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Metabolic Syndrome - Drug Management-

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1 Metabolic Syndrome - Drug Management-
Chih-Hsing Wu, MD Body Composition, Obesity and Osteoporosis Research Center, Department of Family Medicine, NCKUH


3 Definition of Metabolic Syndrome in Taiwan 2007-01-18
修正前(臺灣2004年版) 修正後(臺灣2006年版) 危 險 因 子 異 常 值 腹部肥胖(Central obesity) /或身體質量指數(BMI) 腰圍(waist): 男性 ≧90 cm 女性 ≧80 cm ;或 BMI ≧27 腹部肥胖(Central obesity) 女性 ≧80 cm 血壓(BP)上升 SBP ≧130 mmHg /DBP ≧85 mmHg 高密度酯蛋白膽固醇(HDL-C)過低 男性 <40 mg/dl 女性 <50 mg/dl 男性 <40 mg/dl;女性 <50 mg/dl 空腹血糖值(Fasting glucose)上升 FG ≧110 mg/dl FG ≧100 mg/dl 三酸甘油酯(Triglyceride)上升 TG ≧150 mg/dl

4 代謝症候群臨床案例 60歲陳xx先生,有心血管疾病家族史 不抽煙,偶而應酬喝酒,週末爬山運動
身高168公分,體重70公斤,腰圍92(90)公分,體脂率28% 血壓136 / 86 (130/85) mmHg,心跳 72/min 抽血檢查 空腹血糖 mg/dl (100), 膽固醇 mg/dl, 三酸甘油脂 mg/dl (150), 高密度膽固醇 36 mg/dl (40), 尿酸值 mg/dl, 肌酸酐 1.1 mg/dl, 腹部超音波:中度脂肪肝

5 Metabolic Syndrome = Pre-Disease
Hyperglycemia Hypertension Dyslipidemia Insulin Resistance 6 Metabolic syndrome Macrovascular Disease “Pre-diabetes” Type 2 Diabetes 5 4 To General Population Risk Relative 3 Microvascular Complications 2 1 -20 -15 -10 -5 5 10 15 20 Years of Diabetes © 2001 International Diabetes Center. All rights reserved. Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.

6 新陳代謝症候群個案的主要成份組 人數 佔新陳代謝症候群個案(1023)之百分比 新陳代謝症候群 1023 100% 肥胖 852 83.3%
肥胖+高三酸甘油酯症 696 68.04% 肥胖+高三酸甘油酯症+高血壓 457 44.67% 肥胖+高三酸甘油酯症+高血壓+低的高密度膽固醇 232 22.68%

7 CVD Risks and Anthropometric Index in Male Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8

8 CVD Risks and Anthropometric Index in Female Elderly Taiwanese
- Huang KC, et al. Obes Res 2005;13:170-8

9 Obesity and Metabolic Syndrome: A Cluster of Coronary Heart Disease Risk Factors
Diet Physical Inactivity Stress Raised Blood Pressure Genetic Susceptibility Autonomic Dysfunction Prothrombotic State Obesity and the metabolic syndrome: a cluster of coronary heart disease risk factors The dyslipidemia associated with obesity is multi-factorial, and is frequently associated with a cluster of interrelated cardiovascular disease risk factors that has been designated the metabolic syndrome. Key features of this dyslipidemia include raised triglycerides, reduced HDL cholesterol, and increased numbers of small, dense LDL particles. Obesity is a critical determinant of this dyslipidemia, operating through a number of metabolic influences that include reduced insulin sensitivity and changes in fatty acid metabolism that are described subsequently. Variations in the nature and magnitude of the dyslipidemia are due to the interaction of genetic factors with environmental influences, most notably diet and physical activity, and possibly stress. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 2005;89: Atherogenic Dyslipidemia Insulin Resistance Proinflammatory State Triglycerides High-Density Lipoprotein Cholesterol Small Low-Density Lipoprotein Particles Adapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:


11 身體質量指數=體重(公斤)  身高(公尺)2
肥胖的定義 身體質量指數=體重(公斤)  身高(公尺)2 定義 世界衛生組織 1998 亞太地區 (2000) 台灣 2002 亞太地區 (2005) 過輕 小於18.5 小於18.5 小於18.5 小於18.5 正常 18.5~24.9 18.5~22.9 18.5~23.9 18.5~22.9 23.0~23.9 過重 25.0~29.9 23.0~24.9 24.0~26.9 24.0~26.9 肥胖 (第一度) 30.0~34.9 25.0~29.9 27.0~29.9 27.5~29.9 肥胖 (第二度) 35.0~39.9 30.0~34.9 30.0~34.9 30.0~34.9 肥胖 (第三度) 40以上 35以上 35以上 35以上

12 減重16週前後代謝症候群的比例 Chen YJ, Wu CH, et al.Chin J Fam Med 2005; 15(4): P<0.05* 比例 *配對T檢定

