最新沙格列汀的作用機制精品課件教學(xué)提綱

1、沙格列汀的作用機制腸促胰島激素簡史1902-首次觀察到藏到對胰島分泌的影響1,21932-首次確定腸促胰島素31964-證實倉促胰島素效應(yīng)1,4,51966-首次描述DPP-4 61973-GIP被確定為一種人類長促胰島素11986-證實了長促胰島素在2型糖尿病患者中的作用71995-DPP-4被確定為一種滅活GIP和GLP-1的酶 9,101987-GLP-1被確定為一種人類長促胰島素Creutzfeldt W. Regul Pept. 2005; 128:87-91.Bayliss WM et al. J Phystol. 1902;28:325-353.La Barre J. Bull

2、Acad R. Med Belg. 1932;120:620-634.McIntyre N et al. Lancet. 1964;41:20-21.Elrick H et al. J Clin Endocr. 1964;24:1076-1082.Hopsu-Havu VK, Glenner GG. Histochemle. 1966;7(3):197-201.Nauck M et al. Diabetologia. 1986;29:46-52.Kreymann B et al. Lancet. 1987;2:1300-1304.Kieffer TJ et al. Endocrinology.

3、 1995;136;3385-3596.Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952-957.GLP-1和GIP 是兩類主要的腸促胰素GLP-1（胰高糖素樣肽-1）GIP（葡萄糖依賴的促胰島素釋放多肽）主要合成部位L 細(xì)胞(回腸和結(jié)腸)K 細(xì)胞 (十二指腸和空腸) 2型糖尿病患者中分泌是否 餐后胰高糖素是否 食物攝入是 否延緩胃排空是 否促進細(xì)胞增殖是是促進胰島素生物合成是是Drucker DJ. Diabetes Care. 2003;26:2929-2940.The Incretin Effect is Reduced in T

4、ype 2 DiabetesAdapted from Nauck M, et al. Diabetologia. 1986;29:46-52. Oral glucose (50g)IV glucose (variable)Responses to an oral glucose load of 50 g and intravenous glucose infusion were measured in 14 type 2 diabetic patients and 8 healthy control subjects. Responses to glucose load in type 2 d

5、iabetics and healthy subjectsControl subjects (N=8)Type 2 diabetic patients (N=14)Oral glucose (50g)IV glucose (variable)Venous plasma glucose (mmol/l)Time (min)Time (min)010151201800160051015512018001600202Venous immunoreactiveinsulin (mU/l)(nmol/l)020406080020406080000.10.30.40.60.50.20.10.30.40.6

6、0.50.2*Venous plasma glucose (mmol/l)*P0.05 to the respective value after the oral loadTime (min)Time (min)120180601201806002020101(nmol/l)Venous immunoreactiveinsulin (mU/l)Incretin hormone changesIn patients with type 2 diabetes, levels of GLP-1 released in response to glucose are reduced and GIP

7、activity is decreasedContinuous Infusion of GLP-1 Decreases Fasting Glucose as well as HbA1cAdapted from Zander M, et al. Lancet. 2002;359(9309):824-30. Compared to saline, patients treated with GLP-1 showed fasting and 8-hour mean plasma glucose that was decreased by 4.3 mmol/l and 5.5 mmol/l (P0.0

8、001), and HbA1c that was decreased by 1.3% (P=0.003)Patients assigned saline (N=9)Patients assigned GLP-1 (N=10)Glucose concentration in plasma (mmol/L)008246082462520151050252015105Week 0Week 1Week 6Time (hr)Time (hr)Glucose concentration in plasma (mmol/L)Exogenous GlucoseDependent Insulinotropic

9、Polypeptide Worsens Postprandial Hyperglycaemia in Type 2 DiabetesAdapted from Chia CW, et al. Diabetes. 2009;58(6):1342-9.GIP given at supraphysiological levels still has an early,short-lived insulinotropic effect in type 2 diabetesTime (min)GIPPlacebo455256528018038080-20Insulin (mg/mL)Glucose (mg

