心血管疾病中關(guān)于降糖藥物治療的選擇

1、Antihyperglycemic Agents for Type 2 Diabetes:The Six Classes,,*Awaiting FDA approval.,Antihyperglycemic Agents: Major Sites of Action,,,,,,,,,,,SulfonylureasMeglitinides,Injected Insulin,,Liver,,Plasma glucose,Glitazo

2、nes,,GI tract,?-GlucosidaseInhibitors,+,,Pancreas,Metformin,Muscle/Fat,–,,,(–),,(+),(+),,(–),,(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,,,a-Glucosidase inhib

3、itor,Antihyperglycemic Agents: Major Sites of Action,,,,,,,,,,,SulfonylureasMeglitinides,Injected Insulin,,Liver,,Plasma glucose,Glitazones,,GI tract,?-GlucosidaseInhibitors,+,,Pancreas,Metformin,Muscle/Fat,–,,,(–),,(

4、+),(+),,(–),,(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,,,PPAR?的激活,,Adapted from Arner P. Diabetes Obes Metab 2001; 3 (Suppl 1):S11–S19.,PPAR?激活增加胰島素的活性,,,Youn

5、g et al. Diabetes 1995; 44:1087–1092.,激活前脂肪細胞和脂肪細胞中的PPAR?,,Lipotoxic disease: Rogers Unger,Annu.Rev.Med 2002.53:319-36,PPAR?激活促進脂肪細胞分化,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)其他潛在的抗動脈粥樣硬化特性：改善血管彈性MCP-1(單核細胞化學誘

6、導物蛋白-1) ; MMP-9(基質(zhì)金屬蛋白酶-9) ; ROS(活性氧簇)減少減少平滑肌細胞的增殖,Antihyperglycemic Agents: Major Sites of Action,,,,,,,,,,,SulfonylureasMeglitinides,Injected Insulin,,Liver,,Plasma glucose,Glitazones,,GI tract,?-GlucosidaseInhibit

7、ors,+,,Pancreas,Metformin,Muscle/Fat,–,,,(–),,(+),(+),,(–),,(+),CarbohydrateAbsorption,Hepatic gluconeogenesis,InsulinSecretion,GlucoseUptake,InsulinSecretion,,,Structure of Sulfonylurea,,,,,,,,,,,,,,,,,,,,,,,,,,,,

8、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Tolbutamide

9、(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,Nateg

10、linide,,Repaglinide,Meglitinide氯茴苯酸,Glyburide (Glibenclamide),Structure of Sulfonylurea and Meglitinide,,,SU Moiety,,,達美康,Tolbutamide,優(yōu)降糖,格列美嬲,,促胰島素分泌劑的化學結(jié)構(gòu),,,瑞格列奈分子,磺脲/列奈類藥物作用機理,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

11、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,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,,化學結(jié)構(gòu)與功能的關(guān)系,,S,K+,,Ashcroft FM Diabetologia 1999,,

12、,,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,達美康 對克隆 ?-細胞及心肌通道的不同作用,,不同促分泌劑的選擇性差異,,不同藥物對心血管KATP通道的抑制,在對B細胞KATP通道等效抑制時，不同藥物對心血管KATP通道的抑制百分比,* 與B細胞相比，P<

13、0.05,英國劍橋大學完成尼可地爾為鉀通道激活劑，心絞痛治療新藥， 國際上應(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美康對心臟無作用心絞痛患者服用尼可地爾時，建議選擇達美康,Frank Reimann， Diabetes，Vol。 50， October 2001,抗心絞痛的鉀通道開放劑 —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,,F

14、rank Reimann， Diabetes，Vol。 50， October 2001,+,+,+,尼可地爾,尼可地爾,尼可地爾,“b-細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，尋求更好的心臟或其他器官保護作用,,,達美康對血液生化的影響,使血小板功能正常化 使血管壁的纖溶蛋白溶酶活性正?；?清除自由

15、基 恢復(fù)前列腺素的平衡保護內(nèi)皮功能,,達美康使血小板功能正?；?血小板凝聚(%),40,50,60,70,80,90,100,,,,P<0.01,,,,0,3,,,,,,,,,P=0.006,,,0,3,個月,,優(yōu) 降 糖,,達 美 康,Jennings PE et al. Metabolism. 1992;41:36-39.,NS,,,個月,達美康清除自由基,血漿脂類過氧化物,,優(yōu) 降 糖,,,,0,MDA-LM (

16、?ol/L),P=0.009,,,,,,,達 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,紅細胞SOD (? g/mL),P=0.003,,,,,,,達 美 康,20,40,60,80,100,120,140,160,,,,,,,,,,158,117,Jennings PE et al. Metabolism. 1992;41(supp

17、l 1):36-39.,* 紅細胞,達美康恢復(fù)前列腺素的平衡,微血栓素,TXB2 (ng/L),150,200,250,300,0,3,個月,前列環(huán)素,6-Keto PGF1a (ng/L),60,70,80,90,,,,,,,,,0,3,個月,100,,,,,*,*,* P<0.001,Fu ZZ et al. Metabolism. 1992;90:33-35.,O’Brien R J Diabet Comps 2000,延