13 亞太肥胖治療建議

14 Drugs Approved by FDA for Treating Obesity
-Yanovski SZ, et al. N Engl J Med 2002;346: Generic Name Trade Names DEA Schedule Approved Use Year Approved Orlistat Xenical None Long-term 1999 Sibutramine Meridia IV 1997 Diethylpropion Tenulate Short-term 1973 Phentermine Adipex, lonamin Phendimetrazine Bontril, Prelu-2 III 1961 Benzphetamine Didrex 1960 Drugs approved by FDA for treating obesity This table lists the medications approved by the United States Food and Drug Administration (FDA) for treatment of obesity; only sibutramine (Meridia) and orlistat (Xenical) have been approved for long-term use. All the approved medications act as anorexiants, with the exception of orlistat, which blocks the absorption of dietary fat. Anorexiants increase satiation (level of fullness, which regulates the amount of food consumed during a meal) or satiety (level of fullness after a meal, which determines frequency of eating), or both. Methamphetamine is also approved by the FDA for short-term use, but it is a DEA schedule II drug and should be avoided because of its abuse potential. Three anorexiant medications have been removed from the marketplace because of increased risks of either valvular heart disease (fenfluramine and dexfenfluramine) [1] or hemorrhagic stroke (phenylpropanolamine) [2] associated with their use. Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339: Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:

15 羅氏鮮(Xenical)減重機轉 羅氏鮮可減少食物中30%的脂肪攝取量 30% of triglycerides pass
undigested and are excreted. 羅氏鮮可減少食物中30%的脂肪攝取量

16 Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year
Study or Sub-category WMD (random) 95% CI Hollander 1998* Sjostrom 1998 Davidson 1999 Finer 2000 Heuptman 2000 Lindgarde 2000 Rossner 2000 Bakris 2002 Broom 2002 Kelley 2002* Miles 2002* Total (95% CI) Meta-analysis of RCTs evaluating effect of orlistat therapy on weight loss at 1-year This figure shows the results of a systematic review of long-term double-blind randomized controlled trials that evaluated the effect of orlistat therapy on body weight in obese subjects [1]. Eleven trials that were at least of 1 year duration were identified. Three studies were conducted exclusively in subjects with type 2 diabetes, who may have more difficulty losing weight than obese subjects without diabetes. Average attrition rate among trials was 33%. All trials found a statistically significant beneficial weight loss effect of orlistat therapy. The pooled analysis showed that compared with placebo therapy, orlistat therapy caused a 2.7 kg (95% CI: kg) or 2.9% (95% CI: %) greater decrease in body weight. In addition, 12% (95% CI: 8-16%) more subjects achieved a 10% or greater weight loss with orlistat than with placebo therapy. Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes 2003;27: *All subjects had type 2 diabetes WMD=weighted mean difference -10 -5 5 10 Favours Treatment Favours Control Padwal et al. Int J Obes 2003;27:1437

17 FDA advisory committee approval for a low dose (60 mg) over-the-counter orlistat product (Alli) in 2007.

18 諾美婷(Reductil)的作用機轉 5-HT NA S S S S MAO MAO
Reuptake Catabolism 5-HT RELEASE S S MAO Mechanisms of Action: Sibutramine and Active Metabolites Block Serotonin and Norepinephrine Reuptake1,2 Sibutramine and its active metabolites inhibit the reuptake of 5-HT and NA This action increases the amount of 5-HT and NA in the synapse and at the postsynaptic receptors This mechanism of action does not override the normal physiologic control mechanisms of release Reuptake Catabolism NA RELEASE S S = sibutramine = noradrenaline, = serotonin Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.

19 Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year
Study or Sub-category WMD (random) 95% CI McMahon 2000 Smith 2001 McMahon 2002 * Total (95% CI) Meta-analysis of RCTs evaluating effect of sibutramine therapy on weight loss at 1-year This figure shows the results of a systematic review of long-term, double-blind, randomized, controlled trials that evaluated the effect of sibutramine therapy on body weight in obese subjects [1]. Three trials that were at least of 1 year duration were identified. One study was conducted in subjects who had hypertension. Average attrition rate among trials was 48%. All trials found a statistically significant beneficial weight loss effect of sibutramine therapy. The pooled analysis showed that compared with placebo therapy, sibutramine therapy caused a 4.3 kg (95% CI: kg) or 4.6% (95% CI: %) greater decrease in body weight. In addition, 15% (95% CI: 4-27%) more subjects achieved a 10% or greater weight loss with sibutramine than with placebo therapy. Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes 2003;27: -10 Favours Treatment Favours Control -5 10 5 All subjects had hypertension WMD=weighted mean difference Padwal et al. Int J Obes 2003;27:1437

20 Sibutramine, Orlistat or Combination Therapy for 12 week in Turkey(n=86)
-Aydin N, et al. Tohoku J Exp Med 2004;202:173-80

21 Similar Effects * * * * * The body weight, BMI and body fat change
between baseline and 6-month interval in NCKUH * * * * * Wu CH, et al. 2008: submitted

22 Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.
Average weight loss of subjects completing a minimum 1-year weight-management intervention; based on review of 80 studies (N=26,455; 18,199 completers [69%]). Franz MJ , et al. J Am Diet Assoc. 2007;107:

23 合理實際的減重目標 目標 治療成功 2000年亞太肥胖組織共識 減輕多餘體重 維持BMI 血壓 血糖 血糖控制(HbA1c) 其他危險因素
5-6Kg或初始體重的10% < 23 kg/M 2 任何程度的下降 任何程度的改善 任何程度的減少