10、/dL)45525656040200Time (min)19011015023028018038080-201401902406040200When compared with placebo, exogenous GIP infusion not only did not lower postprandial glucose but further worsened hyperglycaemia during late postprandial period (120360 min) in patients with type 2 diabetes (N=22)Changes in insu

11、linChanges in glucose*P0.05 vs placebo在2型糖尿病的治療中，針對GLP-1的藥物更有價值u腸促胰島素的效應(yīng)在2型糖尿病患者中減弱u在2型糖尿病患者中GIP水平正常甚至略微升高，但其作用很小-GIP抵抗GIP的促胰島素分泌作用的減弱可能是遺傳因素和環(huán)境因素共同作用引起的u2型糖尿病患者中，GLP-1水平降低，但其作用未受損 開發(fā)提高GLP-1 水平的藥物具有重要的臨床意義Nauck.MA et al.J Clin Invest 1993,91:301-307Sites of Action of GLP-1BrainGlucose productionNeur

12、oprotectionAppetiteLiverStomachGastric emptyingGI tractInsulin biosynthesis-cell proliferation-cell apoptosisInsulin secretionGlucagon secretionMuscleHeartCardioprotectionCardiac outputInsulinsensitivityAdapted from Drucker DJ. Cell Metab. 2006;3:153-65.PancreasGLP-1在人體的作用促進飽腹感，降低食欲細(xì)胞: 餐后胰高血糖素分泌肝臟:

13、胰高血糖素減少肝糖輸出胃:有助于調(diào)節(jié)胃排空細(xì)胞:促進血糖依賴性胰島素分泌進食后，小腸開始分泌GLP-1Adapted from: Flint A, et al. J Clin Invest. 1998;101:515-20. Holst JJ. TEM. 2005;10:229-35. Lovshin JA, Drucker DJ. Nat Rev Endocrinol. 2009;5:262-9.細(xì)胞 工作負(fù)荷細(xì)胞 反應(yīng)胰高血糖素樣肽-1 (GLP-1)進食后由腸道L細(xì)胞分泌 GLP-1在進食后數(shù)分鐘內(nèi)開始分泌，對食物中脂類和碳水化合物的反應(yīng)最為明顯Kieffer TJ, et al. En

14、docr Rev. 1999;20:876-913 Drucker DJ. Curr Pharm Des. 2001;7:1399-412. Drucker DJ. Mol Endocrinol. 2003;17:161-71. 在人體和動物體內(nèi)在動物體內(nèi)和體外研究中促進葡萄糖刺激的胰島素分泌抑制胰高血糖素的釋放延緩胃排空減少食物的攝入量 增強胰島素基因的轉(zhuǎn)錄可能通過以下途徑增加 細(xì)胞數(shù)量 - 刺激新生細(xì)胞的形成 - 抑制細(xì)胞凋亡uGLP-1通過其受體（GLP-1R）發(fā)揮作用GLP-1R在胰島細(xì)胞上表達(dá)，受刺激后，可激活cAMP，以及蛋白激酶A依賴性或非依賴性的作用2型糖尿病 (n=10)Ad

15、apted from: Nauck MA, et al. Diabetologia. 1993;36:741-4.-30060120180240270180900安慰劑 * * * * * *GLP-1葡萄糖 (mg/dL)安慰劑GLPGLP-1安慰劑-30060120180240胰島素 (pmol/L)20100*GLP-1安慰劑-30060120180240胰高血糖素 (pmol/L)時間 (分鐘)平均值(SE); *P0.05GLP-1以葡萄糖依賴性方式增加胰島素的分泌T2DM中胰島細(xì)胞對葡萄糖的敏感性降低AGRarg= 2-5分鐘對精氨酸的平均急性胰高糖素反應(yīng)

