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1、糖尿病药物治疗问题与失误,2型糖尿病的病因、病理生理和结局,大小血管并发症,遗传因素环境因素,胰岛素抵抗细胞缺陷,高血糖/IGTHDL,小而致密LDL高血压内皮功能障碍/微蛋白尿低纤维蛋白溶解状态炎症,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,多种病理生理机制自然病程演变,各种病理生理基础发生变化影响因素多,波动性大,需要反复的反馈,ASCOT:Reductions in Total and LDL Cholesterol,2,4,6,0,1,2,3,Atorvasta
2、tin 10 mg,Placebo,1,2,3,4,0,1,2,3,200,150,150,75,125,100,100,(mg/dL),(mg/dL),Total cholesterol(mmol/L),LDL cholesterol(mmol/L),Years,1.3 mmol/L,1.0 mmol/L,1.2 mmol/L,1.0 mmol/L,Sever PS,Dahlf B,Poulter N,Wedel H,et al,for the ASCOT Investigators.Lancet.2003;361:1149-58,LIIFE 研究-相同的降压疗效,研究月份,收缩压,舒张压,
3、平均动脉压,mmHg,阿替洛尔 145.4 mmHg,氯沙坦 144.1 mmHg,阿替洛尔 80.9 mmHg,氯沙坦 81.3 mmHg,Dahlf B et al Lancet 2002;359:995-1003.,阿替洛尔 102.4 mmHg,氯沙坦 102.2 mmHg,1 2 3 4,EDIC,DCCT to EDIC:From experiment to reality,0,6,7,8,9,2,4,6,8,10,HbA,1c,(%),Time from randomization(years),Upper limit of normal=6.2%,0,UKPDS：单一药物治疗的
4、局限性(1998年）,Adapted from UKPDS Group.UKPDS 34.Lancet 1998;352:854865.,*Therapy assigned if FPG 15 mmol/l or symptoms of hyperglycemia Overweight patientsCohort,median values,Saydah SH et al.JAMA.2004;291:335-342.,Patients(%),HbA1C 7%,NHANES III;n=1,204 NHANES 1999-2000;n=370,0,10,20,30,40,50,BP 130/8
5、0 mm Hg,TC 200 mg/dL,Risk Factor Control in Adults With Diabetes:NHANES III(1988-1994)/NHANES 1999-2000,Percentage of Patients With DiabetesHaving A1C 7%,Harris MI et al.Diabetes Care.1999;22:403-408Koro Ce et al.,Diabetes Care 27:17-20,2004,0,20,40,60,80,100,Diet alone,Oral agents,Insulin,NHANES II
6、IUS Adults With Diagnosed Diabetes in 198894,73%,38%,27%,Whole studypopulation,44.5%,Percent at goal,Therapy used,35.8%,NHANES(1999-2000),在单药治疗时发现 HbA1c 8.0%后仍然维持单药治疗的时间*（2004年）,Brown JB,et al.Diabetes Care 2004;27:15351540.,*May include uptitration,0,5,10,15,20,25,Metformin only,Sulfonylurea only,n
7、=513,n=3,394,14.5 个月,20.5 个月,月,0,20,40,60,80,100,%Age of Subjects,Percentage of Subjects advancing when HbA1C 8%,Clinical Inertia:“Failure to advance therapy when required”,Brown et al.The Burden of Treatment Failure in Type 2 Diabetes.Diabetes Care 27:1535-1540,2004,At Insulin Initiation,the averag
8、e 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:高血糖是必要条件,但不是充分条件 血压*,血脂#,炎症#大血管病变:高血糖不是必要条件,但可能促进因素#,*:流行病学证据;#:临床试验证据,A tight blood pressure control policy which achieved blood pressure of 144/82mmHg gave reduced risk of:24%for any diabetes-related endpoint p=0.004632
9、%for diabetes-related deaths p=0.01944%for stroke p=0.01337%for microvascular disease p=0.009256%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,任何糖尿病终点,糖尿病死亡,微血管并发症,-50,-40,-30,-20,-10,0,相对危险度降低（%）,严格血糖控制(目标 6.0 mmol/L或108 mg/dL),严格血压控制(平均 144/82 mmHg),32%,37%,10%
