心血管疾病中降糖藥物治療的選擇.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激活增加胰島素的活性,Young et al. Diabetes 1995; 44:10871092.,激活前脂肪細(xì)胞和脂肪細(xì)胞中的PPAR,Lipotoxic disease: Rogers Unger,Annu.Rev.Med 2002.53:319-36,PPAR激活促進(jìn)脂肪細(xì)胞分化,PPAR激活的其他效應(yīng),減少炎性因子-C反應(yīng)蛋白 減少PAI-1(纖溶酶原激活劑的抑制劑-1) 其他潛在的抗動(dòng)脈粥樣硬化特性： 改善血管彈性 MCP-1(單核細(xì)胞化學(xué)誘導(dǎo)物蛋白-1) ; MMP-9(基質(zhì)金屬蛋白酶-9) ; ROS(活性氧簇)減少 減少平滑肌細(xì)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,達(dá)美康,Tolbutamide,優(yōu)降糖,格列美嬲,促胰島素分泌劑的化學(xué)結(jié)構(gòu),瑞格列奈分子,磺脲/列奈類藥物作用機(jī)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,磺脲類受體亞型結(jié)構(gòu),Gribble FM Diabetes 1998,化學(xué)結(jié)構(gòu)與功能的關(guān)系,S,K+,Ashcroft FM Diabetologia 1999,缺血、缺氧,基礎(chǔ)狀態(tài),基礎(chǔ)狀態(tài),KATP 通道的作用及分布,Gribble FM Diabetes 1998,達(dá)美康 對(duì)克隆 -細(xì)胞及心肌通道的不同作用,不同促分泌劑的選擇性差異,不同藥物對(duì)心血管KATP通道的抑制,在對(duì)B細(xì)胞KATP通道等效抑制時(shí)，不同藥物對(duì)心血管KATP通道的抑制百分比,* 與B細(xì)胞相比，P0.05,英國(guó)劍橋大學(xué)完成 尼可地爾為鉀通道激活劑，心絞痛治療新藥， 國(guó)際上應(yīng)用日趨廣泛 研究發(fā)現(xiàn)格列美脲和優(yōu)降糖明顯抑制尼可地爾活性 達(dá)美康對(duì)心臟無(wú)作用 心絞痛患者服用尼可地爾時(shí)，建議選擇達(dá)美康,Frank Reimann， Diabetes，Vol。 50， October 2001,抗心絞痛的鉀通道開(kāi)放劑 尼可地爾 (Nicorandil)和磺脲類藥物的交互影響,磺脲類與尼可地爾在心臟KATP通道的交互作用,Frank Reimann， Diabetes，Vol。 50， October 2001,+,+,+,尼可地爾,尼可地爾,尼可地爾,“b-細(xì)胞選擇性的磺脲類藥物代表著糖尿病合并有缺血性心臟病的藥物治療的新策略“,Brady P JACC 1998,選擇性研究的結(jié)論提示?,-保證有效降低血糖的同時(shí)，尋求更好的心臟或其他器官保護(hù)作用,達(dá)美康對(duì)血液生化的影響,使血小板功能正?；?使血管壁的纖溶蛋白溶酶活性正?；?清除自由基 恢復(fù)前列腺素的平衡 保護(hù)內(nèi)皮功能,達(dá)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,個(gè)月,優(yōu) 降 糖,達(dá) 美 康,Jennings PE et al. Metabolism. 1992;41:36-39.,NS,個(gè)月,達(dá)美康清除自由基,血漿脂類過(guò)氧化物,優(yōu) 降 糖,0,MDA-LM (ol/L),P=0.009,達(dá) 美 康,1,2,3,4,5,6,7,8,9,7.2,8.8,RBC*超氧歧化酶,優(yōu) 降 糖,0,紅細(xì)胞SOD ( g/mL),P=0.003,達(dá) 美 康,20,40,60,80,100,120,140,160,158,117,Jennings PE et al. Metabolism. 1992;41(suppl 1):36-39.,* 紅細(xì)胞,達(dá)美康恢復(fù)前列腺素的平衡,微血栓素,TXB2 (ng/L),150,200,250,300,0,3,個(gè)月,前列環(huán)素,6-Keto PGF1a (ng/L),60,70,80,90,0,3,個(gè)月,100,*,*,* P0.001,Fu ZZ et al. Metabolism. 