糖尿病藥物治療-問(wèn)題與失誤課件

1、紀(jì)立農(nóng)北京大學(xué)糖尿病中心北京大學(xué)人民醫(yī)院 糖尿病藥物治療問(wèn)題與失誤紀(jì)立農(nóng) 糖尿病藥物治療問(wèn)題與失誤2型糖尿病的病因、病理生理和結(jié)局大小血管并發(fā)癥遺傳因素環(huán)境因素胰島素抵抗細(xì)胞缺陷高血糖/IGTHDL, 小而致密LDL高血壓內(nèi)皮功能障礙/ 微蛋白尿低纖維蛋白溶解狀態(tài)炎癥Adapted from McFarlane S, et al. J Clin Endocrinol Metab 2001; 86:713718.2型糖尿病的病因、病理生理和結(jié)局大小血管并發(fā)癥遺傳因素胰島素血糖是最難控制的代謝異常多種病理生理機(jī)制自然病程演變,各種病理生理基礎(chǔ)發(fā)生變化影響因素多,波動(dòng)性大,需要反復(fù)的反饋血糖是最難控

2、制的代謝異常多種病理生理機(jī)制ASCOT: Reductions in Total and LDL Cholesterol2460123Atorvastatin 10 mgPlacebo1234012320015015075125100100(mg/dL)(mg/dL)Total cholesterol (mmol/L)LDL cholesterol (mmol/L)Years1.3 mmol/L1.0 mmol/L1.2 mmol/L1.0 mmol/LSever PS, Dahlf B, Poulter N, Wedel H, et al, for the ASCOT Investigato

3、rs. Lancet. 2003;361:1149-58ASCOT: Reductions in Total andLIIFE 研究-相同的降壓療效061218243036424854研究月份405060708090100110120130140150160170180收縮壓舒張壓平均動(dòng)脈壓mmHg阿替洛爾 145.4 mmHg氯沙坦 144.1 mmHg阿替洛爾 80.9 mmHg氯沙坦 81.3 mmHgDahlf B et al Lancet 2002;359:995-1003.阿替洛爾 102.4 mmHg氯沙坦 102.2 mmHgLIIFE 研究-相同的降壓療效0612182430

4、361 2 3 4EDICDCCT to EDIC: From experiment to reality1 2 3 4EDICDCCT to EDIC: 06789246810HbA1c (%)Time from randomization (years)Upper limit of normal = 6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：?jiǎn)我凰幬镏委煹木窒扌?1998年）Adapted from UKPDS Group. UKPDS 34. Lancet 1998; 352:854865.*Therapy assigned if

5、 FPG 15 mmol/l or symptoms of hyperglycemia Overweight patientsCohort, median valuesConventional therapy (primarily diet alone*) 06789246810HbA1c (%)Time froSaydah SH et al. JAMA. 2004;291:335-342.Patients (%)HbA1C 7%44.3%NHANES III; n=1,204 NHANES 1999-2000;n=37001020304050BP 130/80 mm HgTC 200 mg/

6、dL29.0%35.8%37.0%Good control7.3%5.2%33.9%P.001 48.2%Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000Saydah SH et al. JAMA. 2004;29Percentage of Patients With DiabetesHaving A1C 8.0%后仍然維持單藥治療的時(shí)間*（2004年）Brown JB, et al. Diabetes Care 2004; 27:15351540.*May include

7、uptitration 0510152025Metformin onlySulfonylurea onlyn = 513n = 3,39414.5 個(gè)月20.5 個(gè)月月在單藥治療時(shí)發(fā)現(xiàn) HbA1c 8.0%后仍然維持單藥治療020406080100%Age of SubjectsPercentage of Subjects advancing when HbA1C 8%Clinical Inertia: “Failure to advance therapy when required”Diet66.6%Sulfonylurea35.3%Metformin44.6%Combination18.

8、6%Brown et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27: 1535-1540, 2004At Insulin Initiation, the average patient had: 5 years with HbA1C 8% 10 years with HbA1C 7%020406080100%Age of SubjectsPe糖尿病藥物治療問(wèn)題與失誤課件多種代謝異?？刂频闹匾晕⒀懿∽? 高血糖是必要條件, 但不是充分條件 血壓*, 血脂#, 炎癥#大血管病變:高血糖不是必要條

9、件, 但可能促進(jìn)因素#*: 流行病學(xué)證據(jù);#: 臨床試驗(yàn)證據(jù)多種代謝異常控制的重要性微血管病變: 高血糖是必要條件, 但A tight blood pressure control policy which achieved blood pressure of 144 / 82mmHg gave reduced risk of:24% for any diabetes-related endpoint p=0.004632% for diabetes-related deaths p=0.01944% for stroke p=0.01337% for microvascular diseas

