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利格列汀

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利格列汀
临床资料
商品名英语Drug nomenclatureTradjenta, Trajenta
AHFS/Drugs.com消费者药物信息
MedlinePlusa611036
核准状况
给药途径Oral
ATC码
法律规范状态
法律规范
药物动力学数据
生物利用度30% oral
血浆蛋白结合率75% to 99% in plasma
识别信息
  • 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione
CAS号668270-12-0  checkY
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard英语CompTox Chemicals Dashboard (EPA)
化学信息
化学式C25H28N8O2
摩尔质量472.54 g/mol
3D模型(JSmol英语JSmol
  • CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
  • InChI=1S/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1 ☒N
  • Key:LTXREWYXXSTFRX-QGZVFWFLSA-N ☒N

利格列汀INNLinagliptin),或称利拉利汀,属于新一代DPP-4抑制剂(dipeptidyl peptidase (DPP)-4 inhibitors)的糖尿病药物,于2011年5月获美国食品及药物管理局(FDA)核准,在配合饮食及运动下,用于治疗成年人二型糖尿病[1]。“利格列汀”是目前唯一一种非主经肾脏排出体外的DPP-4抑制剂口服抗糖尿病药。多项研究发现,只有5% 的“利格列汀”药物由肾脏排出[2],其馀大部分未经代谢的药物会由胆汁及肠道排泄出来,并不如其他同类口服糖尿病药物(如﹕Sitagliptin西他列汀”、Vildagliptin维格列汀”及Saxagliptin沙格列汀”) 有近7成至9成经肾脏排出 [3][4][5][6]

“利格列汀”由德国药厂研发,与美国药厂共同推广,商品名为Trajenta,中文商品则名为 “糖渐平”(台湾) 、“糖安达”(香港)或“欧唐宁”(中国大陆)。

作用机制

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二肽基肽酶-4(DPP-4)是人体酵素的一种,能迅速分解两种肠促胰岛素,包括胰升糖素样肽(GLP-1)及肠抑胃肽(GIP)。GLP-1和GIP的功能,是刺激胰脏beta细胞制造及分泌胰岛素,特别是在进食后血糖水平升高时。GLP-1还有另一项功能,就是抑制胰脏alpha细胞分泌胰升糖素,从而减少肝糖的制造。因此,作为DPP-4抑制剂,“利格列汀”(linagliptin) 能够在血糖浓度高时黏附于DPP-4上,阻止其分解肠促胰岛素[7],延长GLP-1和GIP的寿命,从而促进胰岛素分泌,降低胰升糖素水平,改善血糖控制。

DPP-4抑制剂标志着二型糖尿病治疗的一个创新方向,作用机制独特,与其他类型的二型糖尿病药物有别。

临床研究

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“利格列汀”(linagliptin)已完成第三期临床试验计划,以证实单独治疗及合并其他常用抗糖尿病药(例如甲福明磺胺脲类格列酮类)的疗效、安全性与耐受性。整个计划的试验中心分布全球约40个国家,共纳入超过5,000名二型糖尿病病人,当中有过千名病人患有不同程度的肾功能受损,因此临床试验计划中亦包括两项独立的长期研究,集中评估“利格列汀”对治疗轻度、中度及重度肾功能受损的二型糖尿病病人的安全性及疗效[8] [9][10][11][12] [13][14][15][16]

疗效

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整体研究结果显示[8] [9][10][11][12] [13][14][15],无论单独治疗或合并其他抗糖尿病药物如甲福明、磺胺脲类或格列酮类,“利格列汀”(linagliptin)的控糖疗效均十分显著、持久而且具临床意义。八项随机对照研究共纳入5,239名二型糖尿病病人,评估“利格列汀”的疗效和安全性。共有3,319名二型糖尿病病人接受“利格列汀”治疗,当中929名年龄65岁或以上;1,238名患有轻度肾功能受损;143名患有中度肾功能受损。结果证实,每天一次“利格列汀”能显著改善血糖控制,对病人体重并没有造成具临床意义的影响。所有子群组(性别、年龄、肾功能受损程度、体重指数)的糖化血红素下降幅度相若。

部分研究更发现 ,“利格列汀”能大幅改善beta细胞的功能(beta细胞负责制造及分泌胰岛素)[10][11][12] [13][17]

另外一项为期逾两年的长期研究[16],比较“利格列汀”或格列美脲加入甲福明治疗后的效果12。结果显示,“利格列汀”能有效降糖,疗效不但与格列美脲相若,而且不会引致体重上升,出现血糖过低的风险较格列美脲低,发生心血 管事件的情况也较少。目前的临床研究证实“利格列汀”有以下的特点:

  • 持久稳定血糖至理想目标,具有临床意义
  • 安全性及耐受性良好,血糖过低的风险相当低
  • 不会引致体重上升
  • 无须调节药物剂量。即使服用者同时患有其他疾病或服用其他药物,甚至有肾功能受损,也无须调校“利格列汀”的用药剂量(“利格列汀”并非主要依靠肾脏排出体外)。