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，P 0.05,各种治疗达标的百分率,糖化血红蛋白6.5%,胆固醇4.5 mmol/l,甘油三酯1.7 mmol/l,收缩压130 mmHg,舒张压80 mmHg,8年后达到治疗目标的患者,%,p=0.06,p0.0001,p=0.19,p=0.001,p=0.21,Steno-2,强化组 常规组,强化组 常规组,强化组 常规组,强化组 常规组,强化组 常规组,Targets for control,2型糖尿病患者的
11、药物治疗,代谢控制 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:它汀类药物抗凝 阿司匹林血压控制 降压药,Pancreatic b-cell,Insulin ResistanceInsulin action,Increasedlipolysis,ADIPOSETISSUE,Islet b-cell degranulationreduced insulin content,Insulin Resistance and b-cell Dysfunction ProduceHyperglycaemia in Type 2 Diabetes,low-plasma
12、insulin,Increased glucose output,HYPERGLYCEMIA,Decreased glucose transport&activity(expression)of GLUT4,Elevatedplasma NEFA,ElevatedTNFa,Resistin?,MUSCLE(TG),LIVER,PANCREAS,Sites of Action by Therapeutic Options,Sonnenberg,et al.Curr Opin Nephrol Hypertens 1998;7(5):551-555.,GLUCOSEABSORPTION,MUSCLE
13、,PANCREAS,ADIPOSE TISSUE,LIVER,INTESTINE,HYPERGLYCEMIA,DECREASED PERIPHERAL GLUCOSE UPTAKE,INCREASED GLUCOSE PRODUCTION,DECREASED INSULIN SECRETION,Therapy:Thiazolidinediones(Biguanides),Therapy:InsulinSulfonylureasMetiglinides,Therapy:BiguanidesThiazolidinediones,Therapy:Alpha-glucosidase inhibitor
14、s,正常人血糖的波动,Riddle MC.Diabetes Care 1990;13:676686,3002001000,血浆葡萄糖浓度(mg/dl),06001200180024000600,时间(小时),餐时血糖峰值空腹,2型糖尿病高血糖的构成空腹血糖增高,Riddle MC.Diabetes Care 1990;13:676686,3002001000,血浆葡萄糖浓度(mg/dl),06001200180024000600,时间(小时),肝糖输出正常,肝糖输出不能被关闭,Riddle MC.Diabetes Care 1990;13:676686,3002001000,血浆葡萄糖浓度(m
15、g/dl),06001200180024000600,时间(小时),餐时血糖峰值肝糖输出正常,2型糖尿病高血糖的构成餐后血糖增高,二甲双胍磺脲类噻唑烷二酮胰岛素,二甲双胍磺脲类噻唑烷二酮胰岛素,二甲双胍磺脲类噻唑烷二酮胰岛素,-糖苷酶抑制剂速效胰岛素格列奈类,-糖苷酶抑制剂速效胰岛素格列奈类,-糖苷酶抑制剂速效胰岛素格列奈类,降糖药物改善总体血糖控制水平(HbA1c)的途径,二甲双胍磺脲类噻唑烷二酮胰岛素,Overweight or obese person with diabetes,Where possible,define obesity using regional or nation
16、al criteria,Non-obese person with diabetes,2型糖尿病自然病程,0,50,100,150,200,250,-10,-5,0,5,10,15,20,25,30,糖尿病病史（年）,血糖(mg/dL),相对功能(%),胰岛素抵抗,胰岛素水平,-细胞衰竭,*IFG=impaired fasting glucose,50,100,150,200,250,300,350,空腹血糖,餐后血糖,Adapted from International Diabetes Center(IDC)Minneapolis,Minnesota,肥胖 空腹葡萄糖异常*糖尿病 未控制的
17、高血糖,针对2型糖尿病自然病程中不同时期的病理生理变化特点的药物治疗,7,6,9,8,HbA1c(%),10,单药治疗,Diet,口服药联合,口服药物基础胰岛素,传统的非积极的糖尿病治疗模式,加量,病程,口服药物加多次胰岛素,口服药加基础胰岛素,口服药加多此胰岛素注射,Diet,口服药物单药治疗（胰岛素),口服药联合治疗,积极治疗糖尿病早期联合治疗,口服药物加量,病程,7,6,9,8,HbA1c(%),10,美国糖尿病药物的市场情况,NATURE REVIEWS|DRUG DISCOVERY VOLUME 4|MAY 2005|367,“Combination therapy is stand
18、ard”,Although there are a number of oral drugs on the market to treat diabetes,at present no single marketed drug is capable of lowering HbA1c to the target range for a sustained period of time for the majority of patients with type 2 diabetes.Even when used in combination,these medications tend to
