糖尿病藥物治療—問(wèn)題與失誤課件

1、糖尿病藥物治療問(wèn)題與失誤,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,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/IGT HDL, 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,糖尿病藥物治療問(wèn)題與失誤,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

2、反復(fù)的反饋,糖尿病藥物治療問(wèn)題與失誤,ASCOT: Reductions in Total and LDL Cholesterol,2,4,6,0,1,2,3,Atorvastatin 10 mg,Placebo,1,2,3,4,0,1,2,3,200,150,150,75,125,100,100,mg/dL,mg/dL,Total cholesterol (mmol/L,LDL cholesterol (mmol/L,Years,1.3 mmol/L,1.0 mmol/L,1.2 mmol/L,1.0 mmol/L,Sever PS, Dahlf B, Poulter N, Wedel H,

3、 et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58,糖尿病藥物治療問(wèn)題與失誤,LIIFE 研究-相同的降壓療效,研究月份,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 mmHg,Dahlf B et al Lancet 2002;359:995-1003,阿替洛爾 102.4 mmHg,氯沙坦 102.2 mmHg,糖尿病藥物治療問(wèn)題與失誤,1 2 3 4,EDIC,DCCT to EDIC: From experimen

4、t to reality,糖尿病藥物治療問(wèn)題與失誤,0,6,7,8,9,2,4,6,8,10,HbA,1c,Time from randomization (years,Upper limit of normal = 6.2,0,UKPDS：?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 FPG 15 mmol/l or symptoms of hyperglycemia Overweight patients Cohort, median valu

5、es,糖尿病藥物治療問(wèn)題與失誤,Saydah SH et al. JAMA. 2004;291:335-342,Patients (,HbA1C 7,NHANES III; n=1,204 NHANES 1999-2000; n=370,0,10,20,30,40,50,BP 130/80 mm Hg,TC 200 mg/dL,Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000,糖尿病藥物治療問(wèn)題與失誤,Percentage of Patients With DiabetesH

6、aving A1C 7,Harris MI et al. Diabetes Care. 1999;22:403-408 Koro Ce et al., Diabetes Care 27:17-20, 2004,0,20,40,60,80,100,Diet alone,Oral agents,Insulin,NHANES III US Adults With Diagnosed Diabetes in 198894,73,38,27,Whole study population,44.5,Percent at goal,Therapy used,35.8,NHANES (1999-2000,糖尿

7、病藥物治療問(wèn)題與失誤,在單藥治療時(shí)發(fā)現(xiàn) HbA1c 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 uptitration,0,5,10,15,20,25,Metformin only,Sulfonylurea only,n = 513,n = 3,394,14.5 個(gè)月,20.5 個(gè)月,月,糖尿病藥物治療問(wèn)題與失誤,0,20,40,60,80,100,Age of Subjects,Percentage of Subjects advancing when HbA1C 8

8、,Clinical Inertia: “Failure to advance therapy when required,Brown et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27: 1535-1540, 2004,At Insulin Initiation, the average patient had,5 years with HbA1C 8,10 years with HbA1C 7,糖尿病藥物治療問(wèn)題與失誤,糖尿病藥物治療問(wèn)題與失誤,多種代謝異常控制的重要性,微血管病變: 高血糖是

9、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),糖尿病藥物治療問(wèn)題與失誤,A tight blood pressure control policy which achieved blood pressure of 144 / 82mmHg gave reduced risk of: 24% for any diabetes-related endpoint p=0.0046 32% for diabetes-related deaths p=0.019 44% for stroke p=0.01

10、3 37% for microvascular disease p=0.0092 56% for heart failure p=0.0043,Blood Pressure Control, UKPDS,糖尿病藥物治療問(wèn)題與失誤,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,50,40,30,20,10,0,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.

11、 2000;36(3):646-661,與嚴(yán)格血糖控制比較，P 0.05,糖尿病藥物治療問(wèn)題與失誤,糖尿病藥物治療問(wèn)題與失誤,糖尿病藥物治療問(wèn)題與失誤,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 mmHg,8年后達(dá)到治療目標(biāo)的患者,p=0.06,p0.0001,p=0.19,p=0.001,p=0.21,Steno-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,糖尿病藥物治療問(wèn)題與失誤,Targets for control,糖尿病藥物治療問(wèn)題與失誤,2型糖

12、尿病患者的藥物治療,代謝控制 降糖藥：格列酮類(lèi)；雙胍類(lèi)；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(lèi)藥物 抗凝 阿司匹林 血壓控制 降壓藥,糖尿病藥物治療問(wèn)題與失誤,Pancreatic b-cell,Insulin Resistance Insulin action,Increased lipolysis,ADIPOSE TISSUE,Islet b-cell degranulation reduced insulin content,Insulin Resistance and b-cell Dysfunction Produce Hyperglycaemia in

13、Type 2 Diabetes,low-plasma insulin,Increased glucose output,HYPERGLYCEMIA,Decreased glucose transport 7(5):551-555,GLUCOSE ABSORPTION,MUSCLE,PANCREAS,ADIPOSE TISSUE,LIVER,INTESTINE,HYPERGLYCEMIA,DECREASED PERIPHERAL GLUCOSE UPTAKE,INCREASED GLUCOSE PRODUCTION,DECREASED INSULIN SECRETION,Therapy: Thi

