Metabolik Sendrom Sınırlar ve Kararlar

Giriş ve Hedefler Bu sunum metabolik sendromun temel özelliklerini ve idaresini tartışıyor. Metabolik sendrom şu an neredeyse epidemik bir prevalansa sahip. Metabolik sendrom koroner,periferal vasküler ve CNS endotelyal hasarla sonuçlanır. Metabolik sendrom kesinlikle artmış CVD olayları ve ölüm riskiyle ilişkilidir. CVD risk faktör modifikasyonu metabolik sendromun kontrolünde anahtar role sahiptir. Metabolic syndrome is a cluster of clinical and biochemical abnormalities associated with the onset and progression of atherosclerotic cardiovascular disease (CVD). Adults with metabolic syndrome experience significantly greater mortality from coronary artery disease (CAD), vascular disease, stroke, and other causes in comparison with those who do not have the disorder. An enormous population is at risk, with important implications for public health. Comprehensive treatment strategies to modify CVD risk factors can ameliorate many of the pathophysiologic markers of metabolic syndrome and contribute to improved outcome. This presentation will discuss epidemiologic, clinical, and therapeutic issues relevant to metabolic syndrome, with the goal of improving early identification and appropriate treatment of this near-epidemic condition. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004;110:1245-1250. CNS = merkezi sinir sistemi; CVD = kardiyo vasküler hastalık .  Malik S, et al. Circulation. 2004;110:1245-1250.

Metabolik Sendrom: Genel Tanım Metabolik sendrom birbiriyle ilişkili klinik ve biyokimyasal bozuklukların bir bütünüdür.İçerdikleri: Abdominal obezite Yükselmiş trigliserid ve düşük HDL-C (atherojenik dislipidemi) Yükselmiş kan basıncı Insulin direnci, glukoz intoleransıyla birlikte veya değil Protrombotik ve proinflamatuar belirteçler (artmış CRP, fibrinojen, ve diğer koagulasyon faktörleri) Metabolic syndrome is a cluster of physical and biochemical derangements, including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, a prothrombotic state, and a proinflammatory state.1 Atherogenic dyslipidemia is a complex of lipid abnormalities—elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), and, often, a high concentration of small low-density lipoprotein (LDL) particles—that commonly occur together and can be considered a single target of therapy. Insulin resistance is considered by some investigators to be the prime underlying cause of metabolic syndrome, since elevated triglycerides and low HDL-C are characteristic lipid changes seen in patients with type 2 diabetes mellitus (DM).1,2 Signs of systemic inflammation, clinically assessed by C-reactive protein (CRP), and elevated concentrations of proteins involved in thrombosis, are also components of metabolic syndrome.1 As will be shown, specific criteria have been established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the World Health Organization (WHO), and the International Diabetes Federation (IDF). 1. Grundy SM, Brewer HB, Cleeman JI, et al, for the Conference Participants. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation. 2004;109:433-438. 2. Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol. 2002;90(suppl):19G-26G. HDL-C = high-density lipoprotein cholesterol; CRP = C-reactive protein. Grundy SM, et al. Circulation. 2004;109:433-438.

Metabolik Sendromun Tanımları NCEP ATP III1 WHO1,2 Aşağıdakilerin üçü veya daha fazlası: Insulin direnci artı aşağıdakilerin 2 veya daha fazlası Bel çevresi>102 cm (>40 in) erkeklerde, >88 cm (>35 in) kadınlarda Santral Obezite: WHR >0.9 erkeklerde, >0.85 kadınlarda ve/veya BMI >30 kg/m2 Trigliserid 150 mg/dL Trigliserid 150 mg/dL ve/veya HDL-C <35 mg/dL erkeklerde, <39 mg/dL kadınlarda HDL-C <40 mg/dL erkeklerde, <50 mg/dLkadınlarda TA 130/85 mm Hg TA 140/90 mm Hg AKŞ 110 mg/dL Mikroalbuminüri: UAE 20 g/min veya albumin:kreatinin 30 mg/g Criteria issued by NCEP ATP III and WHO have points of difference, but both sets are widely utilized.1,2 Both classification schemes define metabolic syndrome as a collection of risk factors that result largely from core defects of obesity and insulin resistance. Abdominal obesity is defined by NCEP ATP III only in terms of waist circumference, whereas the WHO criteria allow a definition by body mass index.2 In addition, NCEP ATP III criteria consider impaired glucose regulation as only one of an array of potential findings that can support the presence of metabolic syndrome. In contrast, WHO criteria require that insulin resistance be demonstrated before proceeding further with the evaluation for metabolic syndrome. Insulin resistance is demonstrated by the presence of impaired glucose tolerance, impaired fasting glucose, diabetes or, in patients with normal fasting glucose values, glucose uptake below the lowest quartile of the background population in the presence of hyperinsulinemia and euglycemia. The WHO classification may require special testing of glucose regulation that is beyond routine clinical evaluations.2 1. Grundy SM, Brewer HB, Cleeman JI, et al, for the Conference Participants. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation. 2004;109:433-438. 2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med. 1998;15:539-553. NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; WHO = World Health Organization; IGT = impaired glucose tolerance; IFG = impaired fasting glucose; BMI = body mass index; WHR = waist-to-hip ratio; BP = blood pressure; FPG = fasting plasma glucose; UAE = urinary albumin excretion. 1. Grundy SM, et al. Circulation. 2004;109:433-438. 2. Alberti KG, Zimmet PZ. Diabet Med. 1998;15:539-553.

Metabolik Sendromun Tanımları IDF Santral obeziteyle birlikte aşağıdakilerin iki veya daha fazlası: Artmış trigliserid seviyesi: ≥150 mg/dL, veya bu lipid bozukluğu için spesifik tedavi uygulanması Azalmış HDL-C: <40 mg/dL erkeklerde ve <50 mg/dL kadınlarda, veya bu lipid bozukluğu için spesifik tedavi uygulanması. Artmış Kan Basıncı: Sistolik KB ≥130 veya diyastolik KB ≥85 mm Hg, veya daha önce tanımlanmış hipertansiyon için tedavi almış olmak. Artmış AKŞ: ≥100 mg/dL, veya daha önce tip 2 diabet teşhisi almak. Eğer 100 mg/dL’nin üzerindeyse, OGTT şiddetle önerilir ama sendromun varlığını kanıtlamak için şart değildir. The most recently proposed definition of metabolic syndrome, that of the IDF, adopts the criterion of waist circumference for the evaluation of obesity, but curtails some of the variability of criterion permutations possible with the NCEP ATP III definition by making obesity a prerequisite of the syndrome.3 International Diabetes Federation. IDF Consensus Worldwide Definition of the Metabolic Syndrome. Available at: http://www.idf.org/webdata/docs/Metac_syndrome_def.pdf. Accessed June 10, 2005. IDF = International Diabetes Federation; OGTT = oral glucose tolerance test. International Diabetes Federation. Available at http://www.idf.org/webdata/docs/Metac_syndrome_def.pdf. Accessed June 10, 2005.