19、lose much of their efficacy after 34 years of treatment.,NATURE REVIEWS|DRUG DISCOVERY VOLUME 4|MAY 2005|367,口服糖尿病药物联合的策略,理性化联合（rational combination）：药物之间的作用机制互补，针对糖尿病的多种缺陷 积极联合（provative approach）：早期联合，发挥药物联合之间最大 的治疗潜力 以达标为驱动力：用HbA1c作为“金标准”同时减少大、小血管病变的危险性,Inzucchi SE.JAMA 2002;287:360372.,改善血糖控制减少C
20、VD危险性,磺脲类,促进胰岛素分泌,格列酮类,强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素,+,格列酮磺脲类：不同作用机制间的互补作用改善多重缺陷,Inzucchi SE.JAMA 2002;287:360372.,改善血糖控制减少CVD危险性,二甲双胍,弱胰岛素增敏作用减少肝糖输出改善大血管病变临床终点,格列酮类,强胰岛素增敏作用增加骨骼肌血糖利用改善大血管病变危险因素,+,格列酮二甲双胍：不同作用机制间的互补作用改善多重缺陷,Inzucchi SE.JAMA 2002;287:360372.,改善血糖控制减少CVD危险性,二甲双胍,弱胰岛素增敏作用减少肝糖输出改善大血管病变临床
21、终点,促分泌剂,增加胰岛素分泌,+,促泌剂二甲双胍：不同作用机制间的互补作用改善多重缺陷,2型糖尿病口服药物联合治疗思维的改变,传统思维：单一药物逐渐加量至推荐最大剂量新思维：在单一药物的半量或次大剂量时联合用药(理性 结合）,*,*,1.0,0.8,0.6,0.4,0.2,0.0,Mean change in HbA1c from baseline(%),半量二甲双胍罗格列酮与二甲双胍加量的比较(EMPIRE Study)HbA1c,Baseline HbA1c(%)n=,7.95313,8.05322,MET 1 g/day+RSG 8 mg/day,Patients were treat
22、ed for 24 weeksAll patients were inadequately controlled on MET 1 g/day alone*Significant vs.baseline,MET 1 g/day+MET 1 g/day,Error bars=95%CI,Rosenstock J,et al.Diabetes 2004;53(Suppl.2):A144145.,0.63%,0.82%,N=635 Patients were treated for 24 weeksAll patients were inadequately controlled on MET 1
23、g/day alone*P 0.05 vs.MET 1 g/day+MET 1 g/day,Error bars=95%CI,Rosenstock J,et al.Diabetes 2004;53(Suppl.2):A144145.,25.9%,0,10,20,30,40,50,60,Patients achieving HbA1c goals(%),AACE/IDF goal 6.5%,ADAgoal 7%*,MET 1 g/day+MET 1 g/dayn=313,MET 1 g/day+RSG 8 mg/dayn=322,38.5%,45%,55%,半量二甲双胍罗格列酮与二甲双胍加量的比
24、较(EMPIRE Study)达标率,20,Geometric mean percent change from baseline in HOMA-cell function,Time(weeks),0,24,52,76,104,0,20,40,60,80,100,99,86,90,64,87,51,83,Error bars=SE,SU+RSG(up to 8 mg/day),SU加量+PBO,罗格列酮加磺脲类与磺脲类加量比较(RESULT study)-b-细胞功能,SU+PBO n=106,SU+RSG n=105,n=number of patients with on-therapy
25、 value at the visit ITT without LOCF,Vinik AI,et al.Diabetes 2004;53(Suppl.2):A162.ADA 2004,Poster 680.,0.0,0,24,52,Time(weeks),76,104,6.8,7.0,7.2,7.4,7.6,7.8,SU加量+PBOn=110,Mean HbA1c(%),SU+RSGn=115,Error bars=SE,ITT population,older T2D patients(60 years)in whom glycemic control was inadequateOn-th
26、erapy values,Rosenstock J,et al.Diabetes Metab 2003;29:4S2474S248.IDF 2003,Poster 2278.,罗格列酮加磺脲类与磺脲类加量比较(RESULT study)-HbA1c,9%,29%,0,20,40,60,HbA1c responders(%),Uptitrated SU+PBOn=106,SU+RSG113,22%,50%,AACE/IDFgoal 6.5%,ADAgoal 7.0%,Rosenstock J,et al.Diabetes Metab 2003;29:4S2474S248.IDF 2003,Poster 2278.,罗格列酮加磺脲类与磺脲类加量比较(RESULT study)达标率,加强“内-心”合作，催生“预防血管病学”,
