捷诺维突破2型糖尿病治疗的新希望课件.ppt

1、捷诺维（西格列汀） 突破2型糖尿病治疗的新希望,概 述,2型糖尿病治疗现状及挑战 以肠促胰岛激素为基础的治疗 捷诺维（西格列汀）的临床数据 临床疗效 安全性,Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 1

2、6th ed. New York: McGraw-Hill, 2005:21522180; Rhodes CJ Science 2005;307:380384.,2型糖尿病的病理生理包括三方面主要缺陷,高血糖,肝脏,胰岛素不足,糖输出过多,胰岛素抵抗 (葡萄糖摄取减少),胰腺,肌肉和脂肪,过多胰高糖素,不同降糖药的主要作用部位,Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:14271483; DeFronzo RA. Ann Intern Med.

3、1999;131:281303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247254.,DPP-4=二肽基肽酶 4; TZDs=噻唑烷二酮类.,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,2型糖尿病现有治疗选择,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,DP

4、P-4抑制剂：2型糖尿病治疗新选择,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,成人2型糖尿病患者HbA1c 达标的比例不足50%,NHANES=美国人群的一项全国健康营养检查调查. Saydah SH et al. JAMA. 2004;291:335342.,中国2型糖尿病患者 HbA1c 达标率,中国糖尿病健康管理调查

5、2004 华北、华南、华东、华西和东北5 个地区49 家市级中心医院 参与分析的患者 2248 例,中国糖尿病健康管理调查 2006 中国18个城市60家医院登记治疗超过12个月的糖尿病患者 参与分析的患者 2779 例,DiabCare Study 2006, Data on file,潘长玉等中华内分泌代谢杂志20:420-424,2004,达标率（%）,25.9%,29.5%,44.6%,0,10%,20%,30%,40%,50%,6.5%, 7.5%,7.5%,达标率（%）,25%,35%,0,10%,20%,30%,40%,50%,6.5%, 7.0%,7.5%,40%,平均HbA1

6、c：7.6%,平均HbA1c：7.7%,副作用的增加和依从性的降低是治疗的两大潜在障碍,美国社区单中心. N=128 2型糖尿病患者 Grant RW et al. Diabetes Care. 2003;26:14081412.,大部分与不依从相关的 常见因素,United States study; Medi-Cal claims data January 1996 through September 1998.Compliance was defined as total days of drug supply (measured by number of doses prescribe

7、d) during the follow-up period; compliance rate was calculated by dividingthe number of compliance days by the number of days in the follow-up period. Dailey G et al. Clin Ther. 2001;23:13111320.,二甲双胍 (n=2,996),磺脲类 (n=21,987),二甲双胍磺脲类 联合治疗 (n=1,354),多药治疗降低 患者依从性,不良反应,花费,非特异,记住药物剂量困难,概 述,2型糖尿病治疗现状及挑战

8、以肠促胰岛激素为基础的治疗 捷诺维（西格列汀）的临床数据 临床疗效 安全性,Time, min,Control Subjects (n=8),Time, min,IR Insulin, mU/L,180,60,120,0,Oral glucose load,Intravenous (IV) glucose infusion,正常的肠促胰岛激素效应,IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vi

9、lsbll T, Holst JJ. Diabetologia 2004;47:357366.,正常个体的肠促胰岛激素效应,肠促胰岛激素GLP-1和GIP的作用,由远端消化道L细胞分泌 (回肠和结肠) 以葡萄糖依赖的模式促进胰岛素释放 以葡萄糖依赖的模式抑制胰高糖素分泌，从而抑制肝糖输出 在动物模型及离体人类胰岛中增强beta细胞增殖和存活,由近端消化道K细胞分泌（十二指肠） 以葡萄糖依赖的模式促进胰岛素释放在胰岛细胞系中增强beta细胞增殖和存活,GLP-1,GIP,GLP-1=胰高糖素样肽 1; GIP=葡萄糖依赖性促胰岛素多肽 Adapted from Drucker DJ Diabet