1992;90:33-35.,OBrien R J Diabet Comps 2000,延遲LDL氧化時(shí)間,* P0,05 vs control # P0,05 vs GHHb,Vallejo S Diabetologia 2000,評(píng)價(jià)對(duì)內(nèi)皮功能影響,PD2：GHHb抑制緩激肽舒血管反應(yīng)， 產(chǎn)生一半最大效應(yīng)所需劑量的負(fù)對(duì)數(shù)值,GHHb：糖基化的氧合血紅蛋白,Omi H J Diabetes Complications 2001,對(duì)內(nèi)皮功能的保護(hù)作用,脂質(zhì)過(guò)氧化物（mol/l）,對(duì)照組 格列本脲組 達(dá)美康組,* 與正常人相比 P=0.0001， * 與格列本脲治療組相比 P=0.0001。,*,*,*,G. De Mattia, Diabetes UK, Diabetic Medicine, 19, 752-757,脂質(zhì)過(guò)氧化物酶(mol/L),達(dá)美康增強(qiáng)2型糖尿病人的抗氧化能力和一氧化氮介導(dǎo)的舒血管作用,（治療12周）,PPAR激活的其他效應(yīng),減少炎性因子-C反應(yīng)蛋白 減少PAI-1(纖溶酶原激活劑的抑制劑-1) 其他潛在的抗動(dòng)脈粥樣硬化特性： 改善血管彈性 MCP-1(單核細(xì)胞化學(xué)誘導(dǎo)物蛋白-1) ; MMP-9(基質(zhì)金屬蛋白酶-9) ; ROS(活性氧簇)減少 減少平滑肌細(xì)胞的增殖,心血管疾病中降糖藥物的選擇,病人評(píng)價(jià) 一般情況 心臟病變 糖尿病狀態(tài) 肝腎功能,藥物選擇 作用機(jī)制 副作用對(duì)心臟病變的影響 降糖外作用,治療后監(jiān)測(cè) 血糖 副作用程度 肝、腎功能,病人評(píng)價(jià),一般情況： 年齡：45歲、60歲、60歲 BMI：25、25 腰圍：男90、女85 腰圍/身高比值：0.5,病人評(píng)價(jià),病情評(píng)價(jià)： 心臟病變：高血壓、高血脂、心律失常、冠心病、心臟手術(shù)后、 導(dǎo)管術(shù)后、安裝起博器后、心功能 治療藥物： B-阻滯劑、利尿劑 糖尿病評(píng)價(jià)：血糖水平、胰島功能、GAD抗體 腎臟情況：血肌酐、BUN、尿蛋白水平、尿酸 肝臟情況：轉(zhuǎn)氨酶、脂肪肝,基本原則,年齡45歲 BMI25 DM、IGT、IFG,年齡45歲 BMI25 DM、IGT、IFG,GAD（+）,正常IR,必要時(shí),GAD-Ab血清谷氨酸脫羧酶抗體是一型糖尿病早期診斷的一個(gè)關(guān)鍵的自身抗原，GAD正常為陰性，50為陽(yáng)性。,胰島細(xì)胞抗體 (ICA)、 胰島素自身抗體 (IAA) 谷氨酸脫羧酶抗體（GAD）,綜合診斷一型糖尿病的依據(jù),檢測(cè)是否為胰島素敏感還是抵抗型：有高胰島素-正常血糖鉗夾和高葡萄糖變量鉗夾兩種方法,藥物選擇,高血壓、高血脂、心功能正常肥胖,藥物選擇,心絞痛、心梗后、冠脈術(shù)后穩(wěn)定期、心律失常、心功能正常肥胖,* 小劑量長(zhǎng)效胰島素為基礎(chǔ)的多中心研究進(jìn)行中,注意：腎功能異常者不用二甲雙胍 肝功能異常者不用文迪雅（羅格列酮） 腎功能異常者可用糖適平（格列奎酮）,藥物選擇,高血壓、高血脂、心功能正常消瘦,肥胖者首選胰島素增敏劑，而代謝綜合癥的消瘦者注意一型糖尿病，首選促泌劑，根據(jù)肝腎功能選擇具體種類。伴心血管疾病的消瘦者首選增敏劑，注意磺脲類易致低血糖。,藥物選擇,心絞痛、心梗后、冠脈術(shù)后、心律失常穩(wěn)定期、心功能正常消瘦,* 小劑量長(zhǎng)效胰島素為基礎(chǔ)的多中心研究進(jìn)行中,藥物選擇,心絞痛、心梗后、心律失常非穩(wěn)定期 冠脈術(shù)后早期 心功能異常、反復(fù)心衰,胰島素治療 禁任何口服降糖藥,藥物選擇,GAD-Ab （+）或 60,雙胍類 GLITAZONES 糖苷酶抑制劑 胰島素,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)（中效胰島素） 70/30 (evening meal)（短效胰島素） Glargine (bedtime or anytime?)（來(lái)得時(shí) 長(zhǎng)效） Adjust dose by fasting SMBG （空腹自測(cè)血糖） Increase insulin dose weekly as needed Increase 4 U if FBG 140 mg/dL（相當(dāng)于7.8mmol/L) Increase 2 U if FBG = 120-140 mg/dL (相當(dāng)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