心血管疾病中降糖药物治疗的选择

心血管疾病中降糖药物的选择,广东省人民医院 内分泌科 邝 建,Antihyperglycemic Agents for Type 2 Diabetes:The Six Classes,*Awaiting FDA approval.,Antihyperglycemic Agents: Major Sites of Action,SulfonylureasMeglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-GlucosidaseInhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,a-Glucosidase inhibitor,Antihyperglycemic Agents: Major Sites of Action,SulfonylureasMeglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-GlucosidaseInhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,PPAR的激活,Adapted from Arner P. Diabetes Obes Metab 2001; 3 (Suppl 1):S11S19.,PPAR激活增加胰岛素的活性,Young et al. Diabetes 1995; 44:10871092.,激活前脂肪细胞和脂肪细胞中的PPAR,Lipotoxic disease: Rogers Unger,Annu.Rev.Med 2002.53:319-36,PPAR激活促进脂肪细胞分化,PPAR激活的其他效应,减少炎性因子-C反应蛋白减少PAI-1(纤溶酶原激活剂的抑制剂-1)其他潜在的抗动脉粥样硬化特性：改善血管弹性MCP-1(单核细胞化学诱导物蛋白-1) ; MMP-9(基质金属蛋白酶-9) ; ROS(活性氧簇)减少减少平滑肌细胞的增殖,Antihyperglycemic Agents: Major Sites of Action,SulfonylureasMeglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-GlucosidaseInhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,Structure of Sulfonylurea,Tolbutamide (Rastinon),Glibenclamide (Daonil, Glycomin),Glipizide (Minidiab),Glimepiride (Amaryl),CI,O,O,O,O,O,O,S,O,O,O,S,O,O,O,S,O,O,O,S,O,O,N,N,HN,HN,HN,HN,HN,HN,HN,HN,HN,HN,HN,SU moiety,D-phenylalanine D-苯丙氨酸,Nateglinide,Repaglinide,Meglitinide氯茴苯酸,Glyburide (Glibenclamide),Structure of Sulfonylurea and Meglitinide,SU Moiety,达美康,Tolbutamide,优降糖,格列美嬲,促胰岛素分泌剂的化学结构,瑞格列奈分子,磺脲/列奈类药物作用机理,K,i,r,6,.,2,S,U,R,1,S,U,R,1,K,i,r,6,.,2,K,i,r,6,.,2,S,U,R,1,S,U,R,1,K,i,r,6,.,2,磺脲类受体亚型结构,Gribble FM Diabetes 1998,化学结构与功能的关系,S,K+,Ashcroft FM Diabetologia 1999,缺血、缺氧,基础状态,基础状态,KATP 通道的作用及分布,Gribble FM Diabetes 1998,达美康 对克隆 -细胞及心肌通道的不同作用,不同促分泌剂的选择性差异,不同药物对心血管KATP通道的抑制,在对B细胞KATP通道等效抑制时，不同药物对心血管KATP通道的抑制百分比,* 与B细胞相比，P0.05,英国剑桥大学完成尼可地尔为钾通道激活剂，心绞痛治疗新药， 国际上应用日趋广泛研究发现格列美脲和优降糖明显抑制尼可地尔活性达美康对心脏无作用心绞痛患者服用尼可地尔时，建议选择达美康,Frank Reimann， Diabetes，Vol。 50， October 2001,抗心绞痛的钾通道开放剂 尼可地尔 (Nicorandil)和磺脲类药物的交互影响,磺脲类与尼可地尔在心脏KATP通道的交互作用,Frank Reimann， Diabetes，Vol。 50， October 2001,+,+,+,尼可地尔,尼可地尔,尼可地尔,“b-细胞选择性的磺脲类药物代表着糖尿病合并有缺血性心脏病的药物治疗的新策略,Brady P JACC 1998,选择性研究的结论提示?,-保证有效降低血糖的同时，寻求更好的心脏或其他器官保护作用,达美康对血液生化的影响,使血小板功能正常化 使血管壁的纤溶蛋白溶酶活性正常化 清除自由基 恢复前列腺素的平衡保护内皮功能,达美康使血小板功能正常化,血小板凝聚(%),40,50,60,70,80,90,100,P0.01,0,3,P=0.006,0,3,个月,优 降 糖,达 美 康,Jennings PE et al. Metabolism. 1992;41:36-39.,NS,个月,达美康清除自由基,血浆脂类过氧化物,优 降 糖,0,MDA-LM (ol/L),P=0.009,达 美 康,1,2,3,4,5,6,7,8,9,7.2,8.8,RBC*超氧歧化酶,优 降 糖,0,红细胞SOD ( g/mL),P=0.003,达 美 康,20,40,60,80,100,120,140,160,158,117,Jennings PE et al. Metabolism. 1992;41(suppl 1):36-39.,* 红细胞,达美康恢复前列腺素的平衡,微血栓素,TXB2 (ng/L),150,200,250,300,0,3,个月,前列环素,6-Keto PGF1a (ng/L),60,70,80,90,0,3,个月,100,*,*,* P0.001,Fu ZZ et al. Metabolism. 