Ratios of CKD Associated with Individual or Several Components of the MetS Ann Intern Med Feb 3;140(3):167-74
42 CKD, Microalbuminuria and Metabolic Syndrome Background: The MetS is a common risk factor for CVD.Objective: To examine the association between the MetS and risk for CKD and microalbuminuria (MA).Design: Cross-sectional study.Setting: The Third NHANES.Patients: 20 years of age or older were studied in the CKD (n 6217) and MA (n 6125) analyses.Measurements: The MetS was defined by NCEP. CKD was defined as a GFR less than 60 mL/min per 1.73 m2, and MA was defined as a urinary albumin–creatinine ratio of 30 to 300 mg/g.Ann Intern Med Feb 3;140(3):167-74
43 Metabolic Syndrome and the Risk for CKD among Nondiabetic Adults The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults.J Am Soc Nephrol 2005
45 How Does Abdominal Obesity Cause Insulin Resistance ReducedPhysicalActivityExcessivefood intakeInflammationinsulinreceptorSubstrate(IRS-1 & IRS-2) IL-6Geneticfactors TNF- various cytokinesadiponectin As a consequence of the modern and urban way of life, there is an increasing imbalance between excessive food intake, especially with high glycaemic index food, and decreased level of physical activity leading to accumulation of fat in adipocytes, the number and size of which increase in various degrees according to genetic factors.Adipocyte accumulation is located at various sites among which abdominal location (visceral fat) has been demonstrated to have important metabolic consequences. One of these consequences is the release of free fatty acids in the blood stream, which is directly responsible for insulin resistance. In addition, overloaded adipocytes also produce various cytokines involved in subclinical inflammatory process and oxidative stress. An important effect of these adipocytokines is the alteration of insuline receptor sbustrate which is also involved in the insulin resistance process.ABDOMINALOBESITYInsulinresistance leptinHormones blood FFA
47 Common insulin resistance (IR) underlies most cases of T2DM, central obesity and metabolic syndromedriven by overweight/obesity, as a result of adipokines/FFA imbalance and lipotoxicityrepresents a in insulin-mediated glucose uptake (IMGU) and glycogen synthesis, mostly in skeletal muscle, liver and adipocyteBeck-Nielsen et al. in Insulin Resistance, Kumar & O’Rahilly eds John Wiley & Sons, Ltd
48 Insulin Resistance: Multisystem Disorder Adipose tissueIncreased NEFA and adipokine releaseMuscleDecreased glucose disposalLiverIncreased gluconeogenesis and hepatic glucose outputEndotheliumEndothelial dysfunction
49 Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease Genetic variationEnvironmental factorsAbdominal obesityAdipokinesCytokinesAdipocyteInflammatory markersMonocyte/macrophageInsulin resistance Tg Metabolic syndrome HDL BPPathophysiology of the metabolic syndrome leading to atherosclerotic CV diseaseA complex series of interactions of metabolic risk factors with genetic and environmental influences underlies the adverse influence of the metabolic syndrome on cardiovascular prognosis. Abdominal obesity is an important cause of multiple sources of cardiovascular risk within this system. Bioactive substances (adipokines, inflammatory cytokines and other agents) derived from intra-abdominal adipocytes, the liver and/or inflammatory cells help to drive the progression of the cluster of risk factors characteristic of the metabolic syndrome. In turn, exacerbation of these risk factors, in addition to the direct pro-atherogenic effects of adipokines, accelerates the atherosclerotic changes that increased the risk of an occlusive thromboembolic coronary event.It is difficult to intervene successfully once the vicious cycle of promotion of cardiovascular risk factors and atherogenesis is established. Intervening at an earlier stage, for example to combat directly the development of intra-abdominal adiposity, may provide a more successful prospect for intervention to reduce the risk of a cardiovascular event.Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:AtherosclerosisPlaque rupture/thrombosisReilly & Rader 2003;Eckel et al 2005Cardiovascular events
51 Insulin Resistance (IR) Insulin resistance (IR) and the Metabolic Syndrome (MetS) are the most frequent metabolic conditions affecting adult subjects in Westernized countries. They are strongly associated with sedentarity and increased abdominal fat in predisposed subjects. IR and MetS are major players in the development of cardiovascular disease (CVD), in both subjects with normal glucose tolerance (NGT) and subjects with T2DM. Thus, about one-fifth of subjects with IR are unable to compensate this state of IR with increased insulin secretion in the long-term; these are prone to develop both type 2 diabetes and CVD as a result of the presence of IR and MetS. A minority of subjects with T2DM however do not show the features associated with IR and MetS, and their state of hyperglycaemia is not particularly associated with CVD.IS: Insulin SensitiveHaffner SM et al. Diabetes Care, 1999; 22:
52 Who has insulin resistance? %PatientsWho has insulin resistance?Insulin resistance is relatively common in clinical practice, as indicated by results from seven studies show on the slide.As expected, the vast majority of patients with diabetes are also insulin resistant.Insulin resistance is highly prevalent among patients with low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels.Approximately half of all patients referred to a cardiologist are also insulin resistant, as are many patients with stroke and CHD.40% of patients aged 40 to 74 years, as well as at least half of patients with hypertension, are also insulin resistant.DM21↓HDL+ ↑TG2HTN3Stroke4CHD5Refer to cardiol.6Age40 to 7471Haffner et al. Diabetes McLaughlin et al. Am J Cardiol Reaven et al. N Engl J Med NIH.5Lankisch et al. Clin Res Cardiol Savage et al. Am Heart J www.diabetes.niddk.nih.gov/.