16、；PG50 = 對AGRarg的抑制達(dá)最大值的一半時所需的血糖水平T2DM = 2型糖尿病; * 健康者平均年齡 1829歲 NGT* (n = 8)T2DM (n = 8)180 -150 -120 - 90 - 60 - 30 -0100200300400500600700AGRarg (pg/mL) 血糖水平 (mg/dL) PG50Ward WK, et al. J Clin Invest. 1984;74:13181328. Dunning B, et al. Diabetologia. 2005;48:17001713 糖尿病前期胰高糖素異常J J Holst, Diabetolo

17、gia (2009) 52:17141723Bo Ahren, European Journal of Endocrinology (1997) 137 127131糖尿病前期狀態(tài)的病理生理學(xué)胰高血糖素受體敲除小鼠血糖水平降低70010001600200024000.02.55.07.510.0*Time of DayBlood Glucose(mM)GR-/-GR+/+RW Gelling et al. PNAS 100: 1438-1443, 2003血糖 (隨意飼養(yǎng))血糖時間 (天)T2DM是胰島素分泌不足和胰高糖素分泌增加致高血糖 Mller WA, et al. N Engl J M

18、ed. 1970;283:109115碳水化合物膳食胰高糖素時間 (分鐘)7510012515060060120180240pg/mL胰島素050100150U/mL0血糖100200300400mg/dL正常葡萄糖耐量2型糖尿病正常葡萄糖耐量2型糖尿病正常葡萄糖耐量2型糖尿病GLP-1降低1型糖尿病患者的胰高糖素和血糖水平Creutzfeldt WO, et al. Diabetes Care. 1996;19:580-6. *GLP-1P .001PlaceboGLP-1 or PlaceboPlaceboGLP-1P .001 *GLP-1 or PlaceboGLP-1抑制胰高糖素分泌

19、并非由胰島素介導(dǎo)uGLP-1抑制胰島 細(xì)胞功能無殘留的1型糖尿病患者的胰高血糖素分泌u在2型糖尿病中，在不足以導(dǎo)致可測出胰島素分泌的血糖水平下，GLP-1能抑制胰高血糖素的分泌l沒有證據(jù)顯示其他非腸促胰素類降糖藥物對人胰高糖素分泌起作用Jesper Gromada Endocrine Reviews 28 (1): 84116GLP-1在體內(nèi)快速降解1 2 330GLP-1 Des-HA-GLP-1 (失活)GLP-1被二肽基肽酶-4（DPP-4）降解失活半衰期1-2分鐘1 23 30DPP-4提高 GLP-1作用的治療方法:模擬 GLP-1作用的藥物 (腸促胰島素類似物) 1)DPP-4 酶

20、抑制劑Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994 DPP4抑制劑作用機理食物攝入胃胃腸道腸增加和延長GLP-1對細(xì)胞的影響:細(xì)胞：胰腺胰島素釋放凈效應(yīng)： 血糖細(xì)胞:增加和延長GLP-1和GIP對細(xì)胞的作用：DPP4抑制劑胰高血糖素分泌Drucker和Nauck, 2006; Idris和Donnelly, 2007; Barnett, 2006腸促胰島素臨床藥效學(xué):穩(wěn)定狀態(tài)下，血漿中不同劑量的DPP-4 活性CV181002 (MAD in T2DM), data are means-100-

21、80-60-40-2002004812162024Time post-dose (h)Plasma DPP4 activity (% change from baseline) .Placebo (n=7)2.5 mg (n=6)5 mg (n=5)血 漿 DPP4 活 性 ( 自基線的變化% )DPP-4抑制劑沙格列汀具有雙重作用機制DPP-4抑制劑沙格列汀Br J Diabetes Vase Dis 2010; 10:14-20b-Cell Stimulation by Saxagliptin in Patients with T2DStudy schemaSAXA: saxaglipti

22、n; PBO, placebo; BMI: body mass index; T2D: type 2 diabetes.n=156n=46SAXA5 mgPBOScreeningSingle-blind lead-in2 weeksDouble-blindtreatment12 weeksInclusion Treatment nave T2D 18-70 years old HbA1c 6-8% BMI 40 kg/m2 Fasting C-peptide1 ng/mLDiet & exerciseplaceboSubjects wereprovided with: Meters t

