型糖尿病治疗新进展

1、会计学1型糖尿病治疗新进展型糖尿病治疗新进展胰岛素抵抗胰高糖素抑制不足细胞功能失调胃肠道吸收葡萄糖慢性细胞功能衰竭胰岛素分泌不足细胞功能异常DeFronzo RA. Br J Diabetes Vasc Dis,2003;3(Suppl 1): S24-40未解决未解决二甲双胍格列酮类磺脲类格列奈类-糖苷酶抑制剂Time, minControl Subjects (n=8)Time, minIR Insulin, mU/L80604020018060120 0Oral glucose loadIntravenous (IV) glucose infusion正常的肠促胰岛激素效应正常的肠促胰岛

2、激素效应IR = immunoreactiveAdapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T, Holst JJ. Diabetologia 2004;47:357366.GLP-1 = 胰高血糖素样肽1：GIP = 葡萄糖依赖性促胰岛素分泌多肽. 引自：Kieffer T. Endocrine Reviews. 1999;20：876913.版权所有 1999，The Endocrine Society. Druck

3、er DJ. Diabetes Care. 2003;26：29292940. Nauck MA et al. Diabetologia. 1993;36：741744. 经允许引自：Creutzfeldt W. Diabetologia. 1979;16：7585.版权所有 1979 Springer-Verlag. 13胰腺胰腺肠肠营养物质信号营养物质信号 葡萄糖葡萄糖激素信号激素信号 GLP-1 GIP胰高血糖胰高血糖素素（GLP-1） 胰岛素胰岛素 （GLP-1,GIP）神经信号神经信号 细胞细胞 细胞细胞GLP-1（胰高糖素样肽1）GIP（葡萄糖依赖性促胰岛素多肽）Adapted f

4、rom Drucker DJ Diabetes Care 2003;26:29292940; Ahrn B Curr Diab Rep 2003;3:365372; Drucker DJ Gastroenterology 2002;122:531544; Farilla L et al Endocrinology 2003;144:51495158; Trmper A et al Mol Endocrinol 2001;15:15591570; Trmper A et al J Endocrinol 2002;174:233246.葡萄糖葡萄糖胰高血糖素胰高血糖素当血糖水平达到正常值，胰高血糖

5、素水平即回升。当血糖水平达到正常值，胰岛素水平即下降。*P0.052型糖尿病患者（型糖尿病患者（N=10）mmol/L15.012.510.07.55.025020015010050mg/dL*pmol/L25020015010050403020100mU/L*注射注射时间时间pmol/L2015105060120180240*pmol/L2015105安慰剂安慰剂GLP-1胰岛素胰岛素2.500000引自：Nauck MA et al. Diabetologia. 1993;36：741744.版权所有 1993 Springer-Verlag.3015Time, minIR Insulin

6、, mU/L806040200180601200Control Subjects (n=8)Patients With Type 2 Diabetes (n=14)Time, minIR Insulin, mU/L80604020018060120 0Oral glucose loadIntravenous (IV) glucose infusion正常的肠促胰岛激素效应正常的肠促胰岛激素效应减弱的肠促胰岛激素效应减弱的肠促胰岛激素效应IR = immunoreactiveAdapted with permission from Nauck M et al. Diabetologia 1986

7、;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T, Holst JJ. Diabetologia 2004;47:357366.DPP-IV=dipeptidyl peptidase IVAdapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87100; Ahrn B Curr Diab Rep 2003;3:365372.肠道GLP-1释放无活性GLP-1 (9-36)进餐活性GLP-1 (7-36)DPP-4酶抑制剂DPP-4 酶 GLP-1 类似物活性肠促胰岛激素活性肠

8、促胰岛激素GLP-1和和GIP释放释放餐前及餐后餐前及餐后葡萄水平葡萄水平摄食摄食胰高血糖素胰高血糖素(GLP-1) 肝糖生成肝糖生成胃肠道DPP-4 酶酶失活的失活的GLP-1X西格列汀西格列汀(DPP-4 inhibitor)肠促胰岛激素GLP-1和GIP由肠道全天性释放，其水平在餐后升高胰岛素胰岛素(GLP-1& GIP) 葡萄糖依赖性的 葡萄糖依赖性的胰腺失活的失活的GIPGLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.西格列汀可升高活性肠促胰岛激素水平，从而增加和延

