糖尿病藥物治療-問題與失誤課件

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.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,波動性大,需要反復(fù)的反饋ASCOT: Reductions in Total and LDL Cholesterol246012

2、3Atorvastatin 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 Investigators. Lancet. 2003;361:1149-58LIIFE 研究-相同的降壓療效061218243036424854研究月份

3、405060708090100110120130140150160170180收縮壓舒張壓平均動脈壓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 mmHg1 2 3 4EDICDCCT to EDIC: From experiment to reality 06789246810HbA1c (%)Time from randomization (years)Upper limit of norm

4、al = 6.2%GlyburideChlorpropamideMetforminInsulin0UKPDS：單一藥物治療的局限性(1998年）Adapted from UKPDS Group. UKPDS 34. Lancet 1998; 352:854865.*Therapy assigned if FPG 15 mmol/l or symptoms of hyperglycemia Overweight patientsCohort, median valuesConventional therapy (primarily diet alone*)在單藥治療時發(fā)現(xiàn) HbA1c 8.0%后

5、仍然維持單藥治療的時間*（2004年）Brown JB, et al. Diabetes Care 2004; 27:15351540.*May include uptitration 0510152025Metformin onlySulfonylurea onlyn = 513n = 3,39414.5 個月20.5 個月月020406080100%Age of SubjectsPercentage of Subjects advancing when HbA1C 8%Clinical Inertia: “Failure to advance therapy when required”D

6、iet66.6%Sulfonylurea35.3%Metformin44.6%Combination18.6%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%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 m

7、mHg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Targets for controlParameterTargetHbA1c 6.5% (DCCT-aligned 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)Triglyce

8、rides1.5 mmol/L (133 mg/dl)Urinary albumin:creatinine2.5 mg/mmol (22 mg/g) men3.5 mg mmol (31 mg/g) - womenExercise 150 minutes/weekPancreatic b-cellInsulin ResistanceInsulin actionIncreasedlipolysisADIPOSETISSUEIslet b-cell degranulationreduced insulin contentInsulin Resistance and b-cell Dysfuncti

9、on ProduceHyperglycaemia in Type 2 Diabeteslow-plasmainsulinIncreased glucose outputHYPERGLYCEMIADecreased glucose transport& activity (expression) of GLUT4Elevatedplasma NEFAElevatedTNFa, Resistin ?MUSCLE( TG )LIVERPANCREASSites of Action by Therapeutic Options Sonnenberg, et al. Curr Opin Nephrol

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

11、onesTherapy:Alpha-glucosidase inhibitors正常人血糖的波動Riddle MC. Diabetes Care 1990;13:6766863002001000血漿葡萄糖濃度 (mg/dl)06001200180024000600時間 (小時)餐時血糖峰值空腹2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)06001200180024000600時間 (小時)肝糖輸出正常 肝糖輸出不能被關(guān)閉Riddle MC. Diabetes Care 1990

12、;13:6766863002001000血漿葡萄糖濃度 (mg/dl)06001200180024000600時間 (小時)餐時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Overweight or obese person with diabetesWhere possible, define obesity using

13、regional or national criteriaNon-obese person with diabetes2型糖尿病自然病程050100150200250-10-5051015202530糖尿病病史（年）血糖(mg/dL)相對功能(%)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 針對2型糖尿病自

14、然病程中不同時期的病理生理變化特點(diǎn)的藥物治療 7698HbA1c (%)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 美國糖尿病藥物的市場情況NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 “Combination therapy is standard”Although there are a numbe

15、r 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 medications tend to lose much of their efficacy

16、after 34 years of treatment.NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367 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)動力：用HbA1c作為“金標(biāo)準(zhǔn)” 同時減少大、小血管病變的危險性Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制減少CVD危險性磺脲類促進(jìn)胰島素分泌格列酮類強(qiáng)胰

17、島素增敏作用增加骨骼肌血糖利用改善大血管病變危險因素+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; 287:360372.改善血糖控制減少CVD危險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Inzucchi SE. JAMA 2002; 287:360372.改善血糖控制減少CVD危險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

18、善多重缺陷2型糖尿病口服藥物聯(lián)合治療思維的改變傳統(tǒng)思維：單一藥物逐漸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聯(lián)合用藥(理性 結(jié)合） *1.00.80.60.40.20.0Mean change 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):A144145.0.63%0.82%N = 635 Patients were treated for 24 weeksAll patients were inadequately controlled on ME