23、omonitor glucose Blood glucose self-monitoring instructionn=20n=16RandomisationAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101入選標(biāo)準(zhǔn)u2型糖尿病病人u篩選訪視時，糖化血紅蛋白 6.0% 和 8.0%u空腹 C-肽 濃度 1.0 ng/mLu未服用藥物的患者uBMI 40 kg/m2u男性 和 女性, 18 和 70 歲.女性必須是不在哺乳期和妊娠期Sourc

24、e: CV181041 3.3.1研究 041有效性終點u主要有效性終點主要有效性終點是在腸內(nèi)給糖的高糖鉗夾試驗中靜脈-口服高糖鉗夾試驗，180-480分鐘 ，胰島素分泌率曲線下面積在12周時自基線變化的百分比。如果沒有12周的測量值，將采用12周前基線后的最后一次測量值。u次要有效性終點次要有效性終點是在靜脈高糖鉗夾試驗中（120-180分鐘），胰島素分泌率曲線下面積在12周時自基線變化的百分比。如果沒有12周的測量值，將采用12周前基線后的最后一次測量值。Source: CV181041 3.5.1.1研究 041b-Cell Stimulation by Saxagliptin in P

25、atients with T2DMethodsSAXA: saxagliptin; PBO: placebo; IV: intravenous.* Glucose infusion to achieve and maintain hyperglycaemia = 280 mg/dL from 0 - 480 min. At 480 min, infusion adjusted to maintain hyperglycaemia = 450 mg/dL. Arginine 5 g (10% solution, 50 mL IV over 30 sec) administered at 505

26、min. Samples drawn at protocol-specified intervals.Sequential IV-Oral hyperglycaemic clamp and arginine stimulation testPlasma glucose (mg/dL)4001005052004503002804805151801200-30Time (min)75 g oralglucosechallengeStartglucoseinfusion*SAXAorPBOIV hyperglycaemic clampIV-Oral hyperglycaemic clampArgin

27、inestimulation testSamplesGlucoseInsulinGlucagonGLP-1GIP0Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.T2D: type 2 diabetes422HQ09NP101基線和12周(LOCF)時，高糖鉗夾試驗中，在空腹（0-180分鐘）和OGTT后（180-480分鐘）狀態(tài)的胰島素分泌率Source: CV181041 Figure 7.1 (App. 5.3.4)研究 041胰島素分泌率平均值 (pmo

28、l/kg*min)分鐘胰島素分泌率平均值 (pmol/kg*min)分鐘10沙格列汀 5mg安慰劑10主要和次要有效性終點Source: CV181041 Table 7.1研究 041有效性終點( 12 周)沙格列汀 5 mgn = 20安慰劑n = 16靜脈-口服鉗夾試驗中胰島素分泌(pmol/kg) (180 - 480 分鐘) 病例數(shù)1615 基線平均值(SE)2817.73687.0 12 周 LOCF平均值3303.13564.3 校正后自基線的幾何平均值的變化%a15.9-2.2 校正后與安慰劑的差異% b18.5 與安慰劑對照的P-值*0.0350*靜脈鉗夾試驗中胰島素分泌(p

29、mol/kg) (120 - 180分鐘) 病例數(shù)1815 基線幾何平均值446.3593.5 24周 LOCF幾何平均值552.1563.1 校正后自基線的幾何平均值的變化% a22.6-4.1 校正后與安慰劑的區(qū)別% b27.9 與安慰劑對照的P-值*0.0204*估值 = 100* exp(校正后自基線的自然對數(shù)平均值的變化) -1估值= 100*exp (校正后沙格列汀5mg 和安慰劑間自然對數(shù)平均值變化的差異)-1在alpha=0.05水平有意義時，比較沙格列汀5mg 和安慰劑b-Cell Stimulation by Saxagliptin in Patients with T2D