9、长其活性作用Beta cellsAlpha cells 外周组织对外周组织对葡萄的摄取葡萄的摄取DPP 4抑制剂DeFronzo RA. Br J Diabetes Vasc Dis,2003;3(Suppl 1): S24-40胰岛素抵抗胰高糖素抑制不足细胞功能失调胃肠道吸收葡萄糖慢性细胞功能衰竭胰岛素分泌不足细胞功能异常二甲双胍格列酮类磺脲类格列奈类-糖苷酶抑制剂 DPP-4 酶抑制剂酶抑制剂GLP-1类似物类似物作用机制作用机制抑制内源性肠促胰岛激抑制内源性肠促胰岛激素降解以增加其水平素降解以增加其水平合成肽，合成肽， 有类似肠促胰有类似肠促胰岛激素的作用岛激素的作用促进胰岛素分泌促进胰

10、岛素分泌+降低胰高血糖素降低胰高血糖素+恶心恶心/ 呕吐呕吐-+体重减轻体重减轻 +给药途径给药途径口服口服注射注射第第1天天GLP-1治疗的细胞治疗的细胞对照对照第第3天天第第5天天Adapted from Farilla L et al Endocrinology 2003;144:51495158.加入加入GLP-1培养的胰培养的胰岛细胞能够更长时间的岛细胞能够更长时间的保持其完整性保持其完整性. -细胞数量细胞数量 -细胞数量细胞数量MU, J et al. Diabetes, 2006; 55: 1695-1704HFD/STZ mice treated with Des-F-sit

11、agliptin for 11-weeks.Mu, J et al. Diabetes, 2006; 55: 1695-1704HFD/STZ mice treated with Des-F-sitagliptin for 11-weeks.Green insulin positive -cellRed glucagon positive -cellMu, J et al. Diabetes, 2006; 55: 1695-1704All-patients-treated population.HOMA- = homeostasis model assessment-.Adapted from

12、 Raz et al. Diabetologia. 2006;49:25642571. Adapted from Aschner et al. Diabetes Care. 2006;29:26322637.At Week 18(18-Week, Monotherapy, Placebo-Controlled Study)At Week 24 (24-Week, Monotherapy, Placebo-Controlled Study)MonotherapyBaseline: proinsulin-to-insulin ratio (sitagliptin + pioglitazone=0.

13、41 pmol/L/pmol/L; placebo + pioglitazone=0.40 pmol/L/pmol/L); HOMA- (sitagliptin=36.2%, placebo=39.6%).Add-onHOMA- = homeostasis model assessment-; LSM = least-squares mean. All-patients-treated population.Adapted from Charbonnel et al. Diabetes Care. 2006;29:26382643; Adapted from Rosenstock et al.

14、 Clin Ther. 2006;28:15561568.24周与二甲双胍联用研究24周与吡格列酮联用研究Baseline: Proinsulin-to-insulin ratio (sitagliptin = 0.357 pmol/L/pmol/L, placebo = 0.369 pmol/L/pmol/L), HOMA- (sitagliptin = 46.4%, placebo = 45.1%). Change from Baseline-5051015Baseline (pmol/L/pmol/L):Sitagliptin = 0.517; Placebo = 0.491p=n.s.

15、Sitagliptin Placebo Proinsulin/Insulin RatioBaseline :Sitagliptin = 50.7; Placebo = 47.4*p=0.021HOMA- *Adapted from Hermansen et al. Diabetes Obes Metab 2007;9:733-745-0.08-0.06-0.04-0.020.000.02Triple Combinationn1. 18周安慰剂对照研究2. 24周安慰剂对照研究3.3. 12 12周日本患者安慰剂对照研究周日本患者安慰剂对照研究4.4. 18 18周亚洲患者单药研究周亚洲患者单药

16、研究MonotherapyAdapted from Raz et al. Diabetologia. 2006;49:25642571Adapted from American Diabetes Association. From Diabetes Care, Vol. 29,2006; 26322637Adapted from Nonaka et al. Poster presented at the 66th Scientific Sessions, American Diabetes Association, Washington, DC, June 913, 2006.7.47.68.

17、08.4Placebo (n=244)Sitagliptin 100 mg (n=229)24-week StudyTime (weeks)06121824-0.79%(p0.001)Japanese 12-week Study-1.05%(p0.001)Placebo (n=75)Sitagliptin 100 mg (n=75)Time (weeks)048127.68.08.47.26.8Dchange vs. placebo* 18-week StudyPlacebo (n=74)Sitagliptin 100 mg (n=168)Time (weeks)0612187.27.68.0

18、8.4-0.6%(p0.001)=MonotherapyHbA1c (% SE)HbA1c (% SE)HbA1c (% SE)7.28.27.47.06.66.47.88.29.29.08.88.68.48.28.07.8061218Time, weeksMean SE Change in HbA1c, %FAS=full analysis set; qd=once a day; SE=standard error. Mohan V et al. Diabetes Res Clin Pract. 2009;83:106116.Sitagliptin 100 mg qd (n=339)Plac

