利拉利汀

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利拉利汀（Linagliptin），屬于新一代DPP-4抑制劑（dipeptidyl peptidase (DPP)-4 inhibitors）的糖尿病藥物，于2011年5月獲美國(guó)食品及藥物管理局(FDA)核準(zhǔn)，在配合飲食及運(yùn)動(dòng)下，用于治療成年人二型糖尿病[1]?！袄　笔悄壳拔ㄒ灰环N非主經(jīng)腎臟排出體外的DPP-4抑制劑口服抗糖尿病藥。多項(xiàng)研究發(fā)現(xiàn)，只有5% 的“利拉利汀”藥物由腎臟排出[2]，其余大部分未經(jīng)代謝的藥物會(huì)由膽汁及腸道排泄出來(lái)，并不如其他同類口服糖尿病藥物(如﹕Sitagliptin“西他列汀”、Vildagliptin“維格列汀”及Saxagliptin“沙格列汀”) 有近7成至9成經(jīng)腎臟排出 [3][4][5][6] 。

“利拉利汀”由德國(guó)藥廠研發(fā)，與美國(guó)藥廠共同推廣，商品名為T(mén)rajenta，中文商品則名為 “糖漸平”(臺(tái)灣) 、“糖安達(dá)”(香港）或“歐唐寧”（中國(guó)大陸)。

目錄

作用機(jī)制

二肽基肽酶-4（DPP-4）是人體酵素的一種，能迅速分解兩種腸促胰島素，包括胰升糖素樣肽（GLP-1）及腸抑胃肽（GIP）。GLP-1和GIP的功能，是刺激胰臟beta細(xì)胞制造及分泌胰島素，特別是在進(jìn)食后血糖水平升高時(shí)。GLP-1還有另一項(xiàng)功能，就是抑制胰臟alpha細(xì)胞分泌胰升糖素，從而減少肝糖的制造。因此，作為DPP-4抑制劑，“利拉利汀”(linagliptin) 能夠在血糖濃度高時(shí)黏附于DPP-4上，阻止其分解腸促胰島素[7]，延長(zhǎng)GLP-1和GIP的壽命，從而促進(jìn)胰島素分泌，降低胰升糖素水平，改善血糖控制。

DPP-4抑制劑標(biāo)志著二型糖尿病治療的一個(gè)創(chuàng)新方向，作用機(jī)制獨(dú)特，與其他類型的二型糖尿病藥物有別。

臨床研究

縮略圖 “利拉利汀”(linagliptin)已完成第三期臨床試驗(yàn)計(jì)劃，以証實(shí)單獨(dú)治療及合并其他常用抗糖尿病藥（例如甲福明、磺胺脲類或格列酮類）的療效、安全性與耐受性。整個(gè)計(jì)劃的試驗(yàn)中心分布全球約40個(gè)國(guó)家，共納入超過(guò)5,000名二型糖尿病病人，當(dāng)中有過(guò)千名病人患有不同程度的腎功能受損，因此臨床試驗(yàn)計(jì)劃中亦包括兩項(xiàng)獨(dú)立的長(zhǎng)期研究，集中評(píng)估“利拉利汀”對(duì)治療輕度、中度及重度腎功能受損的二型糖尿病病人的安全性及療效[8] [9][10][11][12] [13][14][15][16]。

療效

整體研究結(jié)果顯示[17] [18][19][20][21] [22][23][24]，無(wú)論單獨(dú)治療或合并其他抗糖尿病藥物如甲福明、磺胺脲類或格列酮類，“利拉利汀”(linagliptin)的控糖療效均十分顯著、持久而且具臨床意義。八項(xiàng)隨機(jī)對(duì)照研究共納入5,239名二型糖尿病病人，評(píng)估“利拉利汀”的療效和安全性。共有3,319名二型糖尿病病人接受“利拉利汀”治療，當(dāng)中929名年齡65歲或以上；1,238名患有輕度腎功能受損；143名患有中度腎功能受損。結(jié)果證實(shí)，每天一次“利拉利汀”能顯著改善血糖控制，對(duì)病人體重并沒(méi)有造成具臨床意義的影響。所有子群組（性別、年齡、腎功能受損程度、體重指數(shù)）的糖化血紅素下降幅度相若。

部分研究更發(fā)現(xiàn) ，“利拉利汀”能大幅改善beta細(xì)胞的功能（beta細(xì)胞負(fù)責(zé)制造及分泌胰島素）[25][26][27] [28][29]。

另外一項(xiàng)為期逾兩年的長(zhǎng)期研究[30]，比較“利拉利汀”或格列美脲加入甲福明治療后的效果12。結(jié)果顯示，“利拉利汀”能有效降糖，療效不但與格列美脲相若，而且不會(huì)引致體重上升，出現(xiàn)血糖過(guò)低的風(fēng)險(xiǎn)較格列美脲低，發(fā)生心血 管事件的情況也較少。目前的臨床研究証實(shí)“利拉利汀”有以下的特點(diǎn)：

安全性與耐受性

“利拉利汀”的整體副作用發(fā)生率與安慰劑相若，耐受性佳[31][32][33] [34][35]。即使單獨(dú)用藥或合并其他抗糖尿病藥物如甲福明、磺胺脲類或格列酮類，病人出現(xiàn)血糖過(guò)低的風(fēng)險(xiǎn)并無(wú)顯著增加。當(dāng)與其他常用的抗糖尿病藥物合并治療，“利拉利汀”亦無(wú)產(chǎn)生明顯的藥物相互作用，意味著不論病人是否患有其他疾病或同時(shí)服用其他常見(jiàn)的藥物，都適合接受“利拉利汀”治療[36][37]。與磺胺脲類、 格列酮類或胰島素治療不同，“利拉利汀”并不會(huì)引致體重上升，亦不會(huì)產(chǎn)生傳統(tǒng)抗糖尿病藥常見(jiàn)的副作用[38]。與許多傳統(tǒng)二型糖尿病治療相反，開(kāi)始“利拉利汀”治療時(shí)，病人無(wú)需經(jīng)歷一段劑量調(diào)校期（即逐步增加劑量）以找出適當(dāng)?shù)闹委焺┝俊?br />

劑量

“利拉利汀”的一般劑量是5毫克藥片。

不宜服用的人士

副作用

研究証實(shí)少數(shù)服用者會(huì)出現(xiàn)血糖過(guò)低的情況，而極少數(shù)服用者會(huì)出現(xiàn)過(guò)敏的情況。

參考文獻(xiàn)

  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.

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