10、es 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.,Time, min,IR Insulin, mU/L,180,60,120,0,Control Su

11、bjects (n=8),Patients With Type 2 Diabetes (n=14),Time, min,IR Insulin, mU/L,180,60,120,0,Oral glucose load,Intravenous (IV) glucose infusion,正常的肠促胰岛激素效应,减弱的肠促胰岛激素效应,IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T,

12、Holst JJ. Diabetologia 2004;47:357366.,2型糖尿病患者的肠促胰岛激素效应减弱,2型糖尿病患者的GLP-1和GIP水平及活性,*经过性别及BMI校正 Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:37173723; Nauck MA et al J Clin Invest 1993;91:301307.,以肠促胰岛激素为基础的治疗: 作用机制,DPP-IV=dipeptidyl peptidase IV Adapted from Drucker DJ Expert Op

13、in 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 抑制剂,DPP-4,GLP-1 类似物,二肽基肽酶 4 (DPP-4),Adapted from Evans DM IDrugs 2002;5:577585; Drucker DJ Expert Opin Investig Drugs 2003;12:87100; Rasmussen HB et al Nat Struct Biol 2003;10:

14、1925.,DPP-4 是一种prolyl oligopeptidase enzyme 家族的丝氨酸蛋白酶，它有两种存在形式 膜结合 (广泛表达) 溶解,细胞膜,细胞质,N,N,C,C,DPP-4抑制剂捷诺维(西格列汀)的作用机制,活性肠促胰岛激素 GLP-1和GIP释放,餐前及 餐后葡萄糖水平,摄食,胰高血糖素 (GLP-1), 肝糖生成,胃肠道,DPP-4 酶,失活的 GLP-1,X,捷诺维 (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 (GLP-1& GIP), 葡萄糖依赖性的, 葡萄糖依赖性的,胰腺,失活的 GIP,GLP

15、-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，从而增加和延长其活性作用,Beta cellsAlpha cells, 外周组织对 葡萄的摄取,DPP-4 抑制剂与GLP-1类似物的差异,DPP- 4抑制剂获批概况,捷诺维（西格列汀）是全球第一个上市的DPP-4抑制剂,捷诺维(西格列汀)高度选择性阻断DPP-4酶,西格列汀强效阻断DPP-4酶 高亲和力 对DPP-4的高选择性: 2500倍 vs. DPP-8或9 可逆性竞争性,ThornberryNA

16、，et al. Curr Topics in Med Chem, 2007; 7: 557-568,口服西格列汀100mg和600mg的峰浓度是747nM和7000nM可有效抑制DPP-4显著低于抑制DPP-8和DPP-9所需浓度,高度选择性保证了捷诺维无动物毒性反应,1. Leiting B et al. Presented at 64th Scientific Sessions of the American Diabetes Association; 2004. Abstract 6-OR. 2. Lankas GK et al. Diabetes. 2005;54:29882994.,

17、捷诺维(西格列汀)给药24小时后 有效抑制血浆DPP- 4活性达80%,给药后时间（小时）,80%,50%,对DPP-4的抑制,与基线相比对血浆DPP-4的抑制程度 (%),0,1,2,4,8,12,16,20,24,10,0,40,50,60,80,100,90,70,30,20,10,6,10,14,18,22,26,OGTT,西格列汀 25 mg (n=56) 西格列汀 200 mg (n=56) 安慰剂(n=56),Herman GA, et al. J Clin Endocrinol Metab 2006; 91: 4612-4619,GLP-1 在体外保护人胰岛细胞形态,第1天,G

18、LP-1治疗的细胞,对照,第3天,第5天,Adapted from Farilla L et al Endocrinology 2003;144:51495158.,加入GLP-1培养的胰岛细胞能够更长时间的保持其完整性.,捷诺维(西格列汀)使细胞与细胞比例正常,Mu, J et al. Diabetes, 2006; 55: 1695-1704,HFD/STZ mice treated with Des-F-sitagliptin for 11-weeks. Green insulin positive b-cell Red glucagon positive a-cell,捷诺维(西格列汀