Santral Obezite Tanımlaması Country/Ethnic Group Waist Circumference* Europids In the USA, the NCEP ATP III values (102 cm, male; 88 cm, female) are likely to continue to be used for clinical purposes. Male 94 cm Female 80 cm South Asians Based on a Chinese, Malay, and Asian-Indian population. 90 cm Chinese Japanese 85 cm With waist circumference the principal criterion for the diagnosis of metabolic syndrome, it becomes important to ensure that the measurement is capable of appropriately identifying patients with metabolic syndrome across ethnic and racial groups worldwide. For this reason, the IDF has adjusted the cutoff points of waist circumference as a diagnostic criterion of metabolic syndrome to reflect ethnic and racial variations in patterns of fat distribution. For some ethnic and regional groups, not listed on the slide, there are not yet sufficient data to establish specific criteria. Pending such data, the IDF recommends that the South Asian definitions be applied to ethnic South and Central Americans, and the European definitions to sub-Saharan Africans and to Eastern Mediterranean and Middle Eastern (Arab) populations. International Diabetes Foundation. IDF Consensus Worldwide Definition of the Metabolic Syndrome. Available at: http://www.idf.org/webdata/docs/Metac_syndrome_ def.pdf. Accessed June 10, 2005. *In future epidemiologic studies of populations of Europid origin, prevalence should be given using both European and North American cutoff points to allow better comparisons. International Diabetes Federation. Available at http://www.idf.org/webdata/docs/Metac_syndrome_def.pdf. Accessed June 10, 2005.

Metabolik Sendromun Amerikada yetişkinlerdeki yaş ve etnik kökene göre prevalansı. This analysis of NHANES III data incorporates ethnicity and gender, revealing dramatic differences between populations. Among white subjects, males and females displayed a similar prevalence of metabolic syndrome. Both African American and Mexican American women, however, demonstrated a higher proportion of metabolic syndrome compared with their male counterparts (African American women, 20.9%, versus 13.9% for men; Mexican American women, 27.2%, versus 20.8% for men). African American women had a prevalence of the disorder that was 57% higher than that of African American men, and Mexican American women demonstrated a 26% higher prevalence than Mexican American men. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med. 2003;163:427-436. *As defined by NCEP ATP III; NHANES III data. Park YW, et al. Arch Intern Med. 2003;163:427-436.

Yaşlı Amerikan Yetişkinlerindeki Yaşlı Amerikan Yetişkinlerindeki* Metabolik Sendrom Komponentlerinin Prevalansı (%) Metabolik Sendrom? No Yes Total Diabet? Bel Çevresi >102 cm, M; >88 cm, F 34.4 18.5 82.0 86.0 55.0 Trigliserid ≥150 mg/dL 18.0 5.1 77.8 72.1 42.8 HDL-C <40 mg/dL, M; <50 mg/dL, F 16.5 2.6 70.7 69.7 39.5 TA 130/85 mm Hg 45.3 43.0 86.2 82.7 62.5 AKŞ >110 mg/dL 6.2 83.0 30.9 90.2 27.2 This analysis of the US population for prevalence of components of the metabolic syndrome was based on data from the Third National Health and Nutrition Examination Survey (NHANES III). US adults 50 years and older were categorized by the absence of metabolic syndrome, without or with diabetes (54.2% and 2.3%, respectively, of the total population under consideration), or the presence of metabolic syndrome, without or with diabetes (28.7% and 14.8%, respectively). The results demonstrate that the prevalence of metabolic syndrome among US adults aged 50 years is 43.5%, close to double the prevalence in the population at large. Individuals with metabolic syndrome, with or without diabetes, are more comparable than either of the 2 groups without metabolic syndrome, even among those with diabetes. In addition, the analysis indicated that: Among people with diabetes, the prevalence of metabolic syndrome is very high People with diabetes and metabolic syndrome had the highest prevalence of CAD Individuals with diabetes but not metabolic syndrome had no greater prevalence of CAD than those with neither condition Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214. *Aged 50 years; components as defined by NCEP ATP III; NHANES III data. NHANES III = Third National Health and Nutrition Examination Survey; M = male; F = female. Adapted from Alexander CM, et al. Diabetes. 2003;52:1210-1214.

Gençlerde Metabolik Sendrom: Prevalans Yükseliyor 12-19 yaş arası,adolesanlar hakkında NHANES 3 verisi geçtiğimiz son 10 yıl içerisinde: Metabolik Sendrom prevalansı bu yaş grubunda yüzde elliden daha fazla artmıştır.(%4.2'den %6.4'e kadar) Metabolik Sendrom erkeklerde daha yaygındır.(%9.1'e karşılık %3.7) Genel olarak,hakim olan Metabolik Sendrom prevalansı ortalama obezlerde %38.7 iken,aşırı obezlerde %49.7'dir. Adolesanlardaki prevalans,farklı ırklarda,kullanılan lipid eşik değerine göre önemli derecede değişebilir. The prevalence of a metabolic syndrome phenotype has increased dramatically in the interval between the 2 most recent NHANES surveys. It is particularly prevalent (>30%) in overweight adolescents (overweight defined as 95th percentile of body mass index [BMI] for age and sex). The best current estimates for adolescents suggest that more than 2 million have metabolic syndrome. These findings have important fiscal and public health implications. Duncan GE, Li SM, Zhou X-H. Prevalence and trends of a metabolic syndrome phenotype among U.S. adolescents, 1999-2000. Diabetes Care. 2004;27:2438-2443. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:2362-2374. *Population of 439 obese subjects aged from 4 to 20 years; modified National Cholesterol Education Panel Adult Treatment Panel III and World Health Organization definitions of metabolic syndrome; overweight and obesity defined by body mass index.   1. Duncan GE, et al. Diabetes Care. 2004;27:2438-2443. 2. Weiss R, et al. N Engl J Med. 2004;350:2362-2374.

İnsülin Direnci: Metabolik Sendromun Temel Sorunu NCEP ATP III kriterlerinin hepsini taşıyan bireylerin çoğunda insuline direnç görülür. Şeker hastalığı WHO kriterlerine göre metabolik sendromun teşhisinde zorunlu bir birleşenidir. Şeker hastalığı ve obezite,metabolik sendromun altında yatan tanımlayıcı kriterdir. Although explicit demonstration of insulin resistance is not required for a diagnosis of metabolic syndrome by NCEP ATP III criteria, the majority of individuals fulfilling these criteria will be insulin-resistant. According to the WHO criteria, however, insulin resistance must be present for the diagnosis of metabolic syndrome to be made. Numerous cardiovascular risk factors arise as a consequence of insulin resistance, many of which are core constituents of metabolic syndrome. Grundy SM, Brewer HB, Cleeman JI, et al, for the Conference Participants. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation. 2004;109:433-438. Grundy SM, et al. Circulation. 2004;109:433-438.