24 Cardinal Behaviors of Successful Long-term Weight Management National Weight Control Registry Data
Self-monitoring: Diet: record food intake daily, limit certain foods or food quantity Weight: check body weight >1 x/wk Low-calorie, low-fat diet: Total energy intake: kcal/d Energy intake from fat: 20%-25% Eat breakfast daily Regular physical activity: kcal/wk (eg, walk 4 miles/d) Cardinal behaviors of successful long-term weight management Data obtained from the National Weight Control Registry (NWCR) have identified specific behaviors that are associated with successful long-term weight loss [1-3]. Participants enrolled in the registry must have maintained a weight loss of 13.6 kg (30 lb) for at least 1 year; on average, subjects have maintained a 32 kg (70 lb) weight loss for 6 years. The major behaviors reported by approximately 3000 NWCR participants were: 1) self-monitoring of food intake and body weight; 2) consuming a low-calorie (1300–1400 kcal/d) and low-fat diet (20%–25% of daily energy intake from fat), 3) eating breakfast every day, and 4) performing regular physical activity that expends 2500 to 3000 kcal per week (eg, walking 4 miles per day). Klem ML, Wing RR, McGuire MT, et al. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr 1997;66: McGuire MT, Wing RR, Klem ML, et al. Long-term maintenance of weight loss: do people who lose weight through various weight loss methods use different behaviors to maintain their weight? Int J Obes Relat Metab Disord 1998;22: Wyatt HR, Grunwald GK, Mosca CL et al. Long-term weight loss and breakfast in the National Weight Control Registry. Obes Res 2002;10:78-82. Klem et al. Am J Clin Nutr 1997;66:239. McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.

25 Pathogenesis of Metabolic syndrome
2 major, interacting causes Obesity and abnormal body fat distribution disorders of adipose tissue. Endogenous metabolic susceptibility  Insulin resistance A constellation of independent factors (e.g. molecules of hepatic, vascular, and immunologic origin) Contributors: aging , proinlfammatory state, hormonal change. Grundy SM et al: Circulation 2004;109:433-8 Grundy SM: Am J Clin Nutr 2006 Aug 1248


27 Mean Efficacy of Pharmacological Treatment Options in Type II DM
- Diabetologia 2003;(suppl 1):M30-M36

28 Side Effect of Oral Hypoglycemic Agents
- Endocrinol Metab Clin North Am 2001; 30(4):

29 Metformin- Mean Weight Change
Placebo Metformin Lifestyle The DPP Research Group, NEJM 346: , 2002

30 Weight Change of DM patients using Acarbose in Taiwan
10 20 30 40 50 60 70 80 Patients 65.5 65.2 65.1 Initial visit First follow-up Second follow-up Third follow-up kg Hung YJ, et al. Clin Drug Invest 2006;26:559-65

31 Similar Effect of Hypoglycemic Agents
Action on insulin resistance Action on insulin secretion HbA1C reduction Primary Goal Glinides 0/+ +++ 0.9 to 1.7% Postprandial Conventional Sulfonylureas 0/+ ++++ 1% to 2% Fasting New SU ++ +++ 1% to 2% Fasting Biguanides ++ 1% to 2% Fasting Glitazones ++++ 0.5% to 1.3% Fasting -glucosidase inhibitors 0.5% to 1% Postprandial Data from Henry. Endocrinol Metab Clin. 1997;26: Gitlin, et al. Ann Intern Med. 1998;129: Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41 Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998: Fonseca, et al. J Clin Endocrinol Metab. 1998;83: Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26: De Fronzo, et al. N Engl J Med. 1995;333: Bailey & Turner. N Engl J Med. 1996;334: Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998: Goldberg, et al. Diabetes Care 21:

32 Characters of individuals in MetS of NHANESIII
- Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62

33 Intra-abdominal adiposity promotes insulin resistance and increased CV risk
 Secretion of metabolically active substances (adipokines)  Hepatic FFA flux (portal hypothesis)  Intra-abdominal adiposity  suppression of lipolysis by insulin  PAI-1  Adiponectin  IL-6  TNFa  FFA Intra-abdominal adiposity promotes insulin resistance and increased CV risk Intra-abdominal adiposity can promote insulin resistance and cardiovascular risk indirectly, though increased secretion of free fatty acids into the portal vein in the setting of insulin resistance, leading to increased hepatic triglyceride biosynthesis (the ‘portal hypothesis’). The direct adverse effects of intra-abdominal adiposity occur via the secretion of a range of bioactive substances. These include: a) Increased secretion of plasminogen activator inhibitor-1 (PAI-1), the endogenous inhibitor of tissue plasminogen activator (tPA). Increased PAI-1 secretion increases the risk of an intravascular thrombus. b) Adiponectin is a fat-derived hormone that protects the cardiovascular system. Decreased secretion of adiponectin in the setting of intra-abdominal adiposity implies increased cardiovascular risk. c) Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFa) are inflammatory mediators. Intravascular inflammation is a key early event in atherogenesis. Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004;28 Suppl 4:S12-21. Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001;60: Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004;28:  Insulin resistance  Dyslipidaemia Net result:  Insulin resistance  Inflammation Pro-atherogenic Heilbronn et al 2004; Coppack 2001; Skurk & Hauner 2004

