糖尿病药物治疗—问题与失误

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,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,各种病理生理根底发生变化,影响因素多,波动性大,需要反复的反响,ASCOT:Reductions in Total and LDL 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.2003;361:1149-58,LIIFE 研究-相同的降压疗效,0,6,12,18,24,30,36,42,48,54,研究月份,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,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(years),Upper limit of normal=6.2%,Glyburide,Chlorpropamide,Metformin,Insulin,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,Conventional therapy(primarily diet alone*),Saydah SH et al.,JAMA,.2004;291:335-342.,Patients(%),HbA,1C,7%,44.3%,NHANES III;n=1,204,NHANES 1999-2000;,n=370,0,10,20,30,40,50,BP 130/80 mm Hg,TC 200 mg/dL,29.0%,35.8%,37.0%,Good control,7.3%,5.2%,33.9,%,P,.001,48.2%,Risk Factor Control in Adults With Diabetes:NHANES III(1988-1994)/NHANES 1999-2000,Percentage 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 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 HbA,1C,8%,Clinical Inertia:“Failure to advance therapy when required,Diet,66.6%,Sulfonylurea,35.3%,Metformin,44.6%,Combination,18.6%,Brown et al.The Burden of Treatment Failure in Type 2 Diabetes.,Diabetes Care 27:1535-1540,2004,At Insulin Initiation,the average patient had:,5 years with HbA,1C,8%,10 years with HbA,1C,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=0.0046,32%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年后到达治疗目标的患者,%,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,Parameter,Target,HbA,1c,6.5%(DCCT-aligned assay),BP,130/80 mmHg,Total cholesterol,4.5 mmol/L(174 mg/dl),LDL-cholesterol,2.5 mmol/L(97 mg/dl),HDL-cholesterol,1.0 mmol/L(39 mg/dl),Triglycerides,1.5 mmol/L(133 mg/dl),Urinary albumin:creatinine,2.5 mg/mmol(22 mg/g)men,3.5 mg mmol(31 mg/g)-women,Exercise,150 minutes/week,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 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,TNF,a,Resistin,?,MUSCLE,(TG,),LIVER,PANCREAS,Sites 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,I,NCREASED,GLUCOSE PRODUCTION,DECREASED,INSULIN SECRETION,Therapy:,Thiazolidinediones,(Biguanides),Therapy:,Insulin,Sulfonylureas,Metiglinides,Therapy:,Biguanides,Thiazolidinediones,Therapy:,Alpha-glucosidase,inhibitors,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),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;13:676686,300,200,100,0,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;13:676686,300,200,100,0,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,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 national criteria,No