基于腸促胰島素的抗糖尿病藥物發(fā)展概況

吳霞

（上海市靜安區(qū)中心醫(yī)院內(nèi)分泌科 上海 200040）

近年來，隨著對糖尿病發(fā)病機(jī)制的不斷研究與認(rèn)識，腸促胰島素（incretin）因可促進(jìn)β細(xì)胞復(fù)制和再生、抑制其凋亡以及改善α細(xì)胞功能而成為研究熱點(diǎn)。腸促胰島素是一組胃腸激素，主要包括胰高血糖素樣肽-1（glucagon-like peptide-1, GLP-1）和葡萄糖依賴性促胰島素 肽（glucose-dependent insulinotropic peptide, GIP）[1]。因?yàn)镚LP-1會被GLP-1降解酶二肽基肽酶-4（dipeptidyl peptidase-4, DPP-4）迅速降解且2型糖尿病患者體內(nèi)或多或少都存在GLP-1水平降