34 Metabolic Syndrome Pathology: Visceral Fat, Atherosclerosis
Physiology: Insulin Resistance Assessment: Abdominal Obesity, CAD risk Regimen: Weight reduction, Insulin Sensitizer

35 Fat Topography in MetS and Diabetic Subjects
High TG High FFA Intramuscular Fat Subcutaneous Fat Harold Bays, Lawrence Mandarino, and Ralph A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., Feb 2004; 89: Intrahepatic Fat Intraabdominal Fat Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:

36 Effect of Thiazolidinediones
on Fat Topography High TG High FFA TG FFA TZD Intramuscular Fat Subcutaneous Fat Harold Bays, Lawrence Mandarino, and Ralph A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., Feb 2004; 89: Intrahepatic Fat Intraabdominal Fat Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:

37 Diabetes prevention trials
Study Intervention RR (%) ACT NOW Pioglitazone vs placebo 78% DREAM Rosiglitazone vs placebo 62% Finnish DPS Intensive lifestyle vs control  58% Da Qing study  38% DPP Intensive lifestyle vs placebo Metformin vs placebo Troglitazone vs placebo 58% 31%  75% IDPP Metformin + lifestyle Metformin 19% TRIPOD Troglitazone (after gestational diabetes)  50% Fasting Hyperglycemic Study Gliclazide or intensive lifestyle No effect STOP-NIDDM Acarbose vs placebo  25% XENDOS Orlistat + lifestyle vs placebo  37% While caution should be exercised when making comparisons in the absence of direct head-to-head studies, the effects of rosiglitazone compare favorably against lifestyle intervention and other agents. The 62% risk reduction observed with rosiglitazone in DREAM1 is greater than that observed with intensive lifestyle changes in the DPP (N = 3,234, study duration 2.8 years),2 the Finnish Diabetes Prevention Study (N = 522, 3.2 years)3 and the Da Qing Study (N = 530, 6 years).4 The risk reduction is greater than that of metformin in the DPP2 and acarbose in STOP-NIDDM (Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus) (N = 1,429, 3.3 years).5 The risk reduction is also greater than that observed with orlistat in an obese population (BMI ≥ 30 kg/m2, NGT 79%, IGT 21%) in XENDOS (XENical in the Prevention of Diabetes in Obese Subjects) (N = 3,305, 4 years).6 Finally, the results are consistent with those of smaller prevention studies carried out with other thiazolidinediones, such as troglitazone in IGT (DPP)7 and gestational diabetes (TRIPOD) (N = 266, 30 months)8 and pioglitazone in PIPOD (Pioglitazone in the Prevention of Diabetes, N = 89, 3 years).9 1. DREAM Trial Investigators. Lancet 2006; 368:1096–1105. 2. Knowler WC, et al. N Engl J Med 2002; 346:393–403. 3. Tuomilehto J, et al. N Engl J Med 2001; 344:1343–1350. 4. Pan XR, et al. Diabetes Care 1997; 20:537–544. 5. Chiasson JL, et al. Lancet 2002; 359:2072–2077. 6. Torgerson JS, et al. Diabetes Care 2004; 27:155–161. 7. Knowler WC, et al. Diabetes 2005; 54:1150–1156. 8. Buchanan TA, et al. Diabetes 2002; 51:2796–2803. 9. Xiang AH, et al. Diabetes 2006; 55:517–522. ACTosNOW. Diabetologia 2008 DREAM Trial Investigators. Lancet 2006; 368:1096–1105. Accessed October 2006. Tuomilehto J, et al. N Engl J Med 2001; Pan XR, et al. Diabetes Care 1997; Knowler WC, et al. N Engl J Med 2002; Ramachandran A, et al. Diabetologia 2006; DREAM Trial Investigators. Lancet, N Engl J Med 2006; Buchanan TA, et al. Diabetes 2002; Karunakaran S, et al. Metabolism 1997; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.

38 ADOPT (A Diabetes Outcome Progression Trial) -Fasting Plasma Glucose Over Time-
mg/dl 120 160 140 130 150 Rosiglitazone vs Metformin 9.8 (12.7 to 7.0), P<0.001 Rosiglitazone vs Glyburide 17.4 (20.4 to 14.5), P<0.001 Glyburide Metformin Rosiglitazone 1 2 3 4 5 Time (years)

39 Gastrointestinal, n (%) P<0.05 vs. rosiglitazone
Other Adverse Events Rosiglitazone (N = 1456) Metformin (N = 1454) Glyburide (N = 1441) Gastrointestinal, n (%) 335 (23%) 557 (38%) 316 (22%) Weight gain, n (%) 100 (7%) 18 (1%) 47 (3%) Hypoglycaemia, n (%) 142 (10%) 168 (12%) 557 (39%) Oedema, n (%) 205 (14%) 104 (7%) 123 (9%) P<0.05 vs. rosiglitazone

40 NEJM 2007;356;437-40 Approved Antidiabetes Medications in the United States. NEJM 2007;356;437-40

41 Role of DPP-4, GLP-1, GIP in glucose homeostasis
Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7 The role of DPP-4, GLP-1, GIP in glucose homeostasis. Following meal ingestion, the incretin hormones, intact (active) GLP-1 and GIP, released from gut endocrine cells and function to lower blood glucose levels by stimulating glucose-dependent insulin release from pancreatic -cells (GLP-1 and GIP) and suppressing glucose-dependent glucagon release from pancreatic -cells (GLP-1). However, once released into the circulation, incretin hormones are rapidly inactivated and degraded by plasma protease enzyme DPP-4. DPP-4 inhibitors like sitagliptin inhibit breakdown of incretin hormones, thereby increasing active GLP-1 and GIP levels and promoting fasting and postprandial glycemic control.