İnsülin Direnci CV Riskini Arttırıyor: San Antonio Kalp Çalışması İnsülin direnci ve 8 yıllık CV riski arasındaki bağlantı, altta DM ya da CVD olmayan 2600 vakada sonuçlandı. Quintile 5 Quintile 4 İnsülinn direnci* P (trend) = .0185 Quintile 3 Quintile 2 The San Antonio Heart Study investigated the relationship between increasing levels of insulin resistance and risk for CVD in nearly 2600 randomly selected adults (approximately 65% Mexican American and 35% non-Hispanic white) followed up for 8 years. The results demonstrate an independent association between insulin resistance and CVD risk. Even after adjustment for other known cardiovascular risk factors, including smoking status, blood pressure, serum lipids, ethnicity, and others, patients with higher levels of insulin resistance experienced significantly higher levels of cardiovascular pathology. Hanley AJG, Williams K, Stern MP, et al. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002;25:1177-1184. 1 2 3 4 5 CVD risk oranı ( %95 CI) *Quintile of insulin resistance adjusted for age, sex, ethnicity, LDL, triglycerides, HDL, systolic blood pressure, smoking, alcohol use, exercise, and waist circumference. DM = diabetes mellitus; CI = confidence interval; LDL = low-density lipoprotein; HDL = high-density lipoprotein.  Hanley AJG, et al. Diabetes Care. 2002;25:1177-1184.

İnsülin Direnciyle İlişkili CV Risk Faktörleri: Yüksek tansiyon Hiperinsulinemi Düşük HDL-C Yüksek trigliserid seviyesi Küçük, yoğun LDL partikülleri Yüksek Apo B Endotelyal disfonksiyon Düşük Apo A-1 seviyesi Yüksek fibrinojen seviyesi Yüksek PAI-1 seviyesi Yüksek CRP ve diğer inflamasyon belirteçleri Artmış kan akışkanlığı Mikroalbuminuri Hiperglisemi Insulin resistance, the resulting hyperinsulinemia, and CAD have complex associations. What may be clearly seen here, however, is that many of the cardiovascular risk factors that characterize metabolic syndrome are associated with insulin resistance. Increased fasting insulin levels as well as increased fasting glucose levels predict arterial stiffness, which in turn promotes hypertension, another known risk factor for CVD. Abnormal lipid levels characterized by low HDL-C, the presence of small, dense LDL particles, and elevated triglycerides are promoted by insensitivity to insulin, as normal lipoprotein metabolism becomes dysfunctional. Other consequences include hypercoagulation and impaired fibrinolysis. Enhanced lipid breakdown from insulin-resistant adipose cells results in increased availability of free fatty acids, and ultimately increased deposition of lipid in the arterial wall. This in turn leads to increases in vascular inflammation and the production of inflammatory markers. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab. 2001;86:713-718. Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol. 2002;90(5A):19G-26G. Apo = apolipoprotein; PAI-1 = plasminogen activator inhibitor-1. McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718. Reusch JEB. Am J Cardiol. 2002;90(5A):19G-26G.

WOSCOPS: CAD Riski Metabolik Sendrom Kriterlerinin Sayısıyla Artıyor Metabolik sendrom özellikerinin miktarı 1 2 3 4 In the West of Scotland Coronary Protection Study (WOSCOPS), the presence of metabolic syndrome increased the risk for a CAD event. The risk increased as the number of metabolic syndrome features accumulated, and men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CAD compared with men who had no feature of the syndrome (P<.0001). The inflammatory marker CRP enhanced the prognostic value of this information. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003;108:414-419.   n 695 2077 1984 1339 352 WOSCOPS = West of Scotland Coronary Protection Study; HR = hazard ratio.  Adapted from Sattar N, et al. Circulation. 2003;108:414-419.

CRP, Metabolik Sendrom ve CV Sonuçları: Kadın Sağlığı Araştırması CRP artan seviyelerle, ek prognostik bilgi verir P for trend <.0001 Over 14,000 women were evaluated in the Women’s Health Study. Levels of CRP were assessed in these apparently healthy women, and their correlation with metabolic syndrome and cardiac events was evaluated. 24% of the initially healthy cohort had metabolic syndrome at study entry. There was a strong linear correlation between increasing levels of CRP and the number of components of metabolic syndrome that were present. While the presence of at least 3 components of metabolic syndrome predicted incident events, the incorporation of CRP levels above 3.0 mg/L added prognostic information at all levels of severity of the underlying metabolic syndrome. Finally, these findings were confirmed regardless of which definition of metabolic syndrome was used. Over 8 years of follow-up, cardiovascular event–free survival rates based on CRP levels above 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of metabolic syndrome. Ridker PM, Buring JE, Cook NR, et al. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003;107:391-397.   CV = cardiovascular. Ridker PM, et al. Circulation. 2003;107:391-397.

DECODE: Metabolik Sendrom ve Diabetik olmayan vakalarda Mortalite Metabolik sendromun tüm mortalite riskleri ve kalpten ölümlerin riskinin bağlantısıyla meta-analizinin cinsiyetelere göre kohort 7 DECODE araştırması Sendrom Birleşenlerinin miktarı(vaka miktarı[bay/bayan]) Her Türlü Mortalite CVD MOrtalitesi erkek kadın 2 (1525/1488) 1.39 1.23 1.75 1.56 3 (543/534) 1.47 1.41 1.74 2.17 Hiperinsulinemi + her hangibiri 2 (677/727) 1.44 1.38 2.26 2.78 Hiperinsulinemia+ herhangi biri 3 (331/330) 1.43 1.49 1.98 2.74 The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study examined age- and sex-specific prevalence of metabolic syndrome and its association with all-cause and cardiovascular mortality in nondiabetic European men and women. Based on 11 prospective studies encompassing over 11,000 subjects, DECODE used a modified WHO definition of metabolic syndrome, including hyperinsulinemia as a component, with a median follow-up of 8.8 years. Overall, 15.7% of men and 14.2% of women had metabolic syndrome. A meta-analysis of the association of metabolic syndrome with mortality in 7 study cohorts included in DECODE is shown above. Elevated risk for CVD and all-cause mortality was seen consistently in all nondiabetic subjects in whom the diagnosis of metabolic syndrome was made, and the association with CVD mortality was especially pronounced in cases in which hyperinsulinemia was documented in conjunction with at least 2 additional criteria. During the course of the study, 432 of 1119 recorded deaths were caused by CVD. The overall hazard ratios for all-cause and CVD mortality in persons with metabolic syndrome compared with persons without it were 1.44 (95% confidence interval [CI], 1.17-1.84) and 2.26 (95% CI, 1.61-3.17) in men and 1.38 (95% CI, 1.02-1.87) and 2.78 (95% CI, 1.57-4.94) in women after adjustment for age, blood cholesterol levels, and smoking. Hu G, Qiao Q, Tuomilehto J, et al, 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;164:1066-1076. *Data are given as hazard ratios adjusted for age, cholesterol levels, and smoking. †These components are obesity, dyslipidemia, impaired glucose regulation, and hypertension. DECODE = Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe.  Adapted from Hu G, et al. Arch Intern Med. 2004;164:1066-1076.