10、e p=0.009256% for heart failure p=0.0043 Blood Pressure Control, UKPDS 糖尿病藥物治療問(wèn)題與失誤課件 UKPDS研究顯示：嚴(yán)格降壓比強(qiáng)化降糖更重要? 中風(fēng)任何糖尿病終點(diǎn)糖尿病死亡微血管并發(fā)癥-50-40-30-20-100相對(duì)危險(xiǎn)度降低（%）嚴(yán)格血糖控制 (目標(biāo) 6.0 mmol/L或108 mg/dL)嚴(yán)格血壓控制 (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.*與嚴(yán)格血糖控制比較，P

11、 0.05 UKPDS研究顯示：嚴(yán)格降壓比強(qiáng)化降糖更重要? 糖尿病藥物治療問(wèn)題與失誤課件糖尿病藥物治療問(wèn)題與失誤課件各種治療達(dá)標(biāo)的百分率糖化血紅蛋白6.5%膽固醇4.5 mmol/l甘油三酯1.7 mmol/l收縮壓130 mmHg舒張壓80 mmHg8年后達(dá)到治療目標(biāo)的患者%p=0.06p0.0001p=0.19p=0.001p=0.21Steno-2 強(qiáng)化組 常規(guī)組強(qiáng)化組 常規(guī)組強(qiáng)化組 常規(guī)組強(qiáng)化組 常規(guī)組強(qiáng)化組 常規(guī)組各種治療達(dá)標(biāo)的百分率糖化血紅蛋白6.5%膽固醇甘油三酯收縮Targets for controlParameterTargetHbA1c 6.5% (DCCT-aligne

12、d assay)BP130/80 mmHgTotal cholesterol4.5 mmol/L (174 mg/dl)LDL- cholesterol2.5 mmol/L (97 mg/dl)HDL- cholesterol1.0 mmol/L (39 mg/dl)Triglycerides1.5 mmol/L (133 mg/dl)Urinary albumin:creatinine2.5 mg/mmol (22 mg/g) men3.5 mg mmol (31 mg/g) - womenExercise 150 minutes/weekTargets for controlParamet

13、erTa 2型糖尿病患者的藥物治療代謝控制 降糖藥：格列酮類；雙胍類；糖苷酶抑制劑；促胰島素分泌劑 GLP-1相關(guān)藥物 調(diào)脂藥: 它汀類藥物抗凝 阿司匹林血壓控制 降壓藥 2型糖尿病患者的藥物治療代謝控制Pancreatic b-cellInsulin ResistanceInsulin actionIncreasedlipolysisADIPOSETISSUEIslet b-cell degranulationreduced insulin contentInsulin Resistance and b-cell Dysfunction ProduceHyperglycaemia in Ty

14、pe 2 Diabeteslow-plasmainsulinIncreased glucose outputHYPERGLYCEMIADecreased glucose transport& activity (expression) of GLUT4Elevatedplasma NEFAElevatedTNFa, Resistin ?MUSCLE( TG )LIVERPANCREASPancreatic b-cellInsulin ResisSites of Action by Therapeutic Options Sonnenberg, et al. Curr Opin Nephrol

15、Hypertens 1998;7(5):551-555.GLUCOSEABSORPTIONMUSCLEPANCREASADIPOSE TISSUELIVERINTESTINEHYPERGLYCEMIADECREASED PERIPHERAL GLUCOSE UPTAKEINCREASED GLUCOSE PRODUCTIONDECREASED INSULIN SECRETIONTherapy:Thiazolidinediones(Biguanides)Therapy:InsulinSulfonylureasMetiglinidesTherapy:BiguanidesThiazolidinedi

16、onesTherapy:Alpha-glucosidase inhibitorsSites of Action by Therapeutic正常人血糖的波動(dòng)Riddle MC. Diabetes Care 1990;13:6766863002001000血漿葡萄糖濃度 (mg/dl)06001200180024000600時(shí)間 (小時(shí))餐時(shí)血糖峰值空腹正常人血糖的波動(dòng)Riddle MC. Diabetes Ca2型糖尿病高血糖的構(gòu)成空腹血糖增高Riddle MC. Diabetes Care 1990;13:6766863002001000血漿葡萄糖濃度 (mg/dl)060012001800

17、24000600時(shí)間 (小時(shí))肝糖輸出正常 肝糖輸出不能被關(guān)閉2型糖尿病高血糖的構(gòu)成空腹血糖增高Riddle MC. Riddle MC. Diabetes Care 1990;13:6766863002001000血漿葡萄糖濃度 (mg/dl)06001200180024000600時(shí)間 (小時(shí))餐時(shí)血糖峰值肝糖輸出正常2型糖尿病高血糖的構(gòu)成餐后血糖增高Riddle MC. Diabetes Care 1990;二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍磺脲類噻唑烷二酮胰島素-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列奈類-糖苷酶抑制劑速效胰島素格列