18、遲LDL氧化時間,,* P<0,05 vs control # P<0,05 vs GHHb,Vallejo S Diabetologia 2000,評價對內(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)所需劑量的負對數(shù)值,GHHb：糖基化的氧合血紅蛋白,Omi H J Diabetes Complications 2001,對內(nèi)皮功能的保護作用,,脂質(zhì)過氧化物（?mol/l）,對照組

19、 格列本脲組 達美康組,* 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)過氧化物酶(∪mol/L),達美康增強2型糖尿病人的抗氧化能力和一氧化氮介導的舒血管作用,（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P

20、AI-1(纖溶酶原激活劑的抑制劑-1)其他潛在的抗動脈粥樣硬化特性：改善血管彈性MCP-1(單核細胞化學誘導物蛋白-1) ; MMP-9(基質(zhì)金屬蛋白酶-9) ; ROS(活性氧簇)減少減少平滑肌細胞的增殖,心血管疾病中降糖藥物的選擇,病人評價一般情況心臟病變糖尿病狀態(tài)肝腎功能,藥物選擇作用機制副作用對心臟病變的影響降糖外作用,治療后監(jiān)測血糖副作用程度肝、腎功能,,,,病人評價,一般情況：年齡：<45

21、歲、＜60歲、≥60歲BMI：＜25、≥25腰圍：男＞90、女＞85腰圍/身高比值：≥0.5,病人評價,病情評價：心臟病變：高血壓、高血脂、心律失常、冠心病、心臟手術(shù)后、 導管術(shù)后、安裝起博器后、心功能治療藥物： B-阻滯劑、利尿劑糖尿病評價：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BMI<25DM、IGT、IFG,年

22、齡≥45歲BMI≥25DM、IGT、IFG,GAD（+）,正常IR,,必要時,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關(guān)鍵的自身抗原，GAD正常為陰性，＞50為陽性。,,胰島細胞抗體 (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?！逝?,藥

23、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,,** 小劑量長效胰島素為基礎(chǔ)的多中心研究進行中,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?！?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、

24、心梗后、冠脈術(shù)后、心律失常穩(wěn)定期、心功能正?！?,** 小劑量長效胰島素為基礎(chǔ)的多中心研究進行中,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 mono

25、therapy,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,α-glucosidaseinhibitors,,,,,,,,Recent type 2 DM diagnosisType 2 DM < 5 yrs’ duration,,Recent type 2 DM diagnosisElevated PPG,,Overweight / obeseIns

26、ulin resistant,,Insulin resistantOverweight/ obese,,Diet controlElevated PPGContraindications to other agents,,Advantages,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,α-glucosidaseinhibitors,,,,,,,,Ra

27、pid FPG reductionLow costSome antioxidative…,,↓Risk of hypoglycemiaShort-actingMeal-adjusted dosingSafe and effective in renal dysfunction (Metabolised in the liver, biliary excretion , Metabolites are inactive),,N

28、o weight gain↓ Risk of hypoglycemia,,↓Amount of insulin↓Risk hypoglycemiaNo GI side effectNo drug interactionNo adjust dose in RF,,↓ Risk of hypoglycemia Non systemic action↓PPG,,,Insulin sensitizers No stimulat

29、ion of insulin secretion Beneficial lipid profile,Disadvantages,Sulfonylureas,Meglitinides,Biguanides,Thiazolidinediones,α-glucosidaseinhibitors,,,,,,,,Weight gain↑ Risk of hypoglycemia,,High costsFrequent dosing,,G

30、I side effectsRare lactic acidosis,,High costWeight gainSlow onset of actionIssue of liver toxicity Colonic polyps?Edema（Na,H2O retention)Heart failure?,High costGI side effectsLimited efficacy,,,PART 1,KEN,M

31、onotherapy Pearls,All drugs except AGIs and nateglinide equally reduce HbA1cMetformin usually best for obese- no weight gainNon-SU secretagogues may be useful for irregular mealsMetformin and TZDs avoid hypoglycemia,

32、Options for combination therapy,Sulfonylureas + Biguanide Or ThiazolidinedioneOra-glucosidase inhibitor,Biguanide + meglitinide,Biguanides + Thiazolidinediones,Biguanide +

33、 a-glucosidase inhibitor,,,,,,,Triple combination therapy Sulfonylurea + biguanide + Thiazolidinedione or Sulfonylurea + biguanide + a-glucosidase inhibitor,,,,,If ther

34、apeutic goals are not met using the above combinations; switch to insulin +/- oral agent,Combination Therapy in Type 2 Diabetes:Decision Considerations,HbA1c efficacyReductions from baselineReaching targetSynergy of

35、 mechanisms of actionSide effects and toxicity profileFrequency and severity of hypoglycemiaEffect on weight gainAvoiding polypharmacy and complex regimensCompliance and convenienceCost,5-1a,MANAGEMENT GUIDELINESI

36、nitial Treatment Recommendations,,FBG 126-140 mg/dL,,Metformin,?-Glucosidase Inhibitors,,Sulfonylureas,Metformin,Meglitinides,?-Glucosidase Inhibitors,,Sulfonylureas,Metformin,,No symptoms:,Sulfonylureas,,Symptoms:,Insul