KV Sağlık Seviyeleriyle, Metabolik Sendrom ve CVD Mortalitesi Stres testinde alınan en yüksek oksijen seviyeleri The Aerobics Center Longitudinal Study evaluated the relationship between cardiorespiratory fitness and mortality in healthy men and men with metabolic syndrome. Men with and without metabolic syndrome underwent a maximal treadmill exercise test and were classified as fit or unfit by quintiles based on maximum oxygen uptake during the test. The sample included 19,223 men, aged 20 to 83 years, entered into the study between 1979 and 1996, representing 196,298 subject-years of follow-up. All-cause and cardiovascular death rates were found to be greater among men with metabolic syndrome compared with their healthy counterparts. In both groups, however, death rates were markedly reduced among men with better fitness.1 A prospective study investigating the relationship between cardiovascular fitness and risk for metabolic syndrome found them to be clearly inversely related in both men and women. Reductions in risk for metabolic syndrome among men in the upper and middle tertiles of cardiorespiratory fitness compared with that of men in the lower tertile were 53% and 26%, respectively; the corresponding risk reductions among women were 63% and 20%.2 1. Katzmarzyk PT, Church TS, Blair SN. Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med. 2004;164:1092-1097. 2. 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;112:505-512. CV = cardiovascular.  Katzmarzyk PT, et al. Arch Intern Med. 2004;164:1092-1097.

Women’s Ischemia Syndrome Evaluation (WISE) Vakalar ve Method: Şüpheli myokardiyal iskemi değerlendirilmesi nedeniyle koroner anjiografi çekilen 780 kadın BMI artı metabolik sendrom ve diabet varlığı yönünden sınıflandırıldı. Sonuçlar: Obezitenin eşlik etmediği Metabolik sendrom artmış 3 yıllık ölüm ve CV olay riskiyle ilişkilidir. Metabolik sendromlu kadınların sağkalımları 4 yıl azalmıştır. Metabolik sendrom sadece belirgin anjiografik CAD olduğunda 4 yıllık CV riskini öngörür. In the Women’s Ischemia Syndrome Evaluation (WISE), 780 women referred for coronary angiography to evaluate suspected myocardial ischemia were classified by body mass index (BMI), presence or absence of metabolic syndrome, and presence or absence of DM. Increments of BMI (normal to overweight to obese) were not associated with 3-year risk of death (hazard ratio [HR] 0.92, 95% CI 0.59 to 1.51) or major adverse cardiovascular events (HR 0.95, 95% CI 0.71 to 1.27), but metabolic status (normal to metabolic syndrome to DM) was associated with a doubling of the risk for death (HR 2.01, 95% CI 1.26 to 3.20) and major adverse cardiovascular events (HR 1.88, 95% CI 1.38 to 2.57).1 This finding suggests that the risk factors that constitute metabolic syndrome interact to worsen prognosis more than the presence of a single risk factor, such as obesity, by itself. In an analysis of 4-year data from the same study, metabolic syndrome was associated with a significantly higher risk of cardiovascular events in comparison with women without metabolic syndrome if significant CAD was present at baseline (HR 4.93, 95% CI 1.02 to 23.76); metabolic syndrome without angiographically significant CAD was not associated with increased 4-year cardiovascular risk (HR 1.41, 95% CI 0.32 to 6.32).2 This suggests that it may be necessary to investigate different strategies to ameliorate the risk associated with metabolic syndrome in patients with and without angiographically significant CAD. 1. Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study. Circulation. 2004;109:706-713. 2. Marroquin OC, Kip KE, Kelley DE, et al, for the Women's Ischemia Syndrome Evaluation Investigators. Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women: a report from the Women's Ischemia Syndrome Evaluation. Circulation. 2004;109:714-721. 1. Kip KE, et al. Circulation. 2004;109:706-713. 2. Marroquin OC, et al. Circulation. 2004;109:714-721.

Metabolik Sendrom için Tedavi Hedefleri (NCEP ATP III) Atherojenik dislipidemiyi düzelt Tedavinin ana hedefi olsa dal, sadece LDL-C düşürülmesi çok karlı olmaz. Hipertansiyonu düzelt Protrombotik durumlar için aspirin başla İnsülin direncini düzelt Kilo ver Artmış fiziksel aktivite İnsülin direncini azaltan ilaçların CAD riskini düşürdüğü henüz ispatlanamamıştır. Tip 2 DM oluşursa , kontrol altına al These are objectives of therapy for metabolic syndrome as formulated by NCEP ATP III. Correction of atherogenic dyslipidemia should address the multiple lipid abnormalities of this condition, including elevated triglycerides, low HDL-C, and small, dense LDL particles. The treatment strategy focuses on triglycerides. Reduction of LDL-C alone does not result in full treatment benefits for patients with metabolic syndrome. Hypertension should be managed appropriately. Aspirin should be taken for the prothrombotic state. Insulin resistance should be corrected. Weight reduction, appropriate increases in physical activity, and other lifestyle modifications should be implemented. If DM is present, glycemic control is imperative, although medications that decrease insulin resistance may not reduce CAD risk. 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;106:3143-3421. National Cholesterol Education Program Adult Treatment Panel III. Circulation. 2002;106:3143-3421.

Metabolik Sendromda Yaşam Stili Değişimleri (NCEP ATP III) Başarılı yaşam stili değişiminden kazanılan en büyük yarar,metabolik sendrom teşhisi konulan insanlarda görülür. TLC (therapeutic lifestyle changes ) bu tip hastalar için kullanılan uygun bir kısaltmadır. As part of a multifaceted approach to reducing risk for CAD, NCEP ATP III guidelines recommend therapeutic lifestyle change(s) (TLC) as an initial treatment. These changes include an emphasis on dietary reductions in saturated fat and cholesterol, moderate physical activity, and possible referral to a dietitian. Successful implementation of TLC is most beneficial in patients with metabolic syndrome; when resources are limited, prioritization should reflect this by preferentially targeting these patients. 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;106:3143-3421. National Cholesterol Education Program Adult Treatment Panel III. Circulation. 2002;106:3143-3421.

TLC’nin Önemli Bileşenleri (NCEP ATP III) Birleşenler Tavsiyeler LDL-C–yüksek besin doymuş yağ <%7 total kalorinin diet kolestrolü <200 mg/d LDL-C düşürülmesi için terapatik seçenekler bitki stanols/sterols Günde 2 g yüksek viscous (soluble) fiber Günde 10-15 g Toplam kaloriler İstenilen kiloya ulaşmak ve sürdürmek için,alınan kaloriye dikkat edin/kilo alımını engelleyin Fiziksel aktiviteler Her gün 200 kalori yakmak için uygun bir egzersin programı yapın Primary dietary components of TLC include limiting intake of LDL-C–raising nutrients (eg, saturated fats, dietary cholesterol). Saturated fats should be restricted to less than 7% of the total caloric intake, and less than 200 mg of cholesterol should be included in the daily diet. In addition, the reduction of LDL-C may be augmented by the addition of 2 grams per day of plant stanols or sterols, and increases of viscous, or soluble, fiber in the daily diet to 10 to 25 grams. Total caloric intake should be adjusted to attain and maintain a desirable body weight and prevent weight gain. Finally, sufficient moderate exercise should be included in the daily routine to expend at least 200 kcal per day. Approximately 45 minutes of walking at 3 mph or 25 to 30 minutes of jogging at 5 mph is an example of moderate exercise expending 200 kcal. Weight loss is a prime objective, as it favorably influences all other components of metabolic syndrome. 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;106:3143-3421. *For example, approximately 45 minutes of walking (3 mph) or 25-30 minutes of jogging (5 mph) = 200 kcal expenditure. National Cholesterol Education Program Adult Treatment Panel III. Circulation. 2002;106:3143-3421.

