7CVD Risks and Anthropometric Index in Male Elderly Taiwanese - Huang KC, et al. Obes Res 2005;13:170-8
8CVD Risks and Anthropometric Index in Female Elderly Taiwanese - Huang KC, et al. Obes Res 2005;13:170-8
9Obesity and Metabolic Syndrome: A Cluster of Coronary Heart Disease Risk Factors Diet Physical Inactivity StressRaised Blood PressureGenetic SusceptibilityAutonomic DysfunctionProthrombotic StateObesity and the metabolic syndrome: a cluster of coronary heart disease risk factorsThe 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 DyslipidemiaInsulin ResistanceProinflammatory StateTriglyceridesHigh-Density Lipoprotein CholesterolSmall Low-DensityLipoprotein ParticlesAdapted from Grundy SM. J Clin Endocrinol Metab. 2005;89:
14Drugs Approved by FDA for Treating Obesity -Yanovski SZ, et al. N Engl J Med 2002;346:Generic NameTrade NamesDEA ScheduleApproved UseYear ApprovedOrlistatXenicalNoneLong-term1999SibutramineMeridiaIV1997DiethylpropionTenulateShort-term1973PhentermineAdipex, lonaminPhendimetrazineBontril, Prelu-2III1961BenzphetamineDidrex1960Drugs approved by FDA for treating obesityThis 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)  or hemorrhagic stroke (phenylpropanolamine)  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 areexcreted.羅氏鮮可減少食物中30%的脂肪攝取量
16Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year Study or Sub-categoryWMD (random) 95% CIHollander 1998*Sjostrom 1998Davidson 1999Finer 2000Heuptman 2000Lindgarde 2000Rossner 2000Bakris 2002Broom 2002Kelley 2002*Miles 2002*Total (95% CI)Meta-analysis of RCTs evaluating effect of orlistat therapy on weight loss at 1-yearThis 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 . 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 diabetesWMD=weighted mean difference-10-5510Favours TreatmentFavours ControlPadwal et al. Int J Obes 2003;27:1437
17FDA 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 ReuptakeCatabolism5-HTRELEASESSMAOMechanisms of Action: Sibutramine and Active MetabolitesBlock Serotonin and Norepinephrine Reuptake1,2Sibutramine and its active metabolites inhibit the reuptake of 5-HT and NAThis action increases the amount of 5-HT and NA in the synapse and at the postsynaptic receptorsThis mechanism of action does not override the normal physiologic control mechanisms of releaseReuptakeCatabolismNARELEASESS = sibutramine = noradrenaline, = serotoninAdapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S.
19Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year Study or Sub-categoryWMD (random) 95% CIMcMahon 2000Smith 2001McMahon 2002 *Total (95% CI)Meta-analysis of RCTs evaluating effect of sibutramine therapy on weight loss at 1-yearThis 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 . 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:-10Favours TreatmentFavours Control-5105All subjects had hypertensionWMD=weighted mean differencePadwal et al. Int J Obes 2003;27:1437
20Sibutramine, Orlistat or Combination Therapy for 12 week in Turkey(n=86) -Aydin N, et al. Tohoku J Exp Med 2004;202:173-80
21Similar Effects * * * * * The body weight, BMI and body fat change between baseline and 6-month interval in NCKUH*****Wu CH, et al. 2008: submitted
22Franz 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:
24Cardinal Behaviors of Successful Long-term Weight Management National Weight Control Registry Data Self-monitoring:Diet: record food intake daily, limit certain foods or food quantityWeight: check body weight >1 x/wkLow-calorie, low-fat diet:Total energy intake: kcal/dEnergy intake from fat: 20%-25%Eat breakfast dailyRegular physical activity: kcal/wk (eg, walk 4 miles/d)Cardinal behaviors of successful long-term weight managementData 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.