19、)改善胰岛功能(离体胰腺),Mu, J et al. Diabetes, 2006; 55: 1695-1704,捷诺维(西格列汀)有效改善胰腺细胞功能,动物实验研究结果西格列汀 增加-细胞数量，使细胞与细胞比例正常 增加胰岛素阳性细胞数量 增加胰腺内胰岛素含量 改善葡萄糖刺激后胰岛素分泌（离体胰腺）,Mu, J et al. Diabetes, 2006; 55: 1695-1704,概 述,2型糖尿病治疗现状及挑战 以肠促胰岛激素为基础的治疗 捷诺维（西格列汀）的临床数据 临床疗效 安全性,捷诺维(西格列汀) III期临床研究评估主要临床终点,降糖疗效: 单药治疗 与其他降糖药物联合细胞功

20、能 HOMA - 胰岛素原/胰岛素比值安全性/耐受性 临床不良事件 体重改变 低血糖发生率 实验室不良事件,HbA1c (所有研究主要终点)FPGPPGHbA1c（7%或6.5%)达标率,捷诺维(西格列汀) III期临床研究汇总,单药治疗 18周安慰剂对照研究 24周安慰剂对照研究 12周日本人群安慰剂对照研究 18周亚洲人群单药研究（PN 040） 与其它降糖药物联用 与二甲双胍联用 24周与二甲双胍联合治疗研究 52周与二甲双胍联合治疗活性对照研究 24周与吡格列酮联合治疗研究 起始联合治疗 二甲双胍和西格列汀对肠促胰岛激素的作用 二甲双胍/西格列汀起始联合治疗 三联治疗 52周与磺脲或磺

21、脲加二甲双胍联合治疗,Adapted from Raz et al. Diabetologia. 2006;49:25642571 Adapted from American Diabetes Association. From Diabetes Care, Vol. 29,2006; 26322637 Adapted from Nonaka et al. Poster presented at the 66th Scientific Sessions, American Diabetes Association, Washington, DC, June 913, 2006.,7.4,7.6

22、,8.0,8.4,Placebo (n=244) Sitagliptin 100 mg (n=229),24-week Study,Time (weeks),0,6,12,18,24,-0.79% (p0.001),Japanese 12-week Study,-1.05% (p0.001),Placebo (n=75) Sitagliptin 100 mg (n=75),Time (weeks),0,4,8,12,change vs. placebo*,18-week Study,Placebo (n=74) Sitagliptin 100 mg (n=168),Time (weeks),0

23、,6,12,18,7.2,7.6,8.0,8.4,-0.6% (p0.001),=,捷诺维一天一次单药治疗持续显著降低HbA1C,Monotherapy,HbA1c (% SE),HbA1c (% SE),HbA1c (% SE),7.2,8.2,7.4,7.0,6.6,6.4,7.8,8.2,捷诺维在亚洲人群(中国、印度、韩国)降糖效果显著 HbA1c 从基线的改变 (FAS Population),9.2,9.0,8.8,8.6,8.4,8.2,8.0,7.8,0,6,12,18,Time, weeks,Mean SE Change in HbA1c, %,FAS=full analysi

24、s 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),Placebo (n=169),Monotherapy,-1.03%,Screening,Single-blind placebo,Double-blind treatment period: Sulfonylurea or sitagliptin 100 mg/day,Metformin monotherapy,Week 2: Eligibl

25、e if HbA1c 6.5% to 10%,If on an OHA, D/C Continue/start metformin,Day 1 Randomization,Week 52,D/C = discontinued; OHA = oral antihyperglycemic agent; T2DM = type 2 diabetes. *Specifically, glipizide 5 mg/day increased to 20 mg/day (dose not uptitrated if finger stick 110 mg/dL or hypoglycemia).Adapt