19、ebo (n=169)Monotherapy-1.03%1. 与二甲双胍联用与二甲双胍联用24周安慰剂对照，与二甲双胍联合治疗研究2. 与二甲双胍联用与二甲双胍联用52周活性对照研究 （格列吡嗪），与二甲双胍联合治疗3. 与吡格列酮联用与吡格列酮联用24周安慰剂对照，与吡格列酮联合治疗研究 Add-on HbA1c (% SE)LSM change from baseline (for both groups): 0.67% 达到首要假设：达到首要假设：疗效非劣效于磺脲疗效非劣效于磺脲 LSM = least-squares mean.aSpecifically, glipizide; bsi

20、tagliptin (100 mg/day) with metformin (1500 mg/day); per-protocol population. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.52周西格列汀联合二甲双胍周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究格列吡嗪联合二甲双胍对照研究Weeks5.86.06.26.46.66.87.07.27.47.67.80612182430384652Sulfonylureaa + metformin (n=411)Sitagliptinb + metfo

21、rmin (n=382)Add-on 2aSpecifically, glipizide; bsitagliptin (100 mg/day) with metformin (1500 mg/day); per-protocol population.Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.Sulfonylurea + metforminBaseline HbA1C CategoryChange from baseline in HbA1c (%)n=117n=117112179167828233217%7 to

22、 8%8 to 9% 9%-0.14-0.59-1.11-1.76-0.26-0.53-1.13-1.68-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0Sitagliptinb + metforminAdd-on 2Patients at HbA1c goal (%)HbA1c7% at week 52*Specifically, glipizide. Per-protocol population. Mean baseline HbA1c levels: sitagliptin 100 mg, 7.48%; glipizide, 7.52%. Adap

23、ted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.n=240n=242Add-on 2Sulfonylurea + metformin (n=584)Sitagliptin 100 mg/day + metformin (n=588)HypoglycemiabP0.00132%5%01020304050Week 52低血糖发生率(%)LSM change in body weight over timeb体重 (kg SE)LSM = least-squares mean.aSpecifically, glipizide; bal

24、l-patients-treated population. LSM between-group difference at week 52 (95% CI): D in body weight = 2.5 kg 3.1, 2.0 (P0.001);LSM change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: 1.5 kg (P0.001).Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.Sulfonylurea + metformin (n=

25、416)Sitagliptin 100 mg/day + metformin (n=389)Add-on 2SitagliptinN=3145n (%)NonexposedN=2724 n (%)Between-Groups Difference,% (95% CI)a1次或多次临床不良事件2150 (63.0)1711 (62.8)0.1 (2.3, 2.6)药物相关临床不良事件b440 (12.9)483 (17.7)4.8 (6.7, 3.0)严重临床不良事件230 (6.7)184 (6.8)0.0 (1.3, 1.2)药物相关严重临床不良事件b8 (0.2)8 (0.3)0.1 (0

26、.4, 0.2)死亡， n (%)11 (0.3)16 (0.6)0.3 (0.7, 0.1)中止治疗, n (%)临床不良事件药物相关临床不良事件严重临床不良事件药物相关严重临床不良事件106 (3.1)30 (0.9)51 (1.5)4 (0.1)101 (3.7)40 (1.5)47 (1.7)4 (0.1)0.6 (1.5, 0.3)0.6 (1.2, 0.1)0.2 (0.9, 0.4)0.0 (0.3, 0.2)AE=adverse experience; CI=confidence interval.aPositive differences indicate that the

27、proportion for the sitagliptin group is higher than the proportion for the nonexposed group. “0.0” represents rounding for values that are slightly less than zero. bDetermined by the investigator to be possibly, probably, or definitely drug related. Williams-Herman D et al. BMC Endocr Disord. 2008;8

28、:14. Copyright BioMed Central. Pooled safety and tolerability analysisSitagliptin N=3415 n (%) Nonexposed N=2724n (%)Between-Groups Difference,% (95% CI)a任一组中3%的临床不良事件腹泻170 (5.0)144 (5.3)0.3 (1.4, 0.8)支气管炎 135 (4.0)83 (3.0)0.9 (0.0, 1.8)流感145 (4.2)127 (4.7)0.4 (1.5, 0.6)鼻咽炎244 (7.1)162 (5.9)1.2 (0.1