1992;90:33-35.,OBrien R J Diabet Comps 2000,延迟LDL氧化时间,* P0,05 vs control # P0,05 vs GHHb,Vallejo S Diabetologia 2000,评价对内皮功能影响,PD2：GHHb抑制缓激肽舒血管反应， 产生一半最大效应所需剂量的负对数值,GHHb：糖基化的氧合血红蛋白,Omi H J Diabetes Complications 2001,对内皮功能的保护作用,脂质过氧化物（mol/l）,对照组 格列本脲组 达美康组,* 与正常人相比 P=0.0001，* 与格列本脲治疗组相比 P=0.0001。,*,*,*,G. De Mattia, Diabetes UK, Diabetic Medicine, 19, 752-757,脂质过氧化物酶(mol/L),达美康增强2型糖尿病人的抗氧化能力和一氧化氮介导的舒血管作用,（治疗12周）,PPAR激活的其他效应,减少炎性因子-C反应蛋白减少PAI-1(纤溶酶原激活剂的抑制剂-1)其他潜在的抗动脉粥样硬化特性：改善血管弹性MCP-1(单核细胞化学诱导物蛋白-1) ; MMP-9(基质金属蛋白酶-9) ; ROS(活性氧簇)减少减少平滑肌细胞的增殖,心血管疾病中降糖药物的选择,病人评价一般情况心脏病变糖尿病状态肝肾功能,药物选择作用机制副作用对心脏病变的影响降糖外作用,治疗后监测血糖副作用程度肝、肾功能,病人评价,一般情况：年龄：45岁、60岁、60岁BMI：25、25腰围：男90、女85腰围/身高比值：0.5,病人评价,病情评价：心脏病变：高血压、高血脂、心律失常、冠心病、心脏手术后、 导管术后、安装起博器后、心功能治疗药物： B-阻滞剂、利尿剂糖尿病评价：血糖水平、胰岛功能、GAD抗体肾脏情况：血肌酐、BUN、尿蛋白水平、尿酸肝脏情况：转氨酶、脂肪肝,基本原则,年龄45岁BMI25DM、IGT、IFG,年龄45岁BMI25DM、IGT、IFG,GAD（+）,正常IR,必要时,GAD-Ab血清谷氨酸脱羧酶抗体是一型糖尿病早期诊断的一个关键的自身抗原，GAD正常为阴性，50为阳性。,胰岛细胞抗体 (ICA)、胰岛素自身抗体 (IAA)谷氨酸脱羧酶抗体（GAD）,综合诊断一型糖尿病的依据,检测是否为胰岛素敏感还是抵抗型：有高胰岛素-正常血糖钳夹和高葡萄糖变量钳夹两种方法,药物选择,高血压、高血脂、心功能正常肥胖,药物选择,心绞痛、心梗后、冠脉术后稳定期、心律失常、心功能正常肥胖,* 小剂量长效胰岛素为基础的多中心研究进行中,注意：肾功能异常者不用二甲双胍肝功能异常者不用文迪雅（罗格列酮）肾功能异常者可用糖适平（格列奎酮）,药物选择,高血压、高血脂、心功能正常消瘦,肥胖者首选胰岛素增敏剂，而代谢综合症的消瘦者注意一型糖尿病，首选促泌剂，根据肝肾功能选择具体种类。伴心血管疾病的消瘦者首选增敏剂，注意磺脲类易致低血糖。,药物选择,心绞痛、心梗后、冠脉术后、心律失常稳定期、心功能正常消瘦,* 小剂量长效胰岛素为基础的多中心研究进行中,药物选择,心绞痛、心梗后、心律失常非稳定期冠脉术后早期心功能异常、反复心衰,胰岛素治疗禁任何口服降糖药,药物选择,GAD-Ab （+）或 60,双胍类GLITAZONES糖苷酶抑制剂胰岛素,Clinical Efficacy of Oral Hypoglycemic Agents,Options for monotherapy,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,-glucosidaseinhibitors,Recent type 2 DM diagnosisType 2 DM 140 mg/dL or HbA1c 8%,240 mg/dL,FBG 126 mg/dL,Diet + exercise,Glitazone,Glitazone,4-33,Glycemic goals not achieved,Modified from American Diabetes Association. Diabetes Care. 1995;18:1510-1518.,Nonpharmacologic TherapyDietExercise,MonotherapySulfonylureasBiguanidesa-Glucosidase InhibitorsGlitazonesMeglitinidesInsulin,Combination TherapyFrequently used or well studiedSulfonylurea + MetforminSulfonylurea + RosiglitazoneSulfonylurea + PioglitazoneSulfonylurea + AcarboseRepaglinide + MetforminRosiglitazone + MetforminPioglitazone + MetforminSulfonylurea + InsulinMetformin + InsulinPioglitazone + InsulinRosiglitazone + InsulinAcarbose + InsulinInfrequently used and/orless well studiedSulfonylurea + Metformin + GlitazoneSulfonylurea + Metformin + InsulinGlitazone + Metformin + Insulin,InsulinIntermediate BIDIntermediate + Regular BIDMultiple (3 or more) injections,Glycemic goals not achieved,Glycemic goals not achieved,Very symptomaticSevere hyperglycemiaKetosisUnrecognized IDDMPregnancy,ADA “Consensus” on Type 2 Diabetes Therapy,5-1,DeFronzo, et al. N Engl J Med. 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469; Coniff, et al. Diabetes Care. 1995;18:817-824; Moses, et al. Diabetes Care. 1999;22:119-124; Schneider, et al. Diabetes. 