糖尿病药物治疗问题与失误.ppt

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1、 糖尿病药物治疗糖尿病药物治疗问题与失误问题与失误2型糖尿病的病因、病理生理和结局型糖尿病的病因、病理生理和结局大小血管并发症大小血管并发症遗传因素遗传因素环境因素环境因素胰岛素抵抗胰岛素抵抗 细胞缺陷细胞缺陷高血糖高血糖/IGTHDL,小而致密小而致密LDL 高血压高血压内皮功能障碍内皮功能障碍/微蛋白尿微蛋白尿低纤维蛋白溶解状态低纤维蛋白溶解状态炎症炎症Adapted from McFarlane S,et al.J Clin Endocrinol Metab 2001;86:713718.血糖是最难控制的代谢异常血糖是最难控制的代谢异常 多种病理生理机制多种病理生理机制 自然病程演变自然

2、病程演变,各种病理生理基础发生变化各种病理生理基础发生变化 影响因素多影响因素多,波动性大波动性大,需要反复的反馈需要反复的反馈ASCOT:Reductions in Total and LDL Cholesterol2460123Atorvastatin 10 mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Total cholesterol(mmol/L)LDL cholesterol(mmol/L)Years1.3 mmol/L1.0 mmol/L1.2 mmol/L1.0 mmol/LSever PS,Dahlf B,Poulter

3、 N,Wedel H,et al,for the ASCOT Investigators.Lancet.2003;361:1149-58LIIFE 研究研究-相同的降压疗效相同的降压疗效061218243036424854研究月份研究月份405060708090100110120130140150160170180收缩压收缩压舒张压舒张压平均动脉压平均动脉压mmHg阿替洛尔阿替洛尔 145.4 mmHg氯沙坦氯沙坦 144.1 mmHg阿替洛尔阿替洛尔 80.9 mmHg氯沙坦氯沙坦 81.3 mmHgDahlf B et al Lancet 2002;359:995-1003.阿替洛尔阿替洛

4、尔 102.4 mmHg氯沙坦氯沙坦 102.2 mmHg1 2 3 4EDICDCCT to EDIC:From experiment to reality 06789246810HbA1c(%)Time from randomization(years)Upper limit of normal=6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：单一药物治疗的局限性(1998年）Adapted from UKPDS Group.UKPDS 34.Lancet 1998;352:854865.*Therapy assigned if FPG

5、15 mmol/l or symptoms of hyperglycemia Overweight patientsCohort,median valuesConventional therapy(primarily diet alone*)Saydah SH et al.JAMA.2004;291:335-342.Patients(%)HbA1C 7%44.3%NHANES III;n=1,204 NHANES 1999-2000;n=37001020304050BP 130/80 mm HgTC 200 mg/dL29.0%35.8%37.0%Good control7.3%5.2%33.

6、9%P.001 48.2%Risk Factor Control in Adults With Diabetes:NHANES III(1988-1994)/NHANES 1999-2000Percentage of Patients With DiabetesHaving A1C 8.0%后仍然后仍然维持单药治疗的时间维持单药治疗的时间*（2004年）年）Brown JB,et al.Diabetes Care 2004;27:15351540.*May include uptitration 0510152025Metformin onlySulfonylurea onlyn=513n=3

7、,39414.5 个月个月20.5 个月个月月020406080100%Age of SubjectsPercentage of Subjects advancing when HbA1C 8%Clinical Inertia:“Failure to advance therapy when required”Diet66.6%Sulfonylurea35.3%Metformin44.6%Combination18.6%Brown et al.The Burden of Treatment Failure in Type 2 Diabetes.Diabetes Care 27:1535-154

8、0,2004At Insulin Initiation,the average patient had:5 years with HbA1C 8%10 years with HbA1C 7%多种代谢异常控制的重要性 微血管病变微血管病变:高血糖是必要条件高血糖是必要条件,但不是充分条件但不是充分条件 血压血压*,血脂血脂#,炎症炎症#大血管病变大血管病变:高血糖不是必要条件高血糖不是必要条件,但可能促进因但可能促进因素素#*:流行病学证据流行病学证据;#:临床试验证据临床试验证据A tight blood pressure control policy which A tight blood

9、pressure control policy which achieved blood pressure of 144/82mmHg gave achieved blood pressure of 144/82mmHg gave reduced risk of:reduced risk of:24%for any diabetes-related endpoint p=0.004624%for any diabetes-related endpoint p=0.004632%for diabetes-related deaths p=0.01932%for diabetes-related