42 Mean Difference in BW Change for Gliptins vs Control in Adults With Type 2 Diabetes
Amori RE, et al. JAMA 2007;298:

43 Major Targeted Sites of Oral Drug Classes
Pancreas Impaired insulin secretion Sulfonylureas Muscle and fat Meglitinides Liver DPP-4 inhibitors ↓Glucose level Major Targeted Sites of Various Oral Drug Classes The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycaemia.1,2 Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of β-cell membranes.1-3 Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the β cells. They are used to control post-prandial hyperglycaemia.1,3 Thiazolidinediones (TZDs) are selective peroxisome proliferator-activated receptor γ agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,3 α-Glucosidase inhibitors lower post-prandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1,3 Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1-3,5 Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product. The dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and that help regulate insulin production and secretion.5,6 This glucose-dependent mechanism targets insulin release and hepatic glucose production.5 Hepatic glucose overproduction Insulin resistance Purpose: To provide a broad overview of the key mechanisms and targeted sites of available anti-hyperglycaemic drug classes. Take-away: Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve HbA1c control. Gut Biguanides TZDs TZDs Biguanides DPP-4 inhibitors DPP-4 inhibitors (indirect) Glucose absorption α-Glucosidase inhibitors Biguanides (indirect) DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287: ; Porte D et al. Clin Invest Med. 1995;18:247–254. References 1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. 3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287: 4. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254. 5. Data on file, MSD. 6. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619. 15

44 Developing Avenue of Ideal OADs
Glycemic Effect B-cell Preserve Insulin Sensitizing Neutral Weight Low Hypoglycemia QD Dosage SU +++ +/- Non-SU ++ + BG A-GI Glitazone - Gliptins

45 Glitazones (supposed)
Weight gain with antidiabetic therapy UK Prospective Diabetes Study and Update Modified from UKPDS 34. Lancet 1998; 352: Weight change (kg) 7 Insulin 6 5 Glitazones (supposed) Diet alone Chlorpropamide Glibenclamide 4 3 Meglitinides (?) 2 Metformin, Acarbose DPP-4 inhibitors (?) 1 -1 2 4 6 8 10 Years from randomisation

46 Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82
Trends in the prescribing patterns of OADs for outpatients in Taiwan, Chiang CW, et al. J Clin Phar Therapeutics 2006;31:73-82 Combination = 62.9% Any three OAD = 10.9%

47 Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease
Genetic variation Environmental factors Abdominal obesity Adipokines Cytokines Adipocyte Inflammatory markers Monocyte/ macrophage Insulin resistance  TG Metabolic syndrome  HDL  BP Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease A 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: Atherosclerosis Plaque rupture/thrombosis Reilly & Rader 2003; Eckel et al 2005 Cardiovascular events

48 Cardiovascular Disease Mortality Increased in the Metabolic Syndrome
Lakka et al. JAMA. 2002;288:2709–16. 15 Metabolic syndrome Yes No RR (95% Cl), 3.55 (1.98–6.43) 10 Cumulative hazard, % 5 2 4 6 8 10 12 Follow-up, y

49 Lawes CCM, et al. Lancet 2008; 371: 1513–18
Disability-adjusted life years (DALYs) attributable to high blood pressure in 2001 Lawes CCM, et al. Lancet 2008; 371: 1513–18 M/L F/L Men (A) and women (B) in low-income and middle-income countries. Men (C) and women (D) in high-income countries. F/H

50 Effect of antihypertensive agents in patients with mild hypertension (TOMHS 4-year data)
Neaton et al. JAMA 1993;270:713–724. Neaton et al. JAMA 1993;270:713–724. SBP after 48 months (mmHg) DBP after 48 months *P<0.01 vs placebo * Acebutolol (n=126) Amlodipine (n=114) Chlorthalidone (n=117) Doxazosin (n=121) Enalapril (n=119) Placebo (n=207)

51 Elliott WJ, Meyer PM. Lancet 2007; 369: 201–207.
New-onset DM with antihypertensives -143,153 subjects, network meta-analysis- Elliott WJ, Meyer PM. Lancet 2007; 369: 201–207. Figure 3: Results of network meta-analysis of 22 clinical trials Trials included patients. Initial diuretic used as referent agent (open box at odds ratio=1・00). Size of squares (representing the point estimate for each class of antihypertensive drugs) is proportional to number of patients who developed incident diabetes. Horizontal lines indicate 95% CI. Odds ratios to the left of the vertical line at unity denote a protective eff ect (compared with initial diuretic). Individual pair-wise comparisons between diuretic vs β blocker (p=0・30), placebo vs CCB (0・72), ACE inhibitor vs ARB (0・16) did not achieve signifi cance (p<0・05). the network meta-analysis was "thorough and comprehensive and corroborates and extends previous work." He notes that given that there are about 20 million patients on thiazide diuretics and an almost equal number on beta blockers, the increased risk of diabetes with these drugs translates into 250 000 cases of new-onset diabetes, accounting for about a quarter of the new cases of diabetes occurring every year in the US. "The prevalence of obesity, metabolic syndrome, and diabetes have doubled in the US within a decade. Hypertensive patients are at a higher risk of becoming diabetic than are matched normotensive subjects. How long are we to prescribe diuretics and beta blockers in uncomplicated hypertension? How many more hypertensive patients will have to become diabetic just because guidelines advise to use diuretics and beta blockers as first-line therapy?" he adds.