1999;48(suppl 1):A106; Egan, et al. Diabetes. 1999;48(suppl 1):A117; Fonseca, et al. Diabetes. 1999:48(suppl 1):A100.,Regimen HbA1c FBGSulfonylurea + metformin1.7%65 mg/dLSulfonylurea + rosiglitazone1.4%60 mg/dLSulfonylurea + pioglitazone1.2%50 mg/dLSulfonylurea + acarbose1.3%40 mg/dLRepaglinide + metformin1.4%40 mg/dLPioglitazone + metformin0.7%40 mg/dLRosiglitazone + metformin0.8%50 mg/dLInsulin + oral agentsOpen to Target Open to Target,COMBINATION THERAPYEstimated Improvements in Glycemic Control,5-1b,MANAGEMENT GUIDELINESCombinations of Oral Agents:Sulfonylurea-Based Regimens,Start withLong-acting sulfonylurea once daily(glimepiride or extended-release glipizide)Add Metformin(preferred order)orGlitazone (if intolerance or contraindication for metformin present)or-Glucosidase inhibitor(if intolerance or contraindication for both metformin and glitazone present),5-8,PRACTICAL GUIDELINESStarting Basal Insulin,Continue oral agent(s) at same dosage (eventually reduce)Add single, evening insulin dose (around 10 U)NPH (bedtime)（中效胰岛素）70/30 (evening meal)（短效胰岛素）Glargine (bedtime or anytime?)（来得时 长效）Adjust dose by fasting SMBG （空腹自测血糖）Increase insulin dose weekly as neededIncrease 4 U if FBG 140 mg/dL（相当于7.8mmol/L)Increase 2 U if FBG = 120-140 mg/dL (相当于6.7-7.8mmol/L）Treat to target (usually 126 mg/dL（7mmol/L）,Diet and Exercise,126-140 mg/dL,140-200 mg/dL,200-240 mg/dL,240-300 mg/dL,300 mg/dL,GlitazonesMetforminAcarbose,Sx,Insulin,No Sx,Sulfonylurea,No Sx/Sx,Sulfonylurea,Evolving criteriaIf FBG 140 mg/dL (126 mg/dL?)HbA1c 8% (7%?)Add second oral agent and titrate to maximum dose,If no improvement:Try triple therapy?Or continue oral agent(s)+ insulin Rx at PM or HS,Sx,Sulfonylurea,No Sx,Sulfonylurea,Metformin,Acarbose,Glitazones,Sulfonylurea,Repaglinide,Metformin,Oral Combination,Triple Therapy,Monotherapy,5-19,MANAGEMENT GUIDELINESCombination Therapy in Type 2 Diabetes:Pragmatic Approach,Early combination of insulin secretagogue + insulin sensitizerMost simple and cost effective:Combination of selective sensitizersIf target HbA1c 7% not achieved:Try triple therapy?Continue oral agent(s) + Insulin Rx at PM or HS using Insulin Pen,once-daily Sulfonylurea (AM) + Metformin (PM),5-20,Combination Therapy in Type 2 Diabetes:Decision Considerations,HbA1c efficacyReductions from baselineReaching targetSynergy of mechanisms of actionSide effects and toxicity profileFrequency and severity of hypoglycemiaEffect on weight gainAvoiding polypharmacy and complex regimensCompliance and convenienceCost,5-1a,糖尿病患者缺乏抗氧化因子，同时内皮功能异常,维生素 E 和 C : 在一组大系列的研究中T2DM患者是缺乏的。 (Sundaram, et al. Clin Sci 1996;90:255-60)浙江114例糖尿病患者和100例健康人糖尿病组的血浆维生素C、维生素E和胡萝卜素平均含量显著降低随着病程延长，患者血浆维生素C、维生素E和胡萝卜素逐渐降低；病程与维生素E 、 胡萝卜素水平相关最密切。,顾惠娟等,实用新医学.2000,2(9).-769-770,抗氧化剂对内皮功能异常的作用,通过去铁铵的铁螯合作用影响冠状动