25Pathogenesis of Metabolic syndrome 2 major, interacting causesObesity and abnormal body fat distribution disorders of adipose tissue.Endogenous metabolic susceptibility Insulin resistanceA 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;109:433-8Grundy SM: Am J Clin Nutr 2006 Aug 1248
27Mean Efficacy of Pharmacological Treatment Options in Type II DM - Diabetologia 2003;(suppl 1):M30-M36
28Side Effect of Oral Hypoglycemic Agents - Endocrinol Metab Clin North Am 2001; 30(4):
29Metformin- Mean Weight Change PlaceboMetforminLifestyleThe DPP Research Group, NEJM 346: , 2002
30Weight Change of DM patients using Acarbose in Taiwan 1020304050607080Patients65.565.265.1Initial visitFirst follow-upSecond follow-upThird follow-upkgHung YJ, et al. Clin Drug Invest 2006;26:559-65
31Similar Effect of Hypoglycemic Agents Action on insulinresistanceAction on insulinsecretionHbA1CreductionPrimary GoalGlinides0/++++0.9 to 1.7%PostprandialConventionalSulfonylureas0/+++++1% to 2%FastingNew SU+++++1% to 2%FastingBiguanides++1% to 2%FastingGlitazones++++0.5% to 1.3%Fasting-glucosidase inhibitors0.5% to 1%PostprandialData from Henry. Endocrinol Metab Clin. 1997;26: Gitlin, et al. Ann Intern Med. 1998;129: Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41Medical 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:
32Characters of individuals in MetS of NHANESIII - Jacobson TA, et al. Diabet Obes Metab 2004;6:353-62
33Intra-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 FFAIntra-abdominal adiposity promotes insulin resistance and increased CV riskIntra-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 DyslipidaemiaNet result: Insulin resistance InflammationPro-atherogenicHeilbronn et al 2004; Coppack 2001;Skurk & Hauner 2004
35Fat Topography in MetS and Diabetic Subjects High TGHigh FFAIntramuscular FatSubcutaneous FatHarold 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 FatIntraabdominal FatBays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:
36Effect of Thiazolidinediones on Fat TopographyHigh TGHigh FFATGFFATZDIntramuscular FatSubcutaneous FatHarold 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 FatIntraabdominal FatBays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:
37Diabetes prevention trials StudyInterventionRR (%)ACT NOWPioglitazone vs placebo78%DREAMRosiglitazone vs placebo62%Finnish DPSIntensive lifestyle vs control 58%Da Qing study 38%DPPIntensive lifestyle vs placeboMetformin vs placeboTroglitazone vs placebo58%31% 75%IDPPMetformin + lifestyleMetformin19%TRIPODTroglitazone (after gestational diabetes) 50%Fasting Hyperglycemic StudyGliclazide or intensive lifestyleNo effectSTOP-NIDDMAcarbose vs placebo 25%XENDOSOrlistat + 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).4The 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).5The 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).6Finally, 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).91. 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 2008DREAM 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.
38ADOPT (A Diabetes Outcome Progression Trial) -Fasting Plasma Glucose Over Time- mg/dl120160140130150Rosiglitazone vs Metformin 9.8 (12.7 to 7.0), P<0.001Rosiglitazone vs Glyburide 17.4 (20.4 to 14.5), P<0.001GlyburideMetforminRosiglitazone12345Time (years)
39Gastrointestinal, n (%) P<0.05 vs. rosiglitazone Other Adverse EventsRosiglitazone(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
40NEJM 2007;356;437-40Approved Antidiabetes Medications in the United States.NEJM 2007;356;437-40
41Role of DPP-4, GLP-1, GIP in glucose homeostasis Herman GA, et al. Clin Pharmacol Ther. 2007;81:761-7The 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.