52 Journal of Hypertension 2007, 25:1105–1187
Conditions favouring use of some antihypertensive drugs-ESC 2007 Guideline Journal of Hypertension 2007, 25:1105–1187


54 Clinical efficacy and tolerability of alpha-blocker
doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism Nutrition, Metabolism & Cardiovascular Diseases (2006) 16, 16 weeks of combined therapy

55 Journal of Hypertension 2007;25:1105-1187
ESH-ESC 2007 Guidelines P. 1141 Journal of Hypertension 2007;25: a1-blockers… have been shown to adequately lower blood pressure and to also have favorable metabolic effects. As the only trial testing an a1-blocker (the doxazosin arm of the ALLHAT trial) was interrupted before crucial evidence could be obtained, the overall benefits or harm of a1-blockers for antihypertensive therapy remain unproved. However, all these agents have been frequently used as added drugs in trials documenting cardiovascular protection and can thus be employed for combination treatment. a1-blockers have a specific indication in the presence of benign prostatic hypertrophy.

56 Multiple antihypertensive agents are needed to achieve target BP
Number of antihypertensive agents Trial Target BP (mmHg) 1 2 3 4 UKPDS DBP <85 ABCD DBP <75 MDRD MAP <92 HOT DBP <80 AASK MAP <92 IDNT SBP <135/DBP <85 ALLHAT SBP <140/DBP <90 DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure Bakris GL, et al. Am J Kidney Dis 2000;36: ; Lewis EJ, et al. N Engl J Med 2001;345: ; Cushman WC, et al. J Clin Hypertens 2002;4: DOX-EM-07004

57 Combination Therapy Emphasized in All Guidelines
JNC 7 Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic WHO/ISH Less than half of hypertension patients will attain target pressures with monotherapy; as many as 30% will need 3 or more drugs Diuretic should be a component of combination therapy ESH-ESC 2007 Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients Use of more than one agent is necessary to achieve target BP in the majority of patients. In several patients BP control is not achieved by two drugs and a combination of three of more drugs is required. The frequent need to treat hypertensive patients with more than 1 agent in order to reach target BPs is highlighted in all 3 of the principal hypertension guidelines. The ESH Guidelines, JNC 7, and the WHO/ISH Statement on Management—all released in 2003—emphasize the importance of achieving goal BP largely independent of the number of agents needed to achieve it. In some cases, depending on the presence of complications, it may be advisable to initiate therapy with a combination of 2 agents. A diuretic should be considered as a constituent of combination regimens.2,53,54 Chobanian et al. JAMA. 2003;289: ; WHO Writing Group. J Hypertens. 2003;21: ESH-ESC J. Hypertens. 2007;25: 2. World Health Organization, International Society of Hypertension Writing Group World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21: 53. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003;289: 54. European Society of Hypertension Guidelines Committee European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21: SLIDE 57 57

58 Model for Origins of Atherogenic Dyslipidemia of Obesity and MetS
Adiposity High carbohydrate diet Insulin resistance Genetic predisposition Pattern A TG pool High Small LDL Low Remnants Larger VLDL Smaller VLDL LDL-R LPL/HL LPL Chol CETP TG IDL Large LDL Smaller LDL HDL Smaller HDL HL <90 >175 Plasma TG Model for origins of atherogenic dyslipidemia of obesity and MetS The relation of plasma triglyceride to LDL particle size and subclass pattern reflects the existence of differing forms of VLDL that give rise to larger and smaller LDL particles. Lower plasma triglyceride levels reflect VLDLs that are secreted with lower triglyceride content and are efficiently lipolyzed to larger LDL particles by the action of lipoprotein lipase (LPL). These LDLs have high affinity for LDL receptors (LDL-R). A higher level of plasma triglyceride is associated with larger VLDL particles that are lipolyzed less efficiently by LPL, giving rise to remnant particles. The properties of these remnants, including increased content of the apoprotein CIII, further slow lipolysis and also lead to reduced receptor-mediated plasma clearance. The remnants are further lipolyzed by the combined action of LPL and hepatic lipase (HL), and also undergo exchange of triglyceride for cholesterol derived from LDL and HDL, a process mediated by cholesterol ester transfer protein (CETP). The resulting triglyceride is, in addition delipidated and remodeled to form smaller, lipid-depleted LDL. These particles have lower affinity for LDL-R. Moreover, higher levels of remnant particles lead to increased exchange of triglyceride for cholesterol in both LDL and HDL, a process mediated by cholesterol ester transfer protein. Triglyceride-rich LDLs and HDLs are degraded further by HL, leading to yet smaller LDLs and to smaller and less stable HDLs that are more rapidly catabolized, resulting in reduced HDL cholesterol. Thus, pattern B LDL is associated with a cluster of interrelated metabolic abnormalities associated with increased risk for cardiovascular disease that has been designated atherogenic dyslipidemia. Factors leading to this dyslipidemia include abdominal adiposity, high dietary carbohydrate (especially simple sugars), insulin resistance, and genetic predisposition. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002;43: CETP, cholesteryl ester transfer protein; Chol, cholesterol; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL receptor; MetS, metabolic syndrome; TG, triglycerides; VLDL, very-low-density lipoprotein. Pattern B Adapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:

59 HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events
N Engl J Med 2007;(Sep 27)357:

60 BNHI Treatment Guideline - Taiwan
Without CVD Patients With CVD or DM Patients ≧ 2 Risk Factors TC ≧ 200 mg/dL or LDL ≧ 130 mg/dL TC < 200mg/dL LDL < 130mg/dL TG ≧200 mg/dL TC/HDL >5 or HDL< 40 mg/dL TG < 200mg/dL TC ≧200mg/dL  < 160mg/dL LDL ≧130mg/dL   100mg/dL TG ≧200 mg/dL - TC/HDL >5 or HDL< 40 mg/dL TG < 200mg/dL

61 Taiwan Association of Diabetes (n=7541)
(%) Total (n = 7541) A+B+C 4.1 (n=310) A1C test >1x/year 96.6 (n=7288) A1C>9.5 14.9 (n=1121) A1C >9 20.0 (n=1507) A1C 7-9 11.4 (n=857) A1C<7 31.3 (n=2363) BP<140/90 64.9 (n=4893) BP<130/80 30.6 (n=2305) LDL-C<130 56.4 (n=4255) LDL-C<100 or TC<160 33.4 (n=2516) LDL test frequency 79.8 (n=6018) Source: TADE data

62 Trends of Higher Dosage of Statins

63 Statins dosage vs LDL-C reduction rate
Response to Minimum/Maximum Statin Dose Fluvastatin 20/80 mg Pravastatin 20/80 mg Lovastatin 20/80 mg Simvastatin 20/80 mg Atorvastatin 10/80 mg Rosuvastatin 10/40 mg % Reduction in LDL-C 施用不同的statin類藥物起始劑量後,LDL膽固醇的下降情形:fluvastatin,19%;pravastatin,27%;lovastatin,28%;simvastatin 35%;atorvastatin,37%。 劑量加倍療效並未加倍 atorvastatin的量若倍增三次(自10 mg增加至80 mg),則LDL膽固醇減少量較atorvastatin起始劑量多 18%。 31 37* 40 47 55 55 Adapted from Illingworth. Med Clin North Am. 2000;84:23. *Pravachol® (pravastatin) PI. *CRESTOR (rosuvastatin) for active control study PI. Illingworth DR. Management of hypercholesterolemia. Med Clin North Am. 2000;84: Pravachol® prescribing information. Princeton, NJ: Bristol-Myers Squibb Company.

64 Statins limitation ( rule of 6% )
10 20 40 mg Statin -10 +10 mg +20 mg +40 mg -20 LDL-Reduction (%) -30 - 6% -40 - 6% - 6% -50 2,5 statin類藥物劑量加倍,則LDL膽固醇下降會增加5%-6% (合於“the rule of 6”)。 Adverse effect 隨著statin劑量加倍成倍數的升高 2,0 2.3 x 4 x 1.7 x 1,5 % Patients of AEs 1,0 0,5 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg Atorvastatin Lovastatin Simvastatin “Physicians Desk Reference (PDR)”

65 Lipid Lowering through Dual Inhibition of Both Cholesterol Production and Absorption
Production in liver Absorption from intestine Bloodstream Dietary cholesterol Biliary cholesterol LDL-C VLDL Cholesterol synthesis (HMG-CoA reductase) Statin Ezetimibe Chylomicrons Points of therapeutic intervention HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A Adapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001; 55:710–716.

66 Ezetimibe Plus Statins in Patients with DM and Metabolic Syndrome
Simons L et al Curr Med Res Opin 2004;20: % of patients achieving target goal of LDL-C Statin + PL Statin + EZE N % to goal DM 80 17.5 73 83.6* Non-DM 149 20.1 128 67.2* MetS 81 27.2 78 71.8* Non-MetS 160 15.6 154 65.6* * p < vs. Statin + Placebo Further reduction in LDL-C ranging from % across the 4 subgroups