TLC Diyeti için Tavsiyeler Birleşenler tavsiyeler Polyunsaturated fat Tüm kalorinin yüzde 10’una kadar Monounsaturated fat Tüm kalorinin yüzde 20’sine kadar Toplam yağ Tüm kalorinin yüzde 25-35’ine kadar karbonhidrat Tüm kalorinin yüzde 60’ına kadar Dietary fiber Her gün20-30 g protein Tüm kalorinin yaklaşık yüzde 15’i A TLC diet substitutes polyunsaturated and monounsaturated fat for saturated fat. Polyunsaturated fat should represent no more than 10% of total calories, while monounsaturated fat may account for up to 20% of total calories. Fat of all kinds may provide 25% to 35% of total calories, and 50% to 60% of total calories may be contributed by carbohydrates. Foods rich in complex carbohydrates (eg, whole grains, fruits, vegetables) are preferred. Individuals should consume 20-30 grams of dietary fiber daily, and protein should account for approximately 15% of total calories. 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;106:3143-3421. *NCEP ATP III allows an increase of total fat to 35% of total calories and a reduction in carbohydrate to 50% for persons with metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat. †Carbohydrate should derive predominantly from foods rich in complex carbohydrates, including grains, especially whole grains, fruits, and vegetables. National Cholesterol Education Program Adult Treatment Panel III. Circulation. 2002;106:3143-3421.

Metabolik Sendromun İlaç Tedavisi (NCEP ATP III) Hastanın riskini saptayın LDL-C amacına ulaşın Atherojenic dislipidemi’yi düzeltin NonHDL-C amacına ulaşın Yüksek trigliserid’li hastalar için ikinci hedef (≥200 mg/dL); non–HDL-C hedef = LDL-C hedef + 30 mg/dL Düşük HDL-C seviyesini yükseltin The first priority in pharmacologic treatment of metabolic syndrome is to achieve LDL-C goals, which depend on the patient’s level of risk for CAD (see the next slide). Pharmacologic treatment should also be directed at correction of overall atherogenic dyslipidemia. Non–HDL-C is a secondary target of therapy for patients with high triglyceride levels (200 mg/dL). Since non–HDL-C comprises LDL-C plus very-low-density lipoprotein cholesterol (VLDL-C), and a VLDL-C level of <30 mg/dL is considered normal, the NCEP ATP III suggests that an appropriate non–HDL-C goal is one 30 mg/dL higher than the LDL-C goal. For example, if the LDL-C goal is <130 mg/dL, the non–HDL-C goal will be <160 mg/dL. Consideration should be given to raising HDL-C, but HDL-C target levels have not been determined. 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;106:3143-3421. National Cholesterol Education Program Adult Treatment Panel III. Circulation. 2002;106:3143-3421.

Metabolik Sendrom için LDL-C’nin bitimi, TLC ve İlaç Terapisi Risk kategorisi Çok yüksek CAD Evet CAD riski eşit evet CAD riski faktörü Metabolik risk faktörünü çarpın, özellikle triglycerides 200 mg/dL ve non–HDL-C 130 mg/dL with HDL-C <40 mg/dL 10-yıl risk (%) N/A Tedavi Yolları LDL-C treatment threshold (mg/dL) Initiate TLC 100 Initiate medication <100 (optional*) LDL-C treatment goal <100 <70 (optional) Although TLC remains an essential aspect of clinical management, it may be necessary to implement pharmacologic therapy to achieve cholesterol-lowering in accord with recent guidelines. These guidelines suggest that subgroups of patients at high or very high risk for cardiovascular events, such as those with metabolic syndrome, may benefit from very aggressive lowering of LDL-cholesterol to levels <70 mg/dL. Such patients may still have lifestyle-related risk factors that are appropriate for aspects of TLC regardless of the LDL-C level. Concurrent TLC and pharmacologic therapy may modify these risk factors at the same time that elevated LDL-C—the primary target of cholesterol-lowering therapy—is being addressed. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. *It is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction of LDL-C. Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.

Metabolik Sendromlu ve Sendromsuz hastalarlardaki Statin tedavisinin Başarı Oranı: MERCURY I * † Metabolic Syndrome No Metabolic Syndrome Drug and Daily Dose The Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY) I trial evaluated the lipid-lowering effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin over two 8-week treatment periods in 3140 randomized patients. Of these patients, 43% met modified NCEP ATP III criteria for metabolic syndrome (obesity evaluated by BMI rather than waist circumference). As shown in this slide, a subsequent subanalysis of the MERCURY results showed that achievement of NCEP ATP III LDL-C treatment goals with statin therapy was comparable between patients with and without metabolic syndrome. Stender S, Schuster J, Barter P, Watkins C, Kallend D; on behalf of the MERCURY Study Group. Comparison of rosuvastatin with atorvastatin, simvastatin and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholesterolaemic patients with or without the metabolic syndrome in the MERCURY I trial. Diabetes Obes Metab. 2005;7:430-438. *P<.0001 and †P<.0125 vs RSV 10 mg. RSV = rosuvastatin; ATV = atorvastatin; SIM = simvastatin; PRA = pravastatin. Stender S, et al. Diabetes Obes Metab. 2005;7:430-438.

Metabolik Sendromlu hastalardaki Statin tedavisinin lipidlere etkisi: STELLAR Results of a post hoc analysis of the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial also showed that statin therapy improved elements of atherogenic dyslipidemia characteristic of the metabolic syndrome. The 3 selected daily doses of rosuvastatin (10 mg, 20 mg, 40 mg) lowered triglycerides from 22.3% to 33.8% and raised HDL-C from 7.6% to 10.4% while lowering LDL-C from 43.9% to 55.3%. The graph illustrates the results achieved with comparable moderate dosages of the 4 statins used in the study. Results with atorvastatin and simvastatin were comparable; pravastatin therapy in this population showed lower efficacy in every lipid category. Deedwania PC, Hunninghake DB, Bays HE, Jones PH, Cain VA, Blasetto JW, for the STELLAR Study Group. Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome. Am J Cardiol. 2005;95:360-366. RSV = rosuvastatin; ATV = atorvastatin; SMV = simvastatin; PRV = pravastatin. Deedwania PC, et al. Am J Cardiol. 2005;95:360-366.

COMETS: Metabolik Sendrom’da beklenen ara : 6 haftada sonuçlanır. † NS The Comparative Study with Rosuvastatin in Subjects with Metabolic Syndrome (COMETS) is the first prospective trial of statins administered specifically for treatment of metabolic syndrome. 397 adults were enrolled and randomized to rosuvastatin 10 mg, atorvastatin 10 mg, or placebo for 6 weeks. The primary end point was the percent change from baseline in LDL-C. Rosuvastatin was significantly more effective than atorvastatin for lowering LDL-C (-42.7% vs -36.6%, P<.001) and total cholesterol, as well as increasing HDL-C (+9.3 vs +4.8, P<.05), in patients with metabolic syndrome. Stalenhoef AF, Ballantyne CM, Sarti C, et al. A COmparative study with rosuvastatin in subjects with METabolic Syndrome: results of the COMETS study. Eur Heart J. 2005;26:2664-2672.   *P <.001 vs ATV †P <.05 vs ATV * COMETS = Comparative Study with Rosuvastatin in Subjects with Metabolic Syndrome; NS = not significant. Stalenhoef AF, et al. Eur Heart J. 2005;26:2664-2672.