42Mean Difference in BW Change for Gliptins vs Control in Adults With Type 2 Diabetes Amori RE, et al. JAMA 2007;298:
43Major Targeted Sites of Oral Drug Classes PancreasImpaired insulinsecretionSulfonylureasMuscle and fatMeglitinidesLiverDPP-4 inhibitors↓Glucose levelMajor Targeted Sites of Various Oral Drug ClassesThe various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycaemia.1,2Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of β-cell membranes.1-3Meglitinides, 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.1,3Thiazolidinediones (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.1,3α-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.1,3Biguanides (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.1-3,5Based 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.5Hepatic glucose overproductionInsulin resistancePurpose: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.GutBiguanidesTZDsTZDsBiguanidesDPP-4 inhibitorsDPP-4 inhibitors (indirect)Glucose absorptionα-Glucosidase inhibitorsBiguanides (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.References1. 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
44Developing Avenue of Ideal OADs Glycemic EffectB-cell PreserveInsulin SensitizingNeutral WeightLowHypoglycemiaQDDosageSU++++/-Non-SU+++BGA-GIGlitazone-Gliptins
45Glitazones (supposed) Weight gain with antidiabetic therapy UK Prospective Diabetes Study and UpdateModified from UKPDS 34. Lancet 1998; 352:Weight change (kg)7Insulin65Glitazones (supposed)Diet aloneChlorpropamideGlibenclamide43Meglitinides (?)2Metformin, AcarboseDPP-4 inhibitors (?)1-1246810Years from randomisation
46Chiang 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;31:73-82Combination = 62.9%Any three OAD = 10.9%
47Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease Genetic variationEnvironmental factorsAbdominal obesityAdipokinesCytokinesAdipocyteInflammatory markersMonocyte/macrophageInsulin resistance TG Metabolic syndrome HDL BPPathophysiology of the metabolic syndrome leading to atherosclerotic CV diseaseA complex series of interactions of metabolic risk factors with genetic and environmental influences underlies the adverse influence of the metabolic syndrome on cardiovascular prognosis. Abdominal obesity is an important cause of multiple sources of cardiovascular risk within this system. Bioactive substances (adipokines, inflammatory cytokines and other agents) derived from intra-abdominal adipocytes, the liver and/or inflammatory cells help to drive the progression of the cluster of risk factors characteristic of the metabolic syndrome. In turn, exacerbation of these risk factors, in addition to the direct pro-atherogenic effects of adipokines, accelerates the atherosclerotic changes that increased the risk of an occlusive thromboembolic coronary event.It is difficult to intervene successfully once the vicious cycle of promotion of cardiovascular risk factors and atherogenesis is established. Intervening at an earlier stage, for example to combat directly the development of intra-abdominal adiposity, may provide a more successful prospect for intervention to reduce the risk of a cardiovascular event.Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:AtherosclerosisPlaque rupture/thrombosisReilly & Rader 2003;Eckel et al 2005Cardiovascular events
48Cardiovascular Disease Mortality Increased in the Metabolic Syndrome Lakka et al. JAMA. 2002;288:2709–16.15Metabolic syndromeYesNoRR (95% Cl), 3.55 (1.98–6.43)10Cumulative hazard, %524681012Follow-up, y
49Lawes CCM, et al. Lancet 2008; 371: 1513–18 Disability-adjusted life years (DALYs) attributable to high blood pressure in 2001Lawes CCM, et al. Lancet 2008; 371: 1513–18M/LF/LMen (A) and women (B) in low-income and middle-income countries. Men (C) and women (D) in high-incomecountries.F/H
50Effect 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)
51Elliott 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 trialsTrials included patients. Initial diuretic used as referent agent (open boxat odds ratio=1・00). Size of squares (representing the point estimate for each classof antihypertensive drugs) is proportional to number of patients who developedincident diabetes. Horizontal lines indicate 95% CI. Odds ratios to the left of thevertical line at unity denote a protective eff ect (compared with initial diuretic).Individual pair-wise comparisons between diuretic vs β blocker (p=0・30), placebovs 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.
52Journal of Hypertension 2007, 25:1105–1187 Conditions favouring use of some antihypertensive drugs-ESC 2007 GuidelineJournal of Hypertension 2007, 25:1105–1187
54Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients withhypertension and impaired glucose metabolismNutrition, Metabolism & Cardiovascular Diseases (2006) 16,16 weeks of combined therapy
55Journal of Hypertension 2007;25:1105-1187 ESH-ESC 2007 GuidelinesP. 1141Journal 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.
56Multiple antihypertensive agents are needed to achieve target BP Number of antihypertensive agentsTrialTarget BP (mmHg)1234UKPDS DBP <85ABCD DBP <75MDRD MAP <92HOT DBP <80AASK MAP <92IDNT SBP <135/DBP <85ALLHAT SBP <140/DBP <90DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressureBakris 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
57Combination Therapy Emphasized in All Guidelines JNC 7Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BPIf 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 diureticWHO/ISHLess than half of hypertension patients will attain target pressures with monotherapy; as many as 30% will need 3 or more drugsDiuretic should be a component of combination therapyESH-ESC 2007Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patientsUse 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.2,53,54Chobanian 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 5757
58Model for Origins of Atherogenic Dyslipidemia of Obesity and MetS AdiposityHigh carbohydrate dietInsulin resistanceGenetic predispositionPattern ATG poolHighSmall LDLLowRemnantsLarger VLDLSmaller VLDLLDL-RLPL/HLLPLCholCETPTGIDLLarge LDLSmaller LDLHDLSmaller HDLHL<90>175Plasma TGModel for origins of atherogenic dyslipidemia of obesity and MetSThe 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 BAdapted from Berneis KK, Krauss RM. J Lipid Res. 2002;43:
59HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events N Engl J Med 2007;(Sep 27)357:
61Taiwan Association of Diabetes (n=7541) (%)Total (n = 7541)A+B+C4.1 (n=310)A1C test >1x/year96.6 (n=7288)A1C>9.514.9 (n=1121)A1C >920.0 (n=1507)A1C 7-911.4 (n=857)A1C<731.3 (n=2363)BP<140/9064.9 (n=4893)BP<130/8030.6 (n=2305)LDL-C<13056.4 (n=4255)LDL-C<100 or TC<16033.4 (n=2516)LDL test frequency79.8 (n=6018)Source: TADE data
63Statins dosage vs LDL-C reduction rate Response to Minimum/Maximum Statin DoseFluvastatin20/80 mgPravastatin20/80 mgLovastatin20/80 mgSimvastatin20/80 mgAtorvastatin 10/80 mgRosuvastatin10/40 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%。3137*40475555Adapted 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.
65Lipid Lowering through Dual Inhibition of Both Cholesterol Production and Absorption Production in liverAbsorption from intestineBloodstreamDietary cholesterolBiliary cholesterolLDL-CVLDLCholesterol synthesis(HMG-CoAreductase)StatinEzetimibeChylomicronsPoints of therapeutic interventionHMG-CoA=3-hydroxy-3-methylglutaryl coenzyme AAdapted from Shepherd J Eur J Cardiol Suppl 2001:3(suppl E):E2–E5; Miettinen TA Int J Clin Pract 2001; 55:710–716.
66Ezetimibe 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-CStatin + PLStatin + EZEN% to goalDM8017.57383.6*Non-DM14920.112867.2*MetS8127.27871.8*Non-MetS16015.615465.6** p < vs. Statin + PlaceboFurther reduction in LDL-C ranging from % across the 4 subgroups
67Relation Between CHD Events and LDL-C in Statin Trials 30LIPS-PlLIPS-RX4S-PIGREACE-UCSecondaryPrevention25204S-Rx% With15GREACE-SCCHD EventLIPID-PICARE-PILIPID-Rx10WOSCOPS-PICARE-RxAFCAPS-PIPrimaryPrevention5WOSCOPS-RxAFCAPS-RxSlide 26This 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.90110130150170190210Mean 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:
68Goals for Management of Hyperlipidemia in Patients With Diabetes GuidelinesLDL-C GoalDiabetes With CVDaDiabetes Without CVDESC/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.1The 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.2–4The 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.5The 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.6LDL-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 IIIaOptional/reasonable goals; bOr LDL-C reduction of 30% from baselineRydén 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.ReferencesRydén 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.