10、deaths p=0.01944%for stroke p=0.01344%for stroke p=0.01337%for microvascular disease p=0.009237%for microvascular disease p=0.009256%for heart failure p=0.0043 56%for heart failure p=0.0043 Blood Pressure Control,UKPDS UKPDS研究显示：严格降压比强化降糖更重要?中风中风任何糖尿病终点任何糖尿病终点糖尿病死亡糖尿病死亡微血管并发症微血管并发症-50-40-30-20-100相对

11、危险度降低（相对危险度降低（%）严格血糖控制严格血糖控制(目标目标 6.0 mmol/L或或108 mg/dL)严格血压控制严格血压控制(平均平均 144/82 mmHg)32%37%10%32%12%24%5%44%Bakris GL,et al.Am J Kidney Dis.2000;36(3):646-661.*与严格血糖控制比较，与严格血糖控制比较，P 0.05 各种治疗达标的百分率各种治疗达标的百分率糖化血红蛋白糖化血红蛋白6.5%胆固醇胆固醇4.5 mmol/l甘油三酯甘油三酯1.7 mmol/l收缩压收缩压130 mmHg舒张压舒张压80 mmHg8年后达到治疗目标的患者年后达

12、到治疗目标的患者%p=0.06p0.0001p=0.19p=0.001p=0.21Steno-2 强化组强化组 常规组常规组强化组强化组 常规组常规组强化组强化组 常规组常规组强化组强化组 常规组常规组强化组强化组 常规组常规组Targets for controlParameterTargetHbA1c 6.5%(DCCT-aligned assay)BP130/80 mmHgTotal cholesterol4.5 mmol/L(174 mg/dl)LDL-cholesterol2.5 mmol/L(97 mg/dl)HDL-cholesterol1.0 mmol/L(39 mg/dl)T

13、riglycerides1.5 mmol/L(133 mg/dl)Urinary albumin:creatinine2.5 mg/mmol(22 mg/g)men3.5 mg mmol(31 mg/g)-womenExercise 150 minutes/week 2型糖尿病患者的药物治疗型糖尿病患者的药物治疗代谢控制代谢控制 降糖药降糖药：格列酮类；双胍类；糖苷酶抑制剂；促胰岛素分泌剂 GLP-1相关药物 调脂药调脂药:它汀类药物它汀类药物抗凝抗凝 阿司匹林阿司匹林血压控制血压控制 降压药降压药Pancreatic -cellInsulin ResistanceInsulin action

14、IncreasedlipolysisADIPOSETISSUEIslet b-cell degranulationreduced insulin contentInsulin Resistance and -cell Dysfunction ProduceHyperglycaemia in Type 2 Diabeteslow-plasmainsulinIncreased glucose outputHYPERGLYCEMIADecreased glucose transport&activity(expression)of GLUT4Elevatedplasma NEFAElevatedTN

15、F,Resistin?MUSCLE(TG )LIVERPANCREASSites of Action by Therapeutic Options Sonnenberg,et al.Curr Opin Nephrol Hypertens 1998;7(5):551-555.GLUCOSEABSORPTIONMUSCLEPANCREASADIPOSE TISSUELIVERINTESTINEHYPERGLYCEMIADECREASED PERIPHERAL GLUCOSE UPTAKEINCREASED GLUCOSE PRODUCTIONDECREASED INSULIN SECRETIONT

16、herapy:Thiazolidinediones(Biguanides)Therapy:InsulinSulfonylureasMetiglinidesTherapy:BiguanidesThiazolidinedionesTherapy:Alpha-glucosidase inhibitors正常人血糖的波动正常人血糖的波动Riddle MC.Diabetes Care 1990;13:6766863002001000血浆葡萄糖浓度(mg/dl)06001200180024000600时间(小时)餐时血糖峰值空腹2 2型糖尿病高血糖的构成空腹血糖增高型糖尿病高血糖的构成空腹血糖增高Riddle MC.Diabetes Care 1990;13:6766863002001000血浆葡萄糖浓度(mg/dl)06001200180024000600时间(小时)肝糖输出肝糖输出 正常正常 肝糖输出不能被关闭肝糖输出不能被关闭Riddle MC.Diabetes Care 1990;13:6766863002001000血浆葡萄糖浓度(mg/dl)06001200180024000600时间