COMETS: 12 haftada sonuçlanır † NS After the first 6-week period, patients receiving rosuvastatin 10 mg/d or placebo received rosuvastatin 20 mg/d, and those receiving atorvastatin 10 mg/d received atorvastatin 20 mg/d. Results at 12 weeks demonstrated responses that were similar and sustained. Patients receiving rosuvastatin demonstrated significantly better improvements in their LDL-C levels (-48.9% vs -42.5%, P<.001) and HDL-C levels (+10.4% vs +5.8%, P<.05). More patients achieved NCEP ATP III goals for LDL-C with rosuvastatin (91% vs 79%, P<.001). Treatment was well tolerated in both groups. Stalenhoef AF, Ballantyne CM, Sarti C, et al. A COmparative study with rosuvastatin in subjects with METabolic Syndrome: results of the COMETS study. Eur Heart J. 2005;26:2664-2672. *P<.001 vs ATV †P<.05 vs ATV * NS = not significant.  Stalenhoef AF, et al. Eur Heart J. 2005;26:2664-2672.

RIO-LIPIDS Vaka Bulma Dislipidemili obez hastalar için selektif CB1-reseptor blokeri rimonabant tedavisinin rastgele, kontrollü çalışması Ana hedef: Rimonabant tedavisinin kilo kaybı ve lipid seviyeleri üzerine olan sonuçlarını hesapla Tedavi araları ve hedefler: 1036 dislipidemik hasta BMI (27-40 kg/m2) 5 mg/d veya 20 mg/d rimonabant veya placebo 1 yıl boyunca Hastalardan aldıkları kaloriyi 600 kalori/d düşürmeleri istendi. Ana son noktalar: 1. yılda, kilo kaybı 5% ve ≥10% ve lipid profilleri değişti Evidence is mounting that obesity, an important cardiovascular risk factor that is a component of metabolic syndrome, as well as smoking, another major risk factor, may be managed with a new class of drugs, selective CB1 blockers. The CB1 receptor subtype of the endocannabinoid system (ES) has a central and peripheral role in metabolism and is implicated in the regulation of eating and fat deposition and in tobacco dependency. The RIO (Rimonabant in Obesity) LIPIDS trial was designed to compare the effects of treatment with two doses of a new cannabinoid receptor antagonist, rimonabant, versus placebo in 1036 obese patients with dyslipidemia. Patients were instructed to reduce their intake by 600 calories per day and received general nutritional counseling on caloric reduction without a specific diet to follow. They were randomized to 5 mg/d or 20 mg/d of rimonabant or placebo for 1 year. Treatment end points at 1 year were a weight loss of 5% of body weight and 10% of body weight and a change in the lipid profile. Despres J-P. Rimonabant in obesity. Presented at the American College of Cardiology Scientific Session 2004. March 9, 2004; New Orleans, La. Late Breaking Clinical Trials II. RIO = Rimonabant in Obesity. Despres J-P. Presented at the American College of Cardiology Scientific Session 2004. March 9, 2004; New Orleans, La.

RIO-LIPIDS Vaka Sonuçları Kilo kaybı 5% P<.001 for high-dose vs placebo. Kilo kaybı 10% P<.001 for high-dose vs placebo. At 1 year, weight losses of more than 5% and 10% per year were significantly greater in patients taking rimonabant versus placebo. Almost 90% of patients on the treatment lost 5% of their total body weight and 44% lost 10%. Patients on high-dose rimonabant lost an average of 20 pounds and 3 inches from their waistline and reported feeling less hungry. High-density lipoprotein cholesterol (HDL-C) levels unexpectedly increased in all 3 groups from baseline to 52 weeks; however, results in rimonabant-treated patients were significantly different from those in placebo patients, with HDL-C levels rising 23% in the 20-mg treatment group. Triglyceride levels decreased 15% and C-reactive protein decreased 27% in the high-dose group as well. There was also a reduction in the proportion of small, dense LDL-C particles. Change in metabolic syndrome status was also shown to improve dramatically. Of the group randomized to rimonabant 20 mg/d treatment, 42.2% had metabolic syndrome as defined by NCEP ATP III. After treatment with rimonabant 20 mg/d, this was reduced by more than half at 19.6% (P<.001). The results of the RIO-LIPIDS trial suggest a potential role of the ES and of CB1 antagonists in the treatment and/or prevention of obesity, metabolic syndrome, and tobacco use.   Despres J-P. Rimonabant in obesity. Presented at the American College of Cardiology Scientific Session 2004. March 9, 2004; New Orleans, La. Late Breaking Clinical Trials II. Rimonabant 20 mg/d Rimonabant 5 mg/d Placebo Rimonabant 20 mg/d Rimonabant 5 mg/d Placebo Despres J-P. Presented at the ACC Scientific Session 2004; March 9, 2004; New Orleans, La. Late Breaking Clinical Trials II. Available at: www.clinicaltrialresults.org/home.htm.

RIO-North America (1 Year)1 RIO–North America ve RIO–Europe: Rimonabant 20 mg/d vs Placebo sonuçları Parameter Change RIO-North America (1 Year)1 RIO-Europe (2 Years)2 Placebo Rimonabant Rimonabant* Kilo (kg) -2.8 -8.7* -2.5 -7.2 Bel çevresi(cm) -3.9 -8.2† -3.4 -7.5 HDL-C (mg/dL) +7.2 +16.1† N/A HDL-C (%) +16.8 +28.2 Trigliserid (mg/dL) +4.1 -11.5 Trigliserid (%) +6.3 -8.8 Metabolik sendromlu hastalardaki değişimin %si -13.7 -20 -50 The results shown in this slide reported for 1 year in RIO–North America and for 2 years in RIO–Europe (N=3040 and N=1507, respectively; patients randomized to placebo, rimonabant 5 mg/d, or rimonabant 20 mg/d) indicate notable reductions in weight and improvements in lipid parameters with rimonabant 20 mg/d vs placebo. 1. Pi-Sunyer X. RIO–North America: 1-year results. Presented at the American Heart Association Scientific Sessions 2004; November 8, 2004; New Orleans, La. 2. Van Gaal L. RIO–Europe: 2-year results. Presented at the ACC Scientific Sessions 2005; March 8, 2005; Orlando, Fla. *P<0.001. †P=0.001. 1. Pi-Sunyer X. Presented at the AHA Scientific Sessions 2004; November 8, 2004; New Orleans, La. 2. Van Gaal L. Presented at the ACC Scientific Sessions 2005; March 8, 2005; Orlando, Fla.