53 Risk of CVD rises as IR increases Quintile of HOMA-IR adjusted for age, sex, ethnicity, LDL-Cholesterol, triglycerides, HDL-Cholesterol, systolic blood pressure, smoking, alcohol consumption, leisure time exercise and waist circumference (median split). Patients without diabetes and CVD at baseline.HOMA uses a mathematical model that enables the degree of insulin resistance and ß-cell function to be estimated from FPG + FPI readings.2 The HOMA technique has a level of accuracy comparable to that of the glucose clamp technique3 or other reference methods.4,5FPG = Fasting Plasma GlucoseFPI = Fasting Plasma Insulin2. Matthews DR, et al. Diabetologia 1985; 28:412–419.3. Bonora E, et al. Diabetes Care 2000; 23:57–63.4. Hermans MP et al., Diabetelogia 1999; 42:5. Hermans MP et al., Diabetes 1999; 48:Hanley A.J. et al. Diabetes Care 2002; 25: (San Antonio Heart Study)
54 Current approaches for assessing insulin sensitivity and resistance in vivo AJP-Endocrinol Metab • 294 • JAN 2008
55 The Metabolic Syndrome Is A Metabolic Time Bomb With the elevated risk of diabetes and cardiovascular disease from the metabolic syndrome, there is an urgent need for strategies to defuse this metabolic time bomb
56 What Can We Do For Patients With the Metabolic Syndrome? 1. Ensure appropriate lifestyle changes- Primary treatment of the metabolic syndrome2. Implement better use of current therapiesImprove complianceBetter use of combination treatments3. Use new agents to target underlying defectsObesityHyperglycaemiaDyslipidaemiaHypertensionOther “vascular risk factors”
58 代謝症候群之防制策略 減重 健康飲食 增加體力活動 戒菸 藥物治療 高血糖 高血壓 高血脂 ASA Etiology of Obesity: Numerous Complex, Interrelated Factors 1,2Obesity is a complex, multifactorial disease involving the disciplines of genetics, neuroscience, physiology, and biochemistry, as well as environmental, cultural, and psychosocial factorsTo be effective, strategies to manage obesity should address as many components as possible戒菸
60 ~10% Weight loss = ~30% Visceral adipose tissue loss Figure 33 A modest loss of body weight in patients with truncal/visceral obesity is associated with substantial reductions in major atherogenic risk factors. A 10% loss of body weight roughly corresponds to a 30% loss of adipose tissue.KW: risk factor, obesity
61 Weight Reduction Moderate weight loss with a very low calories diet in obese patients with the metabolic syndrome markedly improvesall aspects of the metabolic syndromeAmong 185 consecutive obese patients enrolled in a structured weight loss programme during one year, 125 (68%) had a metabolic syndrome according to the NCEP definition : BMI 40.7 ± 9,7 and weight 261,2 ± 72,4 lbs with metabolic syndrome versus BMI 35.7 ± 5,8 and weight 219,8 ± 41,7 lbs without metabolic syndrome.The rapid weight loss programme has well established nutritional and behavioural components. Weight loss is induced by a protein-sparing, very low calorie diet with a total intake of kcal per day.After 4 weeks of very low calorie died, a significant decrease was observed on the risk factors especially on those associated with the metabolic syndrome (BMI, high blood pressure, blood glucose, triglycerides). As shown on this slide, these improvements were sustained at the end of active weight loss (average 16,7 weeks, total weight loss 15.1%).Esposito K, et al. JAMA 2004;292:
62 Effect of Weight Loss on Insulin Sensitivity -17.2 % - (-8.0 %) % - (-1.5 %) % %Tertiles of weight change (DPS)Changes in insulin sensitivity index (SI) by tertiles of 4-year weight change, both groups combined.The p value for the difference among the tertiles after adjustment for age, gender and study group.
64 Optimal management of the metabolic syndrome includes: ConclusionOptimal management of the metabolic syndrome includes:Identification of patients with the metabolic syndromeAppropriate lifestyle changesImproved understanding of therapeutic targets: combination therapy often neededUse of pharmacotherapy to target underlying defectsPrevention of DM & CHD
65 Thank you for your attention Metabolic Syndrome –For preventive purposesThank you for your attention