26、ed from Nauck et al. Diabetes Obes Metab. 2007;9:194205.,52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 研究设计,2型糖尿病患者随机，双盲，平行，活性对照，非劣效性研究 (N=1172) 治疗 西格列汀100 mg/day，二甲双胍1500 mg/day 磺脲* 最大剂量20 mg/day，二甲双胍 1500 mg/day,Metformin (stable dose 1500 mg/day),Add-on 2,HbA1c (% SE),LSM change from baseline (for both groups):

27、0.67%,达到首要假设： 疗效非劣效于磺脲,LSM = least-squares mean. aSpecifically, glipizide; bsitagliptin (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vs格列吡嗪联合二甲双胍对照研究 与二甲双胍联用时， 捷诺维一天一次降糖效果不低于磺脲类(52周),Weeks,5.8,6.0,6.2,6.

28、4,6.6,6.8,7.0,7.2,7.4,7.6,7.8,0,6,12,18,24,30,38,46,52,Sulfonylureaa + metformin (n=411),Sitagliptinb + metformin (n=382),Add-on 2,aSpecifically, glipizide; bsitagliptin (100 mg/day) with metformin (1500 mg/day); per-protocol population. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.,

29、Sulfonylurea + metformin,Baseline HbA1C Category,Change from baseline in HbA1c (%),n=117,n=117,112,179,167,82,82,33,21,7%,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,-0.2,0.0,Sitagliptinb + metformin,52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 基值

30、越高，HbA1c 降幅越大,Add-on 2,Patients at HbA1c goal (%),HbA1c7% at week 52,*Specifically, glipizide.Per-protocol population.Mean baseline HbA1c levels: sitagliptin 100 mg, 7.48%; glipizide, 7.52%.Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.,n=240,n=242,52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 捷诺维联合二

31、甲双胍组更多的患者达到血糖控制目标,Add-on 2,52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 捷诺维组体重下降且低血糖发生率显著低于对照组,Sulfonylurea + metformin (n=584),Sitagliptin 100 mg/day + metformin (n=588),Hypoglycemiab,LSM change in body weight over timeb,体重 (kg SE),LSM = least-squares mean. aSpecifically, glipizide; ball-patients-treated populati

32、on. LSM between-group difference at week 52 (95% CI): 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=416) Sitagliptin 100 mg/day

33、 + metformin (n=389),Add-on 2,bid=twice daily; qd=daily; R=randomization. Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583.,Week 2,Day 1,Single-Blind Placebo Run-In Period,Eligible if HbA1c 7.5%11%,Week 24,R,研究设计,Week 54,24-Week (Phase A),30-Week Continuation Phase,Initial Combination,西

34、格列汀与二甲双胍起始联合治疗 HbA1c 24周时自基线的改变,aLeast squares mean change from baseline with adjustment for placebo. bWithin-group mean change from baseline. bid=twice daily; qd=daily. Goldstein B et al. Diabetes Care. 2007;30:19791987. Please note: Dr. Goldstein is currently a Merck employee but was not at the ti

35、me this study was conducted or when the publication was written.,Metformin 1000 mg bid,Sitagliptin 100 mg qd,Sitagliptin 50 mg + metformin 500 mg bid,Metformin 500 mg bid,Sitagliptin 50 mg + metformin 1000 mg bid,HbA1c Change From Baseline, %,3.5,3.0,2.5,2.0,1.5,1.0,0.5,0.0,0.5,178,177,183,178,175,n

36、=,0.8a,1.0a,1.3a,1.6a,2.1a,24-Week Placebo-Adjusted Results Mean HbA1c = 8.8%,Open-Label Mean Change From Baseline Mean HbA1c= 11.2%,All-Patients-Treated Population,HbA1c change from baseline at week 24 for placebo group (n=165) = 0.17%,Initial Combination,西格列汀与二甲双胍起始联合治疗 54周时改善细胞功能指标,Sita 50 mg + m