67 Relation Between CHD Events and LDL-C in Statin Trials
30 LIPS-Pl LIPS-RX 4S-PI GREACE-UC Secondary Prevention 25 20 4S-Rx % With 15 GREACE-SC CHD Event LIPID-PI CARE-PI LIPID-Rx 10 WOSCOPS-PI CARE-Rx AFCAPS-PI Primary Prevention 5 WOSCOPS-Rx AFCAPS-Rx Slide 26 This slide places the results of the GREACE Study in the context of prior large-scale, placebo-controlled trials of lipid-lowering therapy with statins for both primary prevention and secondary prevention of CHD morbidity and mortality. The data show the relation between the incidence of CHD events and the mean levels of LDL cholesterol achieved during follow-up for the active treatment groups in each study versus the placebo, or control, groups. [In the GREACE Study, the “usual care” group served as the controls.] As would be expected, the overall event rates were higher in secondary prevention trials (eg, 4S, CARE, LIPID) than in the primary prevention trials (AFCAPS/TexCAPS, WOSCOPS). Also, the mean LDL cholesterol levels achieved with active treatment with statins were lower than the levels observed in patients treated with placebo or usual care. 90 110 130 150 170 190 210 Mean LDL-C Level at Follow-up (mg/dL) PI = Placebo; Rx = Treatment; SC = Structured Care; UC = Usual Care. Athyros VG et al. Curr Med Res Opin. 2002;18: Downs JR et al. JAMA. 1998;279: Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. The LIPID Study Group. N Engl J Med. 1998;339: S Study Group. Lancet. 1995;345: Sacks FM et al. N Engl J Med. 1996;335: Shepherd J et al. N Engl J Med. 1995;333:

68 Goals for Management of Hyperlipidemia in Patients With Diabetes
Guidelines LDL-C Goal Diabetes With CVDa Diabetes Without CVD ESC/EASD 2007 <70 mg/dL (<1.8 mmol/L) <97 mg/dL (<2.5 mmol/L) ADA/AHA/ACC 2007 <100 mg/dL (<2.6 mmol/L) JBS2 2005 <77 mg/dLb (<2.0 mmol/L) NCEP ATP III 2004 <70 mg/dL (<1.8 mmol/L) Several international health organizations have issued guidelines for LDL-C goals in patients with diabetes. New guidelines from the European Society of Cardiology and the European Association for the Study of Diabetes include an optional LDL-C goal below 70 mg/dL (<1.8 mmol/L) for secondary prevention of cardiovascular events in patients with diabetes and symptomatic cardiovascular disease, and a goal below 97 mg/dL (<2.5 mmol/L) for primary prevention in patients with diabetes without symptomatic cardiovascular disease.1 The American Heart Association, the American College of Cardiology, and the American Diabetes Association have issued similar guidelines. For secondary prevention in patients with diabetes and overt cardiovascular disease, a goal LDL-C below 70 mg/dL (<1.8 mmol/L) is a reasonable option. For primary prevention in patients with diabetes without overt cardiovascular disease, but at increased risk due to age and other major risk factors, goal LDL-C should be below 100 mg/dL (<2.6 mmol/L) according to these organizations.2–4 The second Joint British Societies’ guidelines currently recommend a target LDL-C below 77 mg/dL (<2.0 mmol/L) or a reduction of at least 30% from baseline for all diabetes patients.5 The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advanced the first set of recommendations that recognized the benefits of intensive lipid-lowering therapy in patients with diabetes. These guidelines suggest that patients with diabetes and cardiovascular disease be treated to a very low optional LDL-C, such as below 70 mg/dL (<1.8 mmol/L). These guidelines also recognized the high risk for cardiovascular events in patients with diabetes even in the absence of established coronary heart disease and recommended an LDL-C goal below 100 mg/dL (<2.6 mmol/L) in these patients.6 LDL-C = low-density lipoprotein cholesterol; CVD = cardiovascular disease; ESC = European Society of Cardiology; EASD = European Association for the Study of Diabetes; ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology; JBS2 = Second Joint British Societies; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III aOptional/reasonable goals; bOr LDL-C reduction of 30% from baseline Rydén L, et al. Eur Heart J doi: /eurheartj/ehl261; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; Smith SC, et al. Circulation. 2006;113:2363–2372; Buse JB, et al. Circulation. 2007;115:114–126; Joint British Societies 2. Heart. 2005; 91(suppl V):v1–v52; Grundy SM, et al. Circulation. 2004;110:227–239. References Rydén L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J doi: / eurheartj/ehl261. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30(suppl 1):S4–S41. Smith SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation. 2006;113:2363–2372. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115:114–126. Joint British Societies 2. Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005;91(suppl V):v1–v52. Grundy SM, Cleeman JI, Merz CNB, et al for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239.

69 Upcoming 2009

70 Change Lifestyle is the Key
Annu. Rev. Pharmacol. Toxicol. 2007;47:565–92

71 Acknowledgement NCKU, Taiwan ORC, SLRHC, NY, USA
Xavier Pi-Sunyer Dympna Gallagher Jack Wang Stanley Heshka ZiMian Wang Richard N. Pierson,Jr Yiying Zhang Experts in ORC…… Kyoto University, Japan Kazuwa Nakao Yoshihiro Ogawa Inje University, Korea Jaeheon Kang NCKU, Taiwan Chih-Jen Chang Yi-Ching Yang Mi-Cha Ma Wei-Jen Yao Cho-Jeng Peng Shu-Hui Chen NTU, Taiwan Kuo-Chin Huang Keh-Song Tsai CMCU, Taiwan Wen-Yuan Lin WF Hospital, Taiwan Liu Tsan-Hung ChangHwa Christian H, Taiwan Shih-Te Tu VGH Taipei, Taiwan Low-Tone Ho Ching-Fai Kwok YangMing University, Taiwan Jin-Jong Chen Beijing Capital H, China Xiangyan Ruan Nat’l KS Normal Univ, Taiwan Ray-Tai Chang TSGH Taipei, Taiwan Shih Kwan-Jong Chu Nan-Fong

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