37、ins,,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

38、 achieved,Modified from American Diabetes Association. Diabetes Care. 1995;18:1510-1518.,Nonpharmacologic TherapyDietExercise,MonotherapySulfonylureasBiguanidesa-Glucosidase InhibitorsGlitazonesMeglitinidesInsuli

39、n,Combination TherapyFrequently used or well studiedSulfonylurea + MetforminSulfonylurea + RosiglitazoneSulfonylurea + PioglitazoneSulfonylurea + AcarboseRepaglinide + MetforminRosiglitazone + MetforminPioglitazo

40、ne + MetforminSulfonylurea + InsulinMetformin + InsulinPioglitazone + InsulinRosiglitazone + InsulinAcarbose + InsulinInfrequently used and/orless well studiedSulfonylurea + Metformin + GlitazoneSulfonylurea + M

41、etformin + InsulinGlitazone + Metformin + Insulin,InsulinIntermediate BIDIntermediate + Regular BIDMultiple (3 or more) injections,Glycemic goals not achieved,,,Glycemic goals not achieved,,,Very symptomaticSevere h

42、yperglycemiaKetosisUnrecognized 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. Diabe

43、tes 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.,

44、Regimen? HbA1c? FBGSulfonylurea + metformin~1.7%~65 mg/dLSulfonylurea + rosiglitazone~1.4%~60 mg/dLSulfonylurea + pioglitazone~1.2%~50 mg/dLSulfonylurea + acarbose~1.3%~40 mg/dLRepaglinide + metformin

45、~1.4%~40 mg/dLPioglitazone + metformin~0.7%~40 mg/dLRosiglitazone + metformin~0.8%~50 mg/dLInsulin + oral agentsOpen to Target Open to Target,,,,,,,,,,,,COMBINATION THERAPYEstimated Improvements in Glycemi

46、c 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)o

47、rGlitazone (if intolerance or contraindication for metformin present)or?-Glucosidase inhibitor(if intolerance or contraindication for both metformin and glitazone present),,,,5-8,PRACTICAL GUIDELINESStarting

48、 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?)（來得時 長效）Adjust dose

49、by fasting SMBG （空腹自測血糖）Increase insulin dose weekly as neededIncrease 4 U if FBG >140 mg/dL（相當于7.8mmol/L)Increase 2 U if FBG = 120-140 mg/dL (相當于6.7-7.8mmol/L）Treat to target (usually <120 mg/dL),,5-18,Practic

50、al 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,,,,,,GlitazonesMetforminAcarbose,Sx,Insulin,No Sx,Sulfonylur

51、ea,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

52、 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 The

53、rapy 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 t

54、riple 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 Considerat

55、ions,HbA1c efficacyReductions from baselineReaching targetSynergy of mechanisms of actionSide effects and toxicity profileFrequency and severity of hypoglycemiaEffect on weight gainAvoiding polypharmacy and comple

56、x regimensCompliance and convenienceCost,5-1a,糖尿病患者缺乏抗氧化因子，同時內(nèi)皮功能異常,維生素 E 和 C : 在一組大系列的研究中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例健康人糖尿病組的血漿維生素C、維生素E和β－胡蘿卜素平均含量顯著降低隨著病程延長，患者血漿維生素C、維生

57、素E和β－胡蘿卜素逐漸降低；病程與維生素E 、 β－胡蘿卜素水平相關(guān)最密切。,顧惠娟等,實用新醫(yī)學.2000,2(9).-769-770,抗氧化劑對內(nèi)皮功能異常的作用,通過去鐵銨的鐵螯合作用影響冠狀動脈的血管舒縮功能 (Nitenberg, et al. Circulation 1998;97:736-43)黃酮類對于毛細血管通透性的影響 (Valensi, et al. Diabet Med

58、1996;13:882-8)(Cohen-Boulakia, et al. Metabolism 2000;49:880-5)維生素C 可以直接逆轉(zhuǎn)NIDDM患者血流障礙導致的依賴內(nèi)皮的舒血管作用的異常 (Ting, et al. JCI 1996;97:22-8)對于1型DM用維生素 E 3個月， 可以使血流障礙導致的依賴內(nèi)皮的舒血管作用恢復(fù)正常

59、 (Skyrme-Jones, et al. Circulation 1999;100: I-756)α硫辛酸 : 對糖尿病神經(jīng)病變的益處 (Cameron, et al. Diabetologia 1994;37:449-59),,,,LiverIncreased Glucose

60、Production,Adipose TissueIncreased Lipolysis,IncreasedFree Fatty Acids,Pancreatic Beta Cells Decreased Insulin Secretion,Thiazolidinedinones (TZDs)Increase GlucoseUptake,Skeletal MuscleDecreasedGlucose Uptake,

61、Defective Insulin Secretion,Insulin Resistance,Small IntestineCarbohydrateAbsorption,,,Hyperglycemia,Glucotoxicity,SulfonylureasandNonsulfonylureaSecretagoguesIncrease InsulinSecretion,,,,,,,TZDs,BiguanidesDecrea