安全性与耐受性

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“利格列汀”的整体副作用发生率与安慰剂相若,耐受性佳[10][11][12] [13][17]。即使单独用药或合并其他抗糖尿病药物如甲福明、磺胺脲类或格列酮类,病人出现血糖过低的风险并无显著增加。当与其他常用的抗糖尿病药物合并治疗,“利格列汀”亦无产生明显的药物相互作用,意味着不论病人是否患有其他疾病或同时服用其他常见的药物,都适合接受“利格列汀”治疗[18][19]。与磺胺脲类、 格列酮类或胰岛素治疗不同,“利格列汀”并不会引致体重上升,亦不会产生传统抗糖尿病药常见的副作用[20]。与许多传统二型糖尿病治疗相反,开始“利格列汀”治疗时,病人无需经历一段剂量调校期(即逐步增加剂量)以找出适当的治疗剂量。

剂量

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“利格列汀”的一般剂量是5毫克药片。

不宜服用的人士

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  • 对“利格列汀”有效成分过敏
  • 患有一型糖尿病
  • 有糖尿病酮症酸中毒症
  • 怀孕、正在授乳或准备授乳

副作用

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研究证实少数服用者会出现血糖过低的情况,而极少数服用者会出现过敏的情况。

参考文献

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  1. ^ FDA approves new treatment for Type 2 diabetes. 3 May 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253501.htm页面存档备份,存于互联网档案馆). Accessed 25 February 2012.
  2. ^ Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010 Apr;38(4):667-678.
  3. ^ Carolyn F Deacon, Jens J Holst. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison, efficacy and safety. Informa Healthcare Expert Opinion Reviews. October 2013, Vol. 14, No. 15 , Pages 2047-2058.
  4. ^ Sitagliptin summary of product characteristics. Available at www.medicines.org.uk/emc/medicine/19609.
  5. ^ Vildaliptin summary of product characteristics. Available at www.medicines.org.uk/emc/medicine/20734.
  6. ^ Saxagliptin summary of product characteristics. Available at www.medicines.org.uk/EMC/medicine/22315.
  7. ^ Thomas L, Tadayyon M, Mark M. Chronic treatment with the dipeptidyl peptidase-4 inhibitor BI 135 [(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazol in-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] increases basal glucagon-like peptide-1 and improves glycemic control in diabetic rodent models. J Pharmacol Exp Ther 2009;328(2):556-563.
  8. ^ 8.0 8.1 Barnett AJH, Harper R, Toorawa R, et al. Linagliptin monotherapy improves glycaemic control in type 2 diabetes patients for who metformin therapy is inappropriate. Poster No 823-P, 46th European Association for the Study of Diabetes Annual Meeting, 20-14 September 2010, Stockholm, Sweden.
  9. ^ 9.0 9.1 Lewin AJ, Arvay L, Liu D, et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster No 821-P, 46th European Association for the Study of Diabetes Annual Meeting, 20-14 September 2010, Stockholm, Sweden.
  10. ^ 10.0 10.1 10.2 10.3 Owens DR, Swallow R, Kugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011;28(11):1352-1361.
  11. ^ 11.0 11.1 11.2 11.3 Taskinen M-R, et al. Efficacy and safety of linagliptin in Type 2 diabetes inadequately controlled on metformin monotherapy. Poster No 579-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, USA.
  12. ^ 12.0 12.1 12.2 12.3 Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 2011;13(3):258-267.
  13. ^ 13.0 13.1 13.2 13.3 Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13(7):653-661.
  14. ^ 14.0 14.1 Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab 2011;Dec 6 [Epub ahead of print].
  15. ^ 15.0 15.1 Kawamori R. et al. Linagliptin monotherapy improves glycemic control in Japanese patients with T2DM over 12 weeks. Poster number 696-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, USA
  16. ^ 16.0 16.1 Gallwitz B, Uhlig-Laske B, Bhattacharaya S, et al. Linagliptin has similar efficacy to glimepiride but improved cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled on metformin 71th Scientific Sessions of the American Diabetes Association, San Diego, California. 2011; Poster 39-LB.
  17. ^ 17.0 17.1 Kawamori R. et al. Linagliptin monotherapy improves glycemic control in Japanese patients with T2DM over 12 weeks. Poster number 696-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, USA.
  18. ^ Scheen AJ. Dipeptidylpeptidase-4 inhibitors (Gliptins). Clin Pharmacokinet 2010;49(9):573-588.
  19. ^ Graefe-Mody U, Friedrich C, Port A, et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster No. 822-P, 46th European Association for the Study of Diabetes Annual Meeting, 20-24 September 2010, Stockholm, Sweden.
  20. ^ Pratley R. Inhibition of DPP-4: a new therapeutic approach for the treatment of Type 2 diabetes. Curr Med Res Opin 2007;23(4):919-931.