29、, 2.4)上呼吸道感染265 (7.8)228 (8.4)0.6 (2.0, 0.8)尿道感染134 (3.9)100 (3.7)0.3 (0.7, 1.2)低血糖b117 (3.4)296 (10.9)7.4 (8.8, 6.1)关节痛113 (3.3)92 (3.4)0.1 (1.0, 0.8)背痛142 (4.2)108 (4.0)0.2 (0.8, 1.2)头痛169 (4.9)129 (4.7)0.2 (0.9, 1.3)高血压110 (3.2)89 (3.3)0.0 (1.0, 0.8)aPositive differences indicate that the proport

30、ion for the sitagliptin group is higher than the proportion for the nonexposed group. “0.0” represents rounding for values that are slightly greater and slightly less than zero, respectively. bIncludes studies in which a sulfonylurea was an active comparator or a background agent. Williams-Herman D

31、et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysisSitagliptin N=3415n (%)Nonexposed N=2724 n (%)Between-Groups Difference,% (95% CI)a 任一组0.2%严重临床不良事件 冠心病5 (0.1)7 (0.3)0.1 (0.4, 0.1) 心肌梗塞4 (0.1)5 (0.2)0.1 (0.3, 0.1) 非心源性胸痛 4 (0.1)9 (0.3)0.2 (0.5, 0.

32、0) 胆结石6 (0.2)2 (0.1)0.1 (0.1, 0.3) 肺炎 4 (0.1)5 (0.2)0.1 (0.3, 0.1)aPositive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the nonexposed group. “0.0” represents rounding for values that are slightly greater than zero. Williams-Herman D et al. BM

33、C Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysisSitagliptin N=3415Nonexposed N=2724 作用机制可能导致的不良事件 胰腺炎, %0.10 急性胰腺炎, %00.1 慢性胰腺炎, % 0.10Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysis

34、Sitagliptin N=3415, %Nonexposed N=2724, %Between-Groups Difference, % (95% CI)a心血管相关不良事件 严重心血管不良事件1.21.50.13 (1.0, 0.3) 心肌缺血不良事件2.02.30.2 (1.0, 0.5) 严重心机缺血不良事件1.11.50.4 (1.0, 0.2)AEs=adverse experiences; CI=confidence interval; CV=cardiovascular.aPositive differences indicate that the proportion for

35、 the sitagliptin group is higher than the proportion for the nonexposed group. Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central.Pooled safety and tolerability analysisSitagliptin N=3415 n (%)Nonexposed N=2724 n (%)Between-Groups Difference, % (95% CI)a发生率1%的可能与免疫功能相关的临

36、床不良事件支气管炎 135 (4.0)83 (3.0)0.9 (0.0, 1.8)蜂窝织炎28 (0.8)26 (1.0)0.1 (0.6, 0.3)肠胃炎68 (2.0)48 (1.8)0.2 (0.5, 0.9)病毒性肠胃炎29 (0.8)27 (1.0)0.1 (0.7, 0.3)流感145 (4.2)127 (4.7)0.4 (1.5, 0.6)鼻咽炎244 (7.1)162 (5.9)1.2 (0.1, 2.4)咽炎52 (1.5)35 (1.3)0.2 (0.4, 0.8)鼻窦炎 80 (2.3)60 (2.2)0.1 (0.6, 0.9)上呼吸道感染265 (7.8)228 (8

37、.4)0.6 (2.0, 0.8)尿道感染134 (3.9)100 (3.7)0.3 (0.7, 1.2)病毒感染36 (1.1)21 (0.8)0.3 (0.2, 0.8)高血糖症34 (1.0)39 (1.4)0.4 (1.0, 0.1)咳嗽88 (2.6)73 (2.7)0.1 (0.9, 0.7)咽痛44 (1.3)34 (1.2)0.0 (0.5, 0.6)AEs=adverse experiences; CI=confidence interval.aPositive differences indicate that the proportion for the sitaglip

38、tin group is higher than the proportion for the nonexposed group.“0.0” and “0.0” represent rounding for values that are slightly greater and slightly less than zero, respectively. Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central.Pooled safety and tolerability analysisW

39、illiams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysis -细胞数量细胞数量 -细胞数量细胞数量MU, J et al. Diabetes, 2006; 55: 1695-1704HFD/STZ mice treated with Des-F-sitagliptin for 11-weeks.aSpecifically, glipizide; bsitagliptin (100 mg/day) with metfo

40、rmin (1500 mg/day); per-protocol population.Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.Sulfonylurea + metforminBaseline HbA1C CategoryChange from baseline in HbA1c (%)n=117n=117112179167828233217%7 to 8%8 to 9% 9%-0.14-0.59-1.11-1.76-0.26-0.53-1.13-1.68-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0Sitagliptinb + metforminAdd-on 2Sulfonylurea + metformin (n=584)Sit