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,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/IGT HDL, 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
2、 Cholesterol,2,4,6,0,1,2,3,Atorvastatin 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. 20
3、03;361:1149-58,LIIFE 研究-相同的降压疗效,研究月份,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 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 (ye
4、ars),Upper limit of normal = 6.2%,0,UKPDS：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 15 mmol/l or symptoms of hyperglycemia Overweight patients Cohort, median values,Saydah SH et al. JAMA. 2004;291:335-342.,Patients (%),HbA1C 7%,NHANES III
5、; n=1,204 NHANES 1999-2000;n=370,0,10,20,30,40,50,BP 130/80 mm Hg,TC 200 mg/dL,Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000,Percentage of Patients With Diabetes Having A1C 7%,Harris MI et al. Diabetes Care. 1999;22:403-408 Koro Ce et al., Diabetes Care 27:17-2
6、0, 2004,0,20,40,60,80,100,Diet alone,Oral agents,Insulin,NHANES III US Adults With Diagnosed Diabetes in 198894,73%,38%,27%,Whole study population,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.,*Ma
7、y include uptitration,0,5,10,15,20,25,Metformin only,Sulfonylurea only,n = 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 Ty
8、pe 2 Diabetes.Diabetes Care 27: 1535-1540, 2004,At 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: 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 pre
9、ssure of 144 / 82mmHg gave reduced risk of:24% for any diabetes-related endpoint p=0.0046 32% for diabetes-related deaths p=0.019 44% for stroke p=0.013 37% for microvascular disease p=0.0092 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,任何糖尿病终点,糖尿病死亡,微血管并发
10、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%,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=0.0
11、6,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 Resistance Insulin action,Increased lipolysis,ADIPOSE TISSUE,Islet b-cell degranulation reduced
12、 insulin content,Insulin Resistance and b-cell Dysfunction Produce Hyperglycaemia in Type 2 Diabetes,low-plasma insulin,Increased glucose output,HYPERGLYCEMIA,Decreased glucose transport & activity (expression) of GLUT4,Elevated plasma NEFA,Elevated TNFa, Resistin ?,MUSCLE ( TG ),LIVER,PANCREAS,Site
13、s of Action by Therapeutic Options,Sonnenberg, et al. Curr Opin Nephrol Hypertens 1998;7(5):551-555.,GLUCOSE ABSORPTION,MUSCLE,PANCREAS,ADIPOSE TISSUE,LIVER,INTESTINE,HYPERGLYCEMIA,DECREASED PERIPHERAL GLUCOSE UPTAKE,INCREASED GLUCOSE PRODUCTION,DECREASED INSULIN SECRETION,Therapy: Thiazolidinedione
14、s (Biguanides),Therapy: Insulin Sulfonylureas Metiglinides,Therapy: Biguanides Thiazolidinediones,Therapy: Alpha-glucosidaseinhibitors,正常人血糖的波动,Riddle MC. Diabetes Care 1990;13:676686,300 200 100 0,血浆葡萄糖浓度 (mg/dl),0600 1200 1800 2400 0600,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 1
15、990;13:676686,300 200 100 0,血浆葡萄糖浓度 (mg/dl),0600 1200 1800 2400 0600,时间 (小时),肝糖输出正常,肝糖输出不能被关闭,Riddle MC. Diabetes Care 1990;13:676686,300 200 100 0,血浆葡萄糖浓度 (mg/dl),0600 1200 1800 2400 0600,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
16、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 national 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
17、),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
18、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 standard”,Although there are a number of oral drugs on the market to treat diabetes, at present no single
19、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 lose much of their efficacy after 34 years of treatment.,NATURE REVIEWS | DRUG DISCOVERY VOLUME 4
20、| 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
21、. 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
22、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 =,7.95 313,8.05 322,MET 1 g/day + RSG 8 mg/day,Patients were treated for 24 weeks All patients were inadequately controlled on MET 1 g/day
23、 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 weeks All patients were inadequately controlled on MET 1 g/day alone *P 0.05 vs. MET 1 g/day + MET 1 g/day,Error
24、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%,ADA goal 7%*,MET 1 g/day + MET 1 g/day n = 313,MET 1 g/day + RSG 8 mg/day n = 322,38.5%,45%,55%,半量二甲双胍罗格列酮与二甲双胍加量的比较 (EMPIRE Study) 达标率,20,Geometr
25、ic 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 value a
26、t 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 + PBO n = 110,Mean HbA1c (%),SU + RSG n = 115,Error bars = SE,ITT population, older T2D patients ( 60 years) in whom glycemic control wa
27、s inadequate On-therapy 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 + PBO n = 106,SU + RSG 113,22%,50%,AACE/ IDF goal 6.5%,ADA goal 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”,
