心血管疾病中降糖药物治疗的选择.ppt

Antihyperglycemic Agents: Major Sites of Action,Sulfonylureas Meglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-Glucosidase Inhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),Carbohydrate Absorption,Hepatic gluconeogenesis,Insulin Secretion,Glucose Uptake,Insulin Secretion,a-Glucosidase inhibitor,Antihyperglycemic Agents: Major Sites of Action,Sulfonylureas Meglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-Glucosidase Inhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),Carbohydrate Absorption,Hepatic gluconeogenesis,Insulin Secretion,Glucose Uptake,Insulin Secretion,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,Sulfonylureas Meglitinides,Injected Insulin,Liver,Plasma glucose,Glitazones,GI tract,-Glucosidase Inhibitors,+,Pancreas,Metformin,Muscle/Fat,(),(+),(+),(),(+),Carbohydrate Absorption,Hepatic gluconeogenesis,Insulin Secretion,Glucose Uptake,Insulin Secretion,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,H N,H N,H N,H N,H N,H N,H N,H N,H N,H N,H N,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 BMI25 DM、IGT、IFG,年龄45岁 BMI25 DM、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,-glucosidase inhibitors,Recent type 2 DM diagnosis Type 2 DM 5 yrs duration,Recent type 2 DM diagnosis Elevated PPG,Overweight / obese Insulin resistant,Insulin resistant Overweight/ obese,Diet control Elevated PPG Contraindications to other agents,Advantages,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,-glucosidase inhibitors,Rapid FPG reduction Low cost Some antioxidative,Risk of hypoglycemia Short-acting Meal-adjusted dosing Safe and effective in renal dysfunction (Metabolised in the liver, biliary excretion , Metabolites are inactive),No weight gain Risk of hypoglycemia,Amount of insulin Risk hypoglycemia No GI side effect No drug interaction No adjust dose in RF, Risk of hypoglycemia Non systemic action PPG,Insulin sensitizers No stimulation of insulin secretion Beneficial lipid profile,Disadvantages,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,-glucosidase inhibitors,Weight gain Risk of hypoglycemia,High costs Frequent dosing,GI side effects Rare lactic acidosis,High cost Weight gain Slow onset of action Issue of liver toxicity Colonic polyps? Edema（Na,H2O retention) Heart failure?,High cost GI side effects Limited efficacy,PART 1,KEN,Monotherapy Pearls,All drugs except AGIs and nateglinide equally reduce HbA1c Metformin usually best for obese- no weight gain Non-SU secretagogues may be useful for irregular meals Metformin and TZDs avoid hypoglycemia,Options for combination therapy,Sulfonylureas + Biguanide Or Thiazolidinedione Or a-glucosidase inhibitor,Biguanide + meglitinide,Biguanides + Thiazolidinediones,Biguanide + a-glucosidase inhibitor,Triple combination therapy Sulfonylurea + biguanide + Thiazolidinedione or Sulfonylurea + biguanide + a-glucosidase inhibitor,If therapeutic goals are not met using the above combinations; switch to insulin +/- oral agent,Combination Therapy in Type 2 Diabetes: Decision Considerations,HbA1c efficacy Reductions from baseline Reaching target Synergy of mechanisms of action Side effects and toxicity profile Frequency and severity of hypoglycemia Effect on weight gain Avoiding polypharmacy and complex regimens Compliance and convenience Cost,5-1a,MANAGEMENT GUIDELINES Initial Treatment Recommendations,FBG 126-140 mg/dL,Metformin,-Glucosidase Inhibitors,Sulfonylureas,Metformin,Meglitinides,-Glucosidase Inhibitors,Sulfonylureas,Metformin,No symptoms:,Sulfonylureas,Symptoms:,Insulins,FBG 140-200 mg/dL,200-240 mg/dL,Early combination therapy,If FPG 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 Therapy Diet Exercise,Monotherapy Sulfonylureas Biguanides a-Glucosidase Inhibitors Glitazones Meglitinides Insulin,Combination Therapy Frequently used or well studied Sulfonylurea + Metformin Sulfonylurea + Rosiglitazone Sulfonylurea + Pioglitazone Sulfonylurea + Acarbose Repaglinide + Metformin Rosiglitazone + Metformin Pioglitazone + Metformin Sulfonylurea + Insulin Metformin + Insulin Pioglitazone + Insulin Rosiglitazone + Insulin Acarbose + Insulin Infrequently used and/or less well studied Sulfonylurea + Metformin + Glitazone Sulfonylurea + Metformin + Insulin Glitazone + Metformin + Insulin,Insulin Intermediate BID Intermediate + Regular BID Multiple (3 or more) injections,Glycemic goals not achieved,Glycemic goals not achieved,Very symptomatic Severe hyperglycemia Ketosis Unrecognized IDDM Pregnancy,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 FBG Sulfonylurea + metformin 1.7% 65 mg/dL Sulfonylurea + rosiglitazone 1.4% 60 mg/dL Sulfonylurea + pioglitazone 1.2% 50 mg/dL Sulfonylurea + acarbose 1.3% 40 mg/dL Repaglinide + metformin 1.4% 40 mg/dL Pioglitazone + metformin 0.7% 40 mg/dL Rosiglitazone + metformin 0.8% 50 mg/dL Insulin + oral agents Open to Target Open to Target,COMBINATION THERAPY Estimated Improvements in Glycemic Control,5-1b,MANAGEMENT GUIDELINES Combinations of Oral Agents: Sulfonylurea-Based Regimens,Start with Long-acting sulfonylurea once daily (glimepiride or extended-release glipizide) Add Metformin (preferred order) or Glitazone (if intolerance or contraindication for metformin present) or -Glucosidase inhibitor (if intolerance or contraindication for both metformin and glitazone present),5-8,PRACTICAL GUIDELINES Starting 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 needed Increase 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 120 mg/dL),5-18,Practical Management of Type 2 Diabetes Mellitus,FBG 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,Glitazones Metformin Acarbose,Sx,Insulin,No Sx,S