37、et 1000 mg bid,Sita 50 mg + met 500 mg bid,Met 1000 mg bid,Met 500 mg bid,Sita 100 mg qd,n=88,n=102,n=126,n=133,n=143,n=61,n=75,n=114,n=100,n=130,Proinsulin-to-Insulin Ratio,n=88,n=102,n=126,n=133,n=143,HOMA- Change,bid=twice daily; HOMA=homeostasis model assessment; LSM=least-squares mean; met=metf

38、ormin; qd=daily; Sita=sitagliptin. Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583.,Continuation All-Patients-Treated Population,Initial Combination,西格列汀与二甲双胍起始联合治疗 54周内持续降低HbA1c,Sita 50 mg + met 1000 mg bid (n=153),Met 1000 mg bid (n=134),Sita 100 mg qd (n=106),Sita 50 mg + met 500 mg

39、 bid (n=147),Met 500 mg bid (n=117),APT=all-patients-treated; bid=twice daily; LSM=least-squares mean; Met=metformin; qd=daily; Sita=sitagliptin. Reproduced with permission from Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583.,24-Week (Phase A),30-Week Continuation Phase,Mean SE Change

40、 in HbA1c, %,6.0,6.5,7.0,7.5,8.0,8.5,9.0,0,6,12,18,24,30,38,46,54,Weeks,Continuation All-Patients-Treated Population,Initial Combination,0 6 12 18 24 30 38 46 54 62 70 78 91 104,6,6.5,7,7.5,8,8.5,9,*Completers population Sita = sitagliptin; Met = metformin,西格列汀与二甲双胍起始联合治疗 持续2年降低HbA1c,Time (weeks),24

41、-Week Phase,Continuation Phase,Extension Phase,HbA1c (LS mean change %),2008 EASD,Initial Combination,捷诺维联合格列吡嗪或格列吡嗪/二甲双胍,*=Pioglitazone 30 mg QD,入选病例： 441例随机化病例，平均56岁， 53% 男性 糖尿病平均病程为8.8年，平均基线 A1C = 8.34%,Add-on to SU,Triple Combination,各组A1c自基线的改变 Placebo-controlled Add-on to Glimepiride (+/- metf

42、ormin) Study,*Difference in LS Mean change from baseline,Weeks,A1C (%),Adapted from Hermansen et al. Diabetes Obes Metab 2007;9:733-745,Mean duration of T2DM: 8.8 years,Triple Combination,Baseline (pmol/L/pmol/L): Sitagliptin = 0.517; Placebo = 0.491 p=n.s.,三联治疗中捷诺维改善细胞功能指标,Sitagliptin,Placebo,Proin

43、sulin/Insulin Ratio,Baseline : Sitagliptin = 50.7; Placebo = 47.4 *p=0.021,HOMA-b,*,Adapted from Hermansen et al. Diabetes Obes Metab 2007;9:733-745,-0.08,-0.06,-0.04,-0.02,0.00,0.02,Triple Combination,联合治疗中捷诺维改善细胞功能指标,Baseline: proinsulin-to-insulin ratio (sitagliptin + pioglitazone=0.41 pmol/L/pmo

44、l/L; placebo + pioglitazone=0.40 pmol/L/pmol/L); HOMA- (sitagliptin=36.2%, placebo=39.6%).,Add-on,HOMA- = 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. Clin Ther

45、. 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%).,单药治疗中捷诺维显著改善细胞功能指标,All-patients-treated population. HOMA- = homeostasis model assessment-. Adapted fro

46、m 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),Monotherapy,捷诺维(西格列汀)治疗组与非西格列汀治疗组间 总体不良事件相似,Pooled safety and tolerability analysis,任一组发生的3%的临床不良事件,Pooled safety and tolerability analysis,安全性荟萃分析： 可能与免疫功能相关的临床不良事件,Pooled safety and tolerability analysis,安全性分析总结,捷诺维(西格列汀)用于2型糖尿病患者治疗，总体耐受性良好 单药治疗 起始联合治疗 联合治疗 捷诺维(西格列汀)的安全性监测还在持续进行,