Metabolik Sendromda Metformin veya Yoğun Hayat Tarzı değişikliğinin etkileri: Diabet Önleme Program Vakası Metabolic Sendrom Komponenti* Cumulative Incidence (%) at 3 Years In Patients With No Metabolic Syndrome at Baseline In Patients With Metabolic Syndrome at Baseline Placebo Metformin ILC† Bel çevresi üst sınır 33 15† 8‡ 93 89‡ 81§ Düşük HDL-C 70 67 68 87 79‡ 78§ Yüksek TG 27 30 18‡ 73 72 60‡ Yüksek AKŞ 40 29† 28‡ 74 55‡ Yüksek TA 41 44 35‡ 81 80 68‡ All patients in this trial exhibited impaired glucose tolerance and 53% of patients had metabolic syndrome. Patients were assigned to one of 3 therapy groups: placebo plus standard lifestyle change, metformin 850 mg bid plus standard lifestyle change, or a program of intensive lifestyle change. The intensive lifestyle program was designed to achieve loss of ≥7% of body weight with a carefully controlled diet and moderate physical exercise for ≥150 minutes weekly. Intense lifestyle change, among patients who did not meet criteria for metabolic syndrome at baseline, was effective in limiting the incidence of all elements of the syndrome except for low levels of HDL-C. Metformin, however, in the same group, was successful compared with placebo only in the categories of obesity/overweight measured by waist circumference and fasting plasma glucose levels. Among patients who had already been diagnosed with metabolic syndrome at baseline, both metformin and intensive lifestyle change successfully reduced the prevalence of the metabolic syndrome characteristics of overweight/obesity measured by waist circumference, low HDL-C levels, and elevated fasting plasma glucose levels. Intensive lifestyle change also significantly lowered the prevalence of elevated blood pressure and triglycerides. Orchard T, Temprosa M, Goldberg R, et al, for the Diabetes Prevention Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program Randomized Trial. Ann Intern Med. 2005;142:611-619. *As defined by the National Cholesterol Education Program Adult Treatment Panel III. †A program of diet and exercise designed to achieve loss of 7% of body weight and 150 minutes a week of moderate physical activity. ‡P<.001 vs placebo. §P<.05 vs placebo. ILC = intensive lifestyle change. Adapted from Orchard T, et al. Ann Intern Med. 2005;142:611-619.

Bezafibrate Retard* 400 mg/d Metabolik Sendromlu hastalardaki MI insidanslarındaki Bezafibrate vs Placebo etkileri Outcome Percent of Patients HR P Value Bezafibrate Retard* 400 mg/d Placebo Nonfatal MI 9.5 13.8 0.67 0.009 Fatal MI 1.9 1.5 1.26 0.60 All MI 11.1 15.2 0.71 0.02 Sudden death 3.4 3.6 0.95 0.80 Primary BIP end point† 14.1 18.4 0.75 0.03 The Bezafibrate Infarction Prevention (BIP) study compared the effects of therapy with bezafibrate retard (a sustained-release formulation of bezafibrate) 400 mg/d or placebo on all-cause and cardiac mortality in 3122 men and women with CAD followed up for a mean of about 6 years. No difference was seen. However, a post hoc analysis indicated that among patients with metabolic syndrome at baseline (740 patients in the bezafibrate group and 730 placebo recipients), treatment with bezafibrate retard did reduce the incidence of MI compared with placebo. The most substantial benefits seen with bezafibrate retard versus placebo in the subanalysis population were desirable changes in HDL-C and triglyceride levels and reduced blood glucose levels. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyka V, Behar S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med. 2005;165:1154-1160. *Sustained-release formulation of bezafibrate. †Fatal or nonfatal MI or sudden death. MI = myocardial infarction; BIP = Bezafibrate Infarction Prevention. Adapted from Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160.

AHA/NHLBI Klinik Yönetim: Hayat Tarzı Risk Faktörleri Metabolik Sendrom tanısı için Modifiye NCEP ATP III kriterleri: AKŞ sınırı 100 mg/d’ye düşürüldü. Hayat Tarzı Faktörlerinin Yönetimi Abdominal obesite: Kilo verme 7% ile 10% a kadar. Mümkünse hedef BMI ve bel çevresine ulaşmak için daha fazla. Fiziksel İnaktivite: Düzenli orta zorlukta aerobik aktivite. Atherojenik diet: Doymuş yağ,kolestrol alımının azaltılması In October 2005, the American Heart Association (AHA) and National Heart, Lung, and Blood Institute (NHLBI) published a Scientific Statement on the diagnosis and management of metabolic syndrome. This will no doubt be an authoritative source of guidance in this area for health care professionals. The AHA/NHLBI statement adopts the diagnostic criteria of the NCEP ATP III (see Slide 4) with slight modifications. The threshold for IFG is reduced from 110 to 100 mg/dL. In addition, any of the criteria of elevated triglycerides, low HDL-C, and elevated blood pressure and fasting glucose is met if the patient is receiving drug treatment for the abnormality in question. Modification of lifestyle-related risk factors is the first line of management. Abdominal obesity is targeted by weight loss and maintenance through modifications of diet and physical activity. A slow loss of about 7% to 10% of body weight is the initial goal, with further reduction thereafter, if possible, to target BMI and waist circumference. Moderate-intensity aerobic activity totaling at least 30 to 60 minutes at least 5 days a week is recommended. Resistance training 2 days a week is encouraged. In the diet, total fat should be limited to 25% to 35% of total calories, and saturated fat to less than 7%; trans fats should also be restricted. Consumption of simple sugars should be limited as well. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. AHA = American Heart Association; NHLBI = National Heart, Lung, and Blood Institute. Grundy SM, et al. Circulation. 2005;112:2735-2752.

AHA/NHLBI Klinik Yönetim: Metabolik Risk Factörleri Atherojenik dislipidemi Ana hedef: yükselmiş LDL-C İkinci Hedef: yükselmiş non–HDL-C. Tedavi* hedefleri Yüksek riskli hastalar: <130 mg/dL (<100 mg/dL çok yüksek riskli hastalar için) Orta-Yüksek riskli hastalar: <160 mg/dL (<130 mg/dL optional) Orta riskli hastalar: <160 mg/dL Düşük riskli hastalar: <190 mg/dL Üçüncü hedef: düşmüş HDL-C; spesifik bir hedef değil Atherogenic dyslipidemia can be a target of therapy after the LDL‑C goal has been achieved. For patients with triglyceride levels of 200 mg/dL or higher after maximal LDL-C lowering, non–HDL-C can be the target of therapy. Elevated total Apo B is an alternative target, but accurate measurement of non–HDL-C is more readily available. Non-HDL-C goals, shown in the slide, are 30 mg/dL higher than the LDL-C goals determined according to the patient’s level of cardiovascular risk. Risk level is determined as follows: • Very high risk: high likelihood of major CVD events in the next few years, eg, recent acute coronary syndrome or established CAD plus multiple major risk factors (especially diabetes), poorly controlled severe risk factors (especially cigarette smoking), or metabolic syndrome • High risk: atherosclerotic CVD, diabetes, or >20% 10-year CAD risk • Moderately high risk: 10% to 20% 10-year CAD risk; factors that may favor the optional non–HDL-C goal of <130 mg/dL include advanced subclinical atherosclerotic disease (eg, carotid intima-media thickness >75th percentile) as well as the same supplementary factors that confer very high risk (above) • Moderate risk: 2+ major risk factors and <10% 10-year risk • Lower risk: 0 or 1 major risk factor and <10% 10-year risk No specific target level of HDL-C is set. To raise HDL-C levels, lifestyle therapies should first be maximized. If HDL-C is undesirably low after maximal LDL-C lowering, a fibrate or niacin may be considered. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. *The first option to achieve the non–HDL-C goal is to intensify LDL-C–lowering therapy. The second is to add a fibrate (preferably fenofibrate) or niacin. Grundy SM, et al. Circulation. 2005;112:2735-2752.