14、azolidinediones (Biguanides,Therapy: Insulin Sulfonylureas Metiglinides,Therapy: Biguanides Thiazolidinediones,Therapy: Alpha-glucosidase inhibitors,糖尿病藥物治療問(wèn)題與失誤,正常人血糖的波動(dòng),Riddle MC. Diabetes Care 1990;13:676686,300 200 100 0,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,糖尿病藥物治療問(wèn)題與失誤,2型糖尿病高血糖的

15、構(gòu)成空腹血糖增高,Riddle MC. Diabetes Care 1990;13:676686,300 200 100 0,血漿葡萄糖濃度 (mg/dl,06001200180024000600,時(shí)間 (小時(shí),肝糖輸出 正常,肝糖輸出不能被關(guān)閉,糖尿病藥物治療問(wèn)題與失誤,Riddle MC. Diabetes Care 1990;13:676686,300 200 100 0,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,糖尿病藥物治療問(wèn)題與失誤,二甲雙胍 磺脲類(lèi) 噻唑烷二酮 胰島素,二

16、甲雙胍 磺脲類(lèi) 噻唑烷二酮 胰島素,二甲雙胍 磺脲類(lèi) 噻唑烷二酮 胰島素,糖苷酶抑制劑 速效胰島素 格列奈類(lèi),糖苷酶抑制劑 速效胰島素 格列奈類(lèi),糖苷酶抑制劑 速效胰島素 格列奈類(lèi),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(lèi) 噻唑烷二酮 胰島素,糖尿病藥物治療問(wèn)題與失誤,Overweight or obese person with diabetes,Where possible, define obesity using regional or national criteria,糖尿病藥物治療問(wèn)題與失誤,Non-obese person with diabetes,

17、糖尿病藥物治療問(wèn)題與失誤,2型糖尿病自然病程,0,50,100,150,200,250,10,5,0,5,10,15,20,25,30,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 glucose,50,100,150,200,250,300,350,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,糖尿病藥物治療問(wèn)題與失誤,針對(duì)2型糖尿病自然病程中不

18、同時(shí)期的病理生理變化特點(diǎn)的藥物治療,糖尿病藥物治療問(wèn)題與失誤,7,6,9,8,HbA1c (,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,糖尿病藥物治療問(wèn)題與失誤,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,7,6,9,8,HbA1c (,10,糖尿病藥物治療問(wèn)題與失誤,美國(guó)糖尿病藥物的市場(chǎng)情況,NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367,糖尿病

19、藥物治療問(wèn)題與失誤,Combination 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

20、 combination, these medications tend to lose much of their efficacy after 34 years of treatment,NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 367,糖尿病藥物治療問(wèn)題與失誤,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)”

21、 同時(shí)減少大、小血管病變的危險(xiǎn)性,糖尿病藥物治療問(wèn)題與失誤,Inzucchi SE. JAMA 2002; 287:360372,改善血糖控制 減少CVD危險(xiǎn)性,磺脲類(lèi),促進(jìn)胰島素分泌,格列酮類(lèi),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(lèi)：不同作用機(jī)制間的互補(bǔ)作用改善多重缺陷,糖尿病藥物治療問(wèn)題與失誤,Inzucchi 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(lèi),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

22、機(jī)制間的互補(bǔ)作用改善多重缺陷,糖尿病藥物治療問(wèn)題與失誤,Inzucchi 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,糖尿病藥物治療問(wèn)題與失誤,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,糖尿病藥物治療問(wèn)題與失誤,1.0,0.8,0.6,0.4,0.2,0.0,Mean change in HbA1c from bas

23、eline (,半量二甲雙胍羅格列酮與二甲雙胍加量的比較 (EMPIRE Study) HbA1c,Baseline HbA1c (%) n,7.95 313,8.05 322,MET 1 g/day + RSG 8 mg/day,Patients were treated for 24 weeks All patients were inadequately controlled on MET 1 g/day alone *Significant vs. baseline,MET 1 g/day + MET 1 g/day,Error bars = 95% CI,Rosenstock J,

24、et al. Diabetes 2004; 53 (Suppl. 2):A144145,0.63,0.82,糖尿病藥物治療問(wèn)題與失誤,N = 635 Patients were treated for 24 weeks All patients were inadequately controlled on MET 1 g/day alone *P 0.05 vs. MET 1 g/day + MET 1 g/day,Error bars = 95% CI,Rosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A144145,25.9,0,10,2

25、0,30,40,50,60,Patients achieving HbA1c goals (,AACE/IDF goal 6.5,ADA goal 7,MET 1 g/day + MET 1 g/day n = 313,MET 1 g/day + RSG 8 mg/day n = 322,38.5,45,55,半量二甲雙胍羅格列酮與二甲雙胍加量的比較 (EMPIRE Study) 達(dá)標(biāo)率,糖尿病藥物治療問(wèn)題與失誤,20,Geometric mean percent change from baseline in HOMA -cell function,Time (weeks,0,24,52,76,104,0,20,40,60,80,100,99,86,90,64,87,51,83,Error bars = SE,SU + RSG (up to 8 mg/day,SU加量 + PBO,羅格列