糖尿病药物治疗-问题与失误课件

1、纪立农北京大学糖尿病中心北京大学人民医院 糖尿病药物治疗问题与失误纪立农 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; 86:713718.2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胰岛素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,需要反复的反馈血糖是最难控

2、制的代谢异常多种病理生理机制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 N, Wedel H, et al, for the ASCOT Investigato

3、rs. Lancet. 2003;361:1149-58ASCOT: Reductions in Total andLIIFE 研究-相同的降压疗效061218243036424854研究月份405060708090100110120130140150160170180收缩压舒张压平均动脉压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 mmHgDahlf B et al Lancet 2002;359:995-1003.阿替洛尔 102.4 mmHg氯沙坦 102.2 mmHgLIIFE 研究-相同的降压疗效0612182430

4、361 2 3 4EDICDCCT to EDIC: From experiment to reality1 2 3 4EDICDCCT to EDIC: 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

5、 FPG 15 mmol/l or symptoms of hyperglycemia Overweight patientsCohort, median valuesConventional therapy (primarily diet alone*) 06789246810HbA1c (%)Time froSaydah 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/

6、dL29.0%35.8%37.0%Good control7.3%5.2%33.9%P.001 48.2%Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000Saydah SH et al. JAMA. 2004;29Percentage of Patients With DiabetesHaving A1C 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

7、uptitration 0510152025Metformin onlySulfonylurea onlyn = 513n = 3,39414.5 个月20.5 个月月在单药治疗时发现 HbA1c 8.0%后仍然维持单药治疗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.

8、6%Brown et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27: 1535-1540, 2004At Insulin Initiation, the average patient had: 5 years with HbA1C 8% 10 years with HbA1C 7%020406080100%Age of SubjectsPe糖尿病药物治疗问题与失误课件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

9、件, 但可能促进因素#*: 流行病学证据;#: 临床试验证据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% for diabetes-related deaths p=0.01944% for stroke p=0.01337% for microvascular diseas

10、e p=0.009256% for heart failure p=0.0043 Blood Pressure Control, UKPDS 糖尿病药物治疗问题与失误课件 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-50-40-30-20-100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%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

11、 0.05 UKPDS研究显示：严格降压比强化降糖更重要? 糖尿病药物治疗问题与失误课件糖尿病药物治疗问题与失误课件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 mmHg8年后达到治疗目标的患者%p=0.06p0.0001p=0.19p=0.001p=0.21Steno-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 常规组各种治疗达标的百分率糖化血红蛋白6.5%胆固醇甘油三酯收缩Targets for controlParameterTargetHbA1c 6.5% (DCCT-aligne

12、d 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)Triglycerides1.5 mmol/L (133 mg/dl)Urinary albumin:creatinine2.5 mg/mmol (22 mg/g) men3.5 mg mmol (31 mg/g) - womenExercise 150 minutes/weekTargets for controlParamet

13、erTa 2型糖尿病患者的药物治疗代谢控制 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 2型糖尿病患者的药物治疗代谢控制Pancreatic b-cellInsulin ResistanceInsulin actionIncreasedlipolysisADIPOSETISSUEIslet b-cell degranulationreduced insulin contentInsulin Resistance and b-cell Dysfunction ProduceHyperglycaemia in Ty

14、pe 2 Diabeteslow-plasmainsulinIncreased glucose outputHYPERGLYCEMIADecreased glucose transport& activity (expression) of GLUT4Elevatedplasma NEFAElevatedTNFa, Resistin ?MUSCLE( TG )LIVERPANCREASPancreatic b-cellInsulin ResisSites of Action by Therapeutic Options Sonnenberg, et al. Curr Opin Nephrol

15、Hypertens 1998;7(5):551-555.GLUCOSEABSORPTIONMUSCLEPANCREASADIPOSE TISSUELIVERINTESTINEHYPERGLYCEMIADECREASED PERIPHERAL GLUCOSE UPTAKEINCREASED GLUCOSE PRODUCTIONDECREASED INSULIN SECRETIONTherapy:Thiazolidinediones(Biguanides)Therapy:InsulinSulfonylureasMetiglinidesTherapy:BiguanidesThiazolidinedi

16、onesTherapy:Alpha-glucosidase inhibitorsSites of Action by Therapeutic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)餐时血糖峰值空腹正常人血糖的波动Riddle MC. Diabetes Ca2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)060012001800

17、24000600时间 (小时)肝糖输出正常 肝糖输出不能被关闭2型糖尿病高血糖的构成空腹血糖增高Riddle MC. Riddle MC. Diabetes Care 1990;13:6766863002001000血浆葡萄糖浓度 (mg/dl)06001200180024000600时间 (小时)餐时血糖峰值肝糖输出正常2型糖尿病高血糖的构成餐后血糖增高Riddle MC. Diabetes Care 1990;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

18、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二甲双胍二甲双胍二甲双胍-糖苷酶抑制剂-糖苷酶抑制剂-Overweight or obese person with diabetesWhere possible, define obesity using regional or national criteriaOverweight or obese person witNon-obese person with diabetesNon-obese person with diabetes2型糖尿病自然病程050100150200250-10-50510152

19、02530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 glucose50100150200250300350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 未控制的高血糖 2型糖尿病自然病程050100150200250-10-50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 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7698HbA1c (%

20、)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7698HbA1c (%)10单药治疗Diet口服药联合口服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 7698HbA1c (%)10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 美国糖尿病药物的市场情况NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 美国糖尿病药物的市场情况NATURE R “Combination

21、therapy is standard”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 me

22、dications tend to lose much of their efficacy after 34 years of treatment.NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 “Combination thera 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

23、 口服糖尿病药物联合的策略 Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制减少CVD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; 287:36Inzucchi 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In

24、zucchi SE. JAMA 2002; 287:36Inzucchi 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Inzucchi SE. JAMA 2002; 287:362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） 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*1.00.80.60.40.20.0Mean chan

25、ge 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) HbA1cBaseline HbA1c (%)n =7.953138.05322MET 1 g/day + RSG 8 mg/dayPatients were treated for 24 weeksAll patients were inadequately controlled on MET 1 g/day alone*Significant vs. baseline MET 1 g/day+ MET 1 g/dayError bars = 95% CIRosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A1