AHA/NHLBI Klinik Yönetim: Metabolik Risk Faktörleri (Cont’d) Yükselmiş TA: TA’yı <140/90 mm Hg a düşürün (diabet veya kronik böbrek hastalıklarında <130/80 mm Hg); mümkün olduğunca hayat tarzı değişiklikleri ile. Artmış Glukoz: AKŞ (100 mg/dL), diabet gelişimini önlemek; kilo vermesi ve fiziksel aktiviteyi arttırması için cesaretlendirin. Diabetlilerde HbA1c’yi <7.0% olacak şekilde tedavi edin. Protrombotik durum: Yüksek riskli hastalara az doz aspirin ile tedavi edin. Ortalama yüksek riskli hastalar için danışın. Atherosklerotik CVD’li hastalarda, aspirin kontrendike ise clopidogreli düşünün. Patients with metabolic syndrome who have overt hypertension without diabetes or chronic kidney disease should receive antihypertensive therapy to achieve BP below 140/90 mm Hg. For patients with diabetes or chronic kidney disease, the goal is BP below 130/80 mm Hg. Even if overt hypertension is not present, reduce BP as far as possible through lifestyle changes. For patients with IFG (100 mg/dL*), emphasize weight reduction and increased physical activity to delay progression to diabetes. For patients with diabetes, treat with lifestyle changes and pharmacotherapy as necessary to achieve an HbA1c level below 7.0%. For high-risk patients with metabolic syndrome, low-dose aspirin therapy is recommended to reduce the prothrombotic state associated with the syndrome, and it may also be considered for patients at moderately high risk. Clopidogrel can be considered for patients with atherosclerotic CVD who cannot tolerate aspirin. No specific treatment is recommended for the proinflammatory state of metabolic syndrome, which may be ameliorated by lifestyle therapies. *The NCEP ATP III 2001 criteria used 110 mg/dL as the definition of IFG. This was changed in 2004 to 100 mg/dL to agree with the American Diabetes Association’s revised definition of IFG. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. Grundy SM, et al. Circulation. 2005;112:2735-2752.

Metabolik Sendrom: A Range of Research Challenges… Kilo verme ve fiziksel aktivite arttırma method ve stratejileri Sendromun genetik ve metabolik etkenlerini tanımlamak Risk yönetimini geliştirmek Dislipidemilerin hepsinde uygulanan tedavilerin geliştirilmesi İnsülin direncine karşı tedavinin geliştirilmesi Proinflamatuar durumun metabolik sendrom ve CAD daki rolünü tanımlamak ve spesifik anti-inflamatuar ilaçlar geliştirmek. The recent AHA/NHLBI Scientific Statement concluded by pointing to several unresolved areas that future investigations will need to address. These areas include the following: 1. Improved strategies for weight reduction and maintenance and increased physical activity 2. Better understanding of the genetic and metabolic factors that contribute to the development of metabolic syndrome 3. Improved risk assessment for CVD 4. Developing therapies for dyslipidemias beyond LDL-C lowering and proving the benefit of new and existing therapies in large trials with clinical end points 5. Developing effective strategies to treat insulin resistance and reduce risk for CVD 6. Better understanding of the relationship between a proinflammatory state and metabolic syndrome and the effectiveness of intervention in this state for the prevention of CVD and DM   Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. Grundy SM, et al. Circulation. 2005;112:2735-2752.

Sonuçlar Metabolik Sendrom ilişkili klinik ve biyokimyasal faktörlerin artmış CVD riskiyle olan bütünüdür. Metabolik sendrom US yetişkinlerinin 25%ini etkiler Metabolik sendromun ana bileşeni Insulin direncidir. Metabolik sendromla ilişkili kardiyovasküler risk çok yüksektir. Metabolik Sendromlu hastalar hayat tarzı (TLC) düzenlemelerinden büyük fayda görürler. Metabolik sendromlu hastalar Statin tedavisinden fayda görürler. Endocannabinoid reseptor blockerleri metabolik sendromla ilişkili obezitenin tedavisinde kullanılacak yeni nesil ilaçlar olabilir. Metabolic syndrome is a cluster of clinical and biochemical abnormalities associated with the development and progression of atherosclerotic disease. It is a major public health problem in the United States, affecting approximately one quarter of all adults. The components of metabolic syndrome, which include abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, and a proinflammatory, prothrombotic state, work synergistically to increase cardiovascular risk to a level beyond what would be expected from the simple accumulation of separate risk factors. Although not required for the diagnosis of metabolic syndrome by NCEP ATP III criteria, insulin resistance is present in most patients with metabolic syndrome and is associated with many cardiovascular risk factors. TLCs, including improved diet and increased physical activity, are the cornerstone of therapy for metabolic syndrome, and it is patients with metabolic syndrome who derive the greatest benefit from such measures. However, patients with metabolic syndrome can also benefit from pharmacologic lipid-lowering therapy, including statins. Promising developments for the management of metabolic syndrome include the development of endocannabinoid receptor blockers, a class of agents that show promise for the treatment of the obesity associated with metabolic syndrome.

List of Abbreviations Icons on slides 8 and 11 courtesy of IIT Bombay. Scandinavian Simvastatin Survival Study IFG impaired fasting glucose AFCAPS/ CAPS Air Force/Texas Coronary Atherosclerosis Protection Study IGT impaired glucose tolerance AHA American Heart Association LDL low-density lipoprotein Apo apolipoprotein MCE major coronary event BMI body mass index MERCURY Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy BP blood pressure MI myocardial infarction CAD coronary artery disease NCEP ATP III National Cholesterol Education Program Adult Treatment Panel III CI confidence interval NHANES III Third National Health and Nutrition Examination Survey COMETS Comparative Study with Rosuvastatin in Subjects with Metabolic Syndrome NHLBI National Heart, Lung, and Blood Institute CRP C-reactive protein OGTT oral glucose tolerance test CV cardiovascular PAI-1 plasminogen activator-inhibitor 1 CVD cardiovascular disease RIO Rimonabant in Obesity DECODE Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe RR relative risk DM diabetes mellitus STELLAR Statin Therapies for Elevated Lipid Levels compared Across Doses to Rosuvastatin ES endocannabinoid system TLC therapeutic lifestyle changes FPG fasting plasma glucose UAE urinary albumin excretion HDL high-density lipoprotein VLDL-C very-low-density lipoprotein cholesterol HDL-C high-density lipoprotein cholesterol WHO World Health Organization HR hazard ratio WHR waist-to-hip ratio IDF International Diabetes Federation WOSCOPS West of Scotland Coronary Protection Study Icons on slides 8 and 11 courtesy of IIT Bombay.