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1、血脂異常合併糖尿病或代謝症候群,臺中榮民總醫院內分泌暨新陳代謝科主治醫師 李奕德,糖尿病 and 高血脂,高血脂是心臟血管疾病的主因糖尿病的角色?,USA 2000:15M2025:21.9M,JAPAN 2000:6.9M2025:8.5M,EUROPE2000:30.8M2025:38.5M,AMERICAS(Ex-US)2000:20M2025:42M,AFRICA2000:9.2M2025:21.5M,ASIA2000:71.8M2025:165.7M,OCEANIA2000:0.8M2025:1.5M,King H et al Diabetes Care 1998;21:1414-1
2、431.,Type 2 Diabetes Prevalence Is Projected to Reach 300 Million by 2025,About 155 million adults worldwide diagnosed with diabetes in 200083 million women and 72 million menType 2 Diabetes Prevalence will reach 300 million in 2025,Percentage,Prevalence of Hyperglycemiaby Age Group in Taiwan,Age Gr
3、oup,20,30-39,80+,Definition:glucose126 or drug.國民健康局.2003.,20-29,40-49,50-59,60-69,70-79,Incidence rate(%),Increased Risk of CV Events Over 7 years in Type 2 Diabetics,Myocardial Infarction,Stroke,CV Death,Nondiabetic MI(n=1,304),Diabetic+MI(169),Nondiabetic+MI(n=69),Diabetic MI(n=890),P0.001*,P0.00
4、1*,P0.001*,-MI+MI,-MI+MI,-MI+MI,-MI+MI,-MI+MI,-MI+MI,Haffner SM et al N Engl J Med 1998;339:229-234.,Prevalence of hyperglycemia with Co-morbid diseases,HTN,Hyperlipidemia,CHD,CVA,P0.001,Percentage,Definition:glucose126 or drug.國民健康局.2003.,糖尿病的治療準則,A1cBlood pressureCholesterol(lipid)Diet controlExer
5、ciseFactors reduction,Therapeutic Life therapy,Stamler J et al Diabetes Care 1993;16:434-444.,心血管的死亡率/10,000 人-年,糖尿病無糖尿病,總膽固醇(mmol/L),0,20,40,60,80,100,120,140,4.7,4.75.1,5.25.7,5.86.2,6.36.7,6.87.2,7.3,160,心血管死亡風險(MRFIT study):低膽固醇糖尿病患者比高膽固醇但無糖尿病的人高,糖尿病合併血脂異常之特性,三酸甘油酯(Triglyceride)過高高密度脂蛋白膽固醇(HDL)較
6、低低密度脂蛋白(LDL)顆粒較小、密度較密,糖尿病的apoB濃度更高,Diabetes,LDL particles,“Normal”LDL-C level,however:,“Normal”LDL-C level,No diabetes,LDL particles,Number of LDL particlesConcentration of apoB,Lower,Risk,Higher,Small,dense LDL with more apoB,Austin MA,Edwards KL Curr Opin Lipidol 1996;7:167-171;Austin MA et al JAM
7、A 1988;260:1917-1921;Sniderman AD et al Diabetes Care 2002;25:579-582.,apoB LDL-C,根據UKPDS 研究中在第二型糖尿病中各種危險因子的重要性,VariableLow-Density Lipoprotein CholesterolHigh-Density Lipoprotein CholesterolHemoglobin A1cSystolic Blood PressureSmoking,P Value0.0001 0.0001 0.0022 0.00650.056,Coronary Artery Disease(
8、n=280),Position in ModelFirstSecondThirdFourthFifth,*Adjusted for age and sex.Turner RC et al.BMJ 1998;316:823-828.,CHD 罹病風險增加%LDL-C 1 mmol/L 57 HDL-C 0.1 mmol/L 15 收縮壓 10 mmHg 15 HbA1c 濃度 1%11 抽菸也是增加 CHD 罹病風險的重要因子,Turner RC et al BMJ 1998;316:823-828.,這些數據證明，糖尿病患者有必要降低其 LDL-C 濃度，以降低 CHD 的罹病風險。,在 UK
9、PDS 研究中LDL-C 是預測糖尿病患者 CHD 罹病風險時最有力的指標,The Pyramid of Recent TrialsRelative Size of the Various Segments of the Population,4S,CARE,WOSCOPS,AFCAPS/TexCAPS,LIPID,過去對心臟血管疾病的大型介入性（治療性）降血脂臨床試驗的結果對糖尿病患一樣有效嗎？,糖尿病合併高血脂症的藥物治療效果,Statins在大型心血管保護研究中 針對整個族群的分析(降LDL效果),Downs JR et al.JAMA 1998;279:1615-1622HPS Inv
