利拉利汀

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利拉利汀Linagliptin),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]。“利拉利汀”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“利拉利汀”药物由肾脏排出[2],其余大部分未经代谢的药物会由胆汁肠道排泄出来,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]

“利拉利汀”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)。

目录

作用机制

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,“利拉利汀”(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

缩略图 “利拉利汀”(linagliptin)已完成第三期临床试验计划,以証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或格列酮类)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“利拉利汀”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

整体研究结果显示[17] [18][19][20][21] [22][23][24],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,“利拉利汀”(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“利拉利汀”的疗效和安全性。共有3,319名二型糖尿病病人接受“利拉利汀”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“利拉利汀”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 ,“利拉利汀”能大幅改善beta细胞的功能(beta细胞负责制造及分泌胰岛素)[25][26][27] [28][29]

另外一项为期逾两年的长期研究[30],比较“利拉利汀”或格列美脲加入甲福明治疗后的效果12。结果显示,“利拉利汀”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。目前的临床研究証实“利拉利汀”有以下的特点:

安全性与耐受性

“利拉利汀”的整体副作用发生率与安慰剂相若,耐受性佳[31][32][33] [34][35]。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,“利拉利汀”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“利拉利汀”治疗[36][37]。与磺胺脲类、 格列酮类或胰岛素治疗不同,“利拉利汀”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[38]。与许多传统二型糖尿病治疗相反,开始“利拉利汀”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

“利拉利汀”的一般剂量是5毫克药片。

不宜服用的人士

副作用

研究証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

  1. FDA approves new treatment for Type 2 diabetes. 3 May 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253501.htm. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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].
  24. 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
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (Gliptins). Clin Pharmacokinet 2010;49(9):573-588.
  37. 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.
  38. 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.

参考来源

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