30、Insulin secretion rates in the postprandial stateSAXA 5 mg (n=16)PBO (n=15)30-101020Geometric mean % changefrom baseline-200-* Values are geometric means; Adjusted % change from baseline, geometric mean and 95% CI (represented by bar)SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last

31、observation carried forward.-2.2-12.49.315.94.229.0Insulin secretion rate during IV-Oral hyperglycaemic clamp:adjusted % change from baseline at Week 12 (LOCF)Insulin secretion rate (pmol/kg)*Baseline28183687Week 12 (LOCF)33033564Adjusted % difference PBO (95% CI):18.5 (1.3, 38.7)P=0.035Adapted from

32、 Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101b-Cell Stimulation by Saxagliptin in Patients with T2DInsulin secretion rates in the fasting state40-101020-200-* Values are geometric means; Adjusted % change from baseline, geometric mean and 95% CI (represe

33、nted by bar)SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.-4.1-17.411.222.67.240.4Insulin secretion rate during IV hyperglycaemic clamp:adjusted % change from baseline at Week 12 (LOCF)Insulin secretion rate (pmol/kg)*Baseline446594Week 12 (LOCF)552563

34、Adjusted % difference PBO (95% CI):27.9 (4.2, 57.1)P=0.02030-SAXA 5 mg (n=18)PBO (n=15)Geometric mean % changefrom baselineAdapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.422HQ09NP101b-Cell Stimulation by Saxagliptin in Patients with T2D Insulin secretion f

35、ollowing IV arginineInsulin secretion in first 5 minutes following IV arginineSAXA 5 mgPBOAcute insulin response, mU/mL(n=16)(n=14) Baseline, median (Q1, Q3)164 (107, 203)204 (175, 268) Week 12, median (Q1, Q3)172 (136, 228)185 (147, 208) Change from baseline*, median (Q1, Q3)24.0 (-5.8, 71.5)-21.7

36、(-52.3, 5.3)* LOCF: last observation carried forward.P value vs PBO = 0.074 (Kruskal-Wallis test)SAXA: saxagliptin; PBO: placebo; IV, intravenous; T2D: type 2 diabetes.Adapted from Henry R, et al. Poster presented at EASD. Sep 27-Oct 1, 2009. Vienna, Austria.Insulin secretion following IV arginine:

37、changes from baseline at Week 12422HQ09NP101靜脈-口服高糖鉗夾試驗中，胰高糖素曲線下面積12周 (LOCF) 時自基線的變化Source: CV181041 Section 7.4.3.1 (App. 5.6.3)研究 041單位: pg*min/mL沙格列汀 5 mgn = 20安慰劑n = 16統(tǒng)計學(xué)結(jié)果 病例數(shù)1714 基線平均值(SE)14279 (1228.2)11177 (880.2) 12周 LOCF 平均值 (SE)11571 (1112.7)12965 (1272.5) 自基線變化的平均值(SE)-2708 (864.9)1788

38、(1247.5)校正后自基線的變化 平均值 (SE)-2191 (957.8)1161 (1061.9) 95% 雙側(cè)檢驗的可信區(qū)間-4153, -229-1014, 3336與安慰劑的不同a 平均值 (SE)b-3352 (1473.8) 95%雙側(cè)檢驗的可信區(qū)間-6371, -333 p-值0.0308a 沙格列汀5 mg與安慰劑自基線變化的差異 b 估值 = 沙格列汀 5 mg校正后平均值變化 安慰劑校正后平均值變化Henry et al. Diabetes, Obesity and Metabolism 2011;13: 850-858.沙格列汀單劑治療降低胰高糖素水平沙格列汀降低胰高糖素水平達(dá) 15.4%胰高血糖素pg/ml75g口服葡萄糖測試沙格列汀5mg:基線沙格列汀5mg:12周SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes.b-Cell Stimulation by Saxagliptin in Patients with T2D GLP-1 and GIP concentrations during IV-Oral hyperglycaemic clamp360Time (min)Mean active GLP-1