10、estigators.Presented at AHA,2001Goldberg RB et al.Circulation 1998;98:2513-2519Pyorala K et al.Diabetes Care 1997;20:614-620Haffner SM et al.Arch Intern Med 1999;159:2661-2667LIPID Study Group.N Engl J Med 1998;339:1349-1357.,Statins在大型心血管保護研究中 針對糖尿病次族群的分析(降LDL效果),Downs JR et al.JAMA 1998;279:1615-1
11、622HPS Investigators.Presented at AHA,2001Goldberg RB et al.Circulation 1998;98:2513-2519Pyorala K et al.Diabetes Care 1997;20:614-620Haffner SM et al.Arch Intern Med 1999;159:2661-2667LIPID Study Group.N Engl J Med 1998;339:1349-1357.,結果,對心臟血管疾病而言，由過去的大型介入性（治療性）臨床試驗事後分析(post hoc analysis)得知，糖尿病患只要接
12、受積極降低血脂治療（尤其是statins藥物），便可得到與非糖尿病患一樣（甚至更多）的好處。,CARDS Study,Patient population:Enrolled at 132 sites in the UK and IrelandType 2 diabetes with no previous MI or CHD1 other CHD risk factor plus LDL-C 4.14 mmol/L(160 mg/dL)and TG 6.78 mmol/L(600 mg/dL)Aged 40-75 years,Colhoun HM,et al.Diabet Med.2002;1
13、9:201-211.,Recruitment and Follow Up,1,398(99.1%)Complete follow up,1,421(99.5%)Complete follow up,1,410 Allocated placebo,4,053 Screened,3,249(80%)Entered baseline,1,428 Allocated atorvastatin 10 mg daily,2,838(70%)Randomized,Mean follow-up of 3.7 years in both groups,Colhoun HM,et al.Diabet Med.20
14、02;19:201-211.,TC and LDL-C Levels,Effect of Atorvastatin on the Primary End Point:Major CV Events Including Stroke,Relative Risk Reduction 37%,Years,Placebo127 events,Atorvastatin83 events,Cumulative hazard(%),0,5,10,15,0,1,2,3,4,4.75,P=0.001,Colhoun HM,Betteridge DJ,Durrington PN,et al.Lancet.2004
15、;364:685-696.,CARDS Summary,statin provided benefits in type 2 diabetes with no history of CVD and with normal to mildly-elevated cholesterol levels37%reduction in major CVD events(P=0.001)48%reduction in stroke(P=0.016)27%reduction in all-cause mortality(P=0.059),Colhoun HM,et al.Diabet Med.2002;19
16、:201-211.,Adult Treatment Panel III(ATP III)Guidelines,National Cholesterol Education Program,治療的主要目標,LDL cholesterol LDL 的升高是心臟血管疾病的主因降低LDL 可減少心臟血管疾病的風險ATP III治療的主要目標著重在 LDL.,高危險群,CHDHistory of CHDCHD risk equivalentsOther clinical forms of atherosclerotic diseaseperipheral arterial diseaseabdomina
17、l aortic aneurysmsymptomatic carotid artery disease Diabetes(糖尿病)Multiple risk factors with a 10-year risk for CHD 20%,ATP III,Risk CategoryCHD and CHD risk equivalentsMultiple(2+)risk factors0-1 one risk factor,LDL Goal(mg/dL)100130160,Three Categories of Risk that Modify LDL-Cholesterol Goals,ATP
18、III,Prevalence of the Metabolic Syndrome Age-Specific Prevalence of the Metabolic Syndrome Among 8814 US Adults Aged at Least 20 Years,National Health and Nutrition Examination Survey III,1988-1994,Harris MI,et al.,Diabetes Care 1998;21:518Ford ES,et al.,JAMA.2002 Jan 16;287(3):356-9.,Prevalence of