18、奈類降糖藥物改善總體血糖控制水平(HbA1c)的途徑二甲雙胍磺脲類噻唑烷二酮胰島素二甲雙胍二甲雙胍二甲雙胍-糖苷酶抑制劑-糖苷酶抑制劑-Overweight or obese person with diabetesWhere possible, define obesity using regional or national criteriaOverweight or obese person witNon-obese person with diabetesNon-obese person with diabetes2型糖尿病自然病程050100150200250-10-50510152

19、02530糖尿病病史（年）血糖(mg/dL)相對(duì)功能(%)胰島素抵抗胰島素水平-細(xì)胞衰竭*IFG = impaired fasting glucose50100150200250300350空腹血糖餐后血糖Adapted from International Diabetes Center (IDC)Minneapolis, Minnesota肥胖 空腹葡萄糖異常* 糖尿病 未控制的高血糖 2型糖尿病自然病程050100150200250-10-50針對(duì)2型糖尿病自然病程中不同時(shí)期的病理生理變化特點(diǎn)的藥物治療 針對(duì)2型糖尿病自然病程中不同時(shí)期的病理生理變化特點(diǎn)的藥物治療7698HbA1c (%

20、)10單藥治療Diet口服藥聯(lián)合口服藥物基礎(chǔ)胰島素傳統(tǒng)的非積極的糖尿病治療模式加量病程 口服藥物加多次胰島素7698HbA1c (%)10單藥治療Diet口服藥聯(lián)合口服口服藥加基礎(chǔ)胰島素口服藥加多此胰島素注射Diet口服藥物單藥治療（胰島素)口服藥聯(lián)合治療積極治療糖尿病早期聯(lián)合治療口服藥物加量病程 7698HbA1c (%)10口服藥加基礎(chǔ)胰島素口服藥加多此胰島素注射Diet口服藥物單藥 美國(guó)糖尿病藥物的市場(chǎng)情況NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 美國(guó)糖尿病藥物的市場(chǎng)情況NATURE R “Combination

21、therapy is standard”Although there are a number of oral drugs on the market to treat diabetes, at present no single marketed drug is capable of lowering HbA1c to the target range for a sustained period of time for the majority of patients with type 2 diabetes. Even when used in combination, these me

22、dications tend to lose much of their efficacy after 34 years of treatment.NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 “Combination thera 口服糖尿病藥物聯(lián)合的策略 理性化聯(lián)合（rational combination）：藥物之間的作用機(jī)制互補(bǔ)， 針對(duì)糖尿病的多種缺陷 積極聯(lián)合（provative approach）：早期聯(lián)合，發(fā)揮藥物聯(lián)合之間最大 的治療潛力 以達(dá)標(biāo)為驅(qū)動(dòng)力：用HbA1c作為“金標(biāo)準(zhǔn)” 同時(shí)減少大、小血管病變的危險(xiǎn)性

23、 口服糖尿病藥物聯(lián)合的策略 Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制減少CVD危險(xiǎn)性磺脲類促進(jìn)胰島素分泌格列酮類強(qiáng)胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險(xiǎn)因素+格列酮磺脲類：不同作用機(jī)制間的互補(bǔ)作用改善多重缺陷Inzucchi SE. JAMA 2002; 287:36Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制減少CVD危險(xiǎn)性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點(diǎn)格列酮類強(qiáng)胰島素增敏作用增加骨骼肌血糖利用改善大血管病變危險(xiǎn)因素+格列酮二甲雙胍：不同作用機(jī)制間的互補(bǔ)作用改善多重缺陷In

24、zucchi SE. JAMA 2002; 287:36Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制減少CVD危險(xiǎn)性二甲雙胍弱胰島素增敏作用減少肝糖輸出改善大血管病變臨床終點(diǎn)促分泌劑增加胰島素分泌+促泌劑二甲雙胍：不同作用機(jī)制間的互補(bǔ)作用改善多重缺陷Inzucchi SE. JAMA 2002; 287:362型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：?jiǎn)我凰幬镏饾u加量至推薦最大劑量新思維：在單一藥物的半量或次大劑量時(shí)聯(lián)合用藥(理性 結(jié)合） 2型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：?jiǎn)我凰幬镏饾u加*1.00.80.60.40.20.0Mean chan

25、ge in HbA1c from baseline (%)半量二甲雙胍羅格列酮與二甲雙胍加量的比較 (EMPIRE Study) HbA1cBaseline HbA1c (%)n =7.953138.05322MET 1 g/day + RSG 8 mg/dayPatients were treated for 24 weeksAll patients were inadequately controlled on MET 1 g/day alone*Significant vs. baseline MET 1 g/day+ MET 1 g/dayError bars = 95% CIRosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A1