19、the Metabolic Syndrome,Ford ES,et al.,JAMA.2002 Jan 16;287(3):356-9.,Difference in Asian,WHO Expert consultation.Lancet 2004;363:157-163,國內成人肥胖定義,肥胖的判定,Metabolic Syndrome,carotid atherosclerosis and LDL size,LDL size in metabolic syndrome,Hulthe J et al.,Arterioscler Thromb Vasc Biol 2000;20:2140.,G
20、emfibrozil for insulin resistance,Rubins HB et al.,Arch Intern Med.2002;162:2597,代謝症候群(metabolic syndrome),第二個治療目標LDL控制之後的目標標準腹部肥胖Men(腹圍)102cm(90cm)Women(腹圍)88cm(80cm)High triglycemiaTG 150 mg/dlLow HDL cholesterolMen 130/85 mmHg空腹血糖高Plasma glucose 110 mg/dl,ATP III,Triglycerides 高,可能原因肥胖(obesity)不運
21、動(physical inactivity)抽煙(cigarette smoking)酗酒(excess alcohol intake)高碳水化合物飲食 high-carbohydrate diets(60%of energy intake)疾病糖尿病 Diabetes慢性腎衰竭 Chronic renal failure腎病症侯群 nephrotic syndrome 藥物 corticosteroids,estrogens,retinoids,higher doses of B-adrenergic blocking agents基因familial combined hyperlipid
22、emia,familial hypertriglyceridemiafamilial dysbetalipoproteinemia,ATP III,Triglycerides 嚴重度,Triglycerides levelNormal 150 mg/dLBorderline high150 199 mg/dLHigh200 499 mg/dLVery high500 mg/dLNon-HDL CholesterolVLDL+LDL=Total cholesterol HDL Target:LDL+30 mg/dl,ATP III,治療triglycerides過高,治療的主要目標著重在 LDL
23、 但當TG 500 mg/dl治療的目標先預防急性胰臟炎低脂肪飲食 Very low fat diets(15%of caloric intake)使用降Triglyceride 藥物(fibrate or nicotinic acid),ATP III,HDL Cholesterol 過低-原因-,Triglycerides 過高肥胖(obesity)不運動(physical inactivity)糖尿病(type 2 diabetes)抽煙(cigarette smoking)高碳水化合物飲食 high-carbohydrate diets(60%of energy intake)藥物be
24、ta-blockers,anabolic steroids,progestational agents,ATP III,HDL Cholesterol 過低-治療-,治療的主要目標著重在 LDL增加運動及控制體重仍依上述原則TG 500Reduce triglycerides before LDL lowering TG:200 499Non-HDL cholesterol is secondary target of therapyTG 200consider nicotinic acid or fibrates in person with CHD or CHD risk,ATP III,
25、Therapeutic Lifer therapy-Diet control and Excercise,The Oslo diet-heart study的11-year 追蹤報告：至少三十年前就證實有效地預防心血管疾病(Leren P,1970),Finnish Diabetes Prevention Study,Subjects522 patients,40-65 y,CaucasiansIGT on 2 occasionsInterventions1.Intensified diet and exercise lifestyle5%reduction in body weightRed
26、uction in dietary fat 30%,saturated fat 10%Increase in dietary fiber,fruits and vegetablesIncrease activity2.Usual care,N Engl J Med 344:1343-1349,2001,生活型態與糖尿病,Finnish DPS:Development of diabetes in the intervention and control groups,Risk reduction:58%,Mean follow-up:3.2 years,N Engl J Med 344:134
27、3-1349,2001,生活型態與糖尿病,US Diabetes Prevention Program,Subjects3234 patients,25 y,45%minoritiesIGT with fasting plasma glucose 5.6 mmol/LInterventions1.Intensified diet and exercise lifestyle 7%reduction in body weight increase calorie expenditure 700 kcal per week2.Metformin 1700 mg per day3.Placebo t
28、ablet,Diabetes Care 23:1619-1629,US DPP:Effect on diabetes incidence,Metformin:31%decrease in incident diabetesLifestyle:58%decrease in incident diabetes,Released early(08/08/01)after a mean follow-up of 3 years,Diabetes Care 23:1619-1629,Therapeutic Lifestyle ChangesNutrient Composition of TLC Diet
29、,NutrientRecommended IntakeSaturated fatLess than 7%of total caloriesPolyunsaturated fatUp to 10%of total caloriesMonounsaturated fat Up to 20%of total caloriesTotal fat2535%of total caloriesCarbohydrate5060%of total caloriesFiber2030 grams per dayProteinApproximately 15%of total caloriesCholesterol
30、Less than 200 mg/dayTotal calories Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain,ATP III,回顧,三十年前，發表運動者比長期辦公者對insulin反應較好 Bjorntorp et al.Metabolism 1970;19:631-638.數天的不運動即造成insulin反應差。Ruderman et al.Diabetes 1979;28:89-92.單一次的運動即可改善insulin作用，而且甚至可達兩天之久。M
31、ikines et al.Am J Physiol 1988;254:E248-E259 若運動後給醣類飲食後，insulin sensitivity只維持了15小時Bogardus et al.J Clin Invest 1983;72:1605-1610.但運動當時的catacholamine升高也可能阻礙insulin作用。Kjr et al.J Appl Physiol 1986;61:1693-1700.,Insulin增加血糖的吸收及利用,與insulin receptor作用經由一些protein下傳訊息Ex:insulin receptor substrate(IRS)其中可經
32、由GLUT4(glucose transporter)移至細胞膜上，以利glucose的傳送,運動增加insulin sensitivity的機轉,運動後，肌肉會比以前更強壯,為了應付下一次的運動增加protein合成增加glycogen貯存局部的效果明顯只運動一腳，發現有運動的一肢比另一肢insulin sensitivity較好。另一肢可能也會改善，只是沒有運動的那肢好。,運動增加insulin sensitivity,Richter et al.J Appl Physiol 1984;246:E476,運動增加insulin sensitivity,Wojtaszewski et al.
33、Acta Physiol Scand 2003;178:321,Glycogen量與insulin sensitivity,Glucose的吸收與消秏的glycogen成正比。Glycogen的合成與肌肉內glycogen量成反相關。因GLUT4到表面的量與glycogen量成反向關係可能經由AMPK(AMP-activated protein kinase)作用,運動增加insulin sensitivity,運動增加insulin sensitivity,Wojtaszewski et al.Acta Physiol Scand 2003;178:321,運動與insulin作用機轉不同,
34、運動後改善insulin sensitivity是由於GLUT4出現於肌肉細胞膜上增多。藉由取得glucose增加使合成glycogen增多。由運動增加glucose的傳送與glycogen的合成與insulin經由的機轉可能不同運動產生GLUT4表現並不一定需要insulin receptor,IR 1/2,PI3K等物質。與AMPK有關,運動增加insulin sensitivity,ConclusionThe clinical approach to treatment of patients with dyslipidaemias-associated Metabolic Syndro
35、me,A broad-based strategyreversal of lipid abnormalities(elevated LDL-C)reduction of triglyceride-rich lipoproteinsimprovement of insulin-resistance.Lifestyle modifications(balanced diet and increased physical exercise)should first be proposeddrug therapy targeting hypertriglyceridaemia and low HDL-C could be proposed in association with diet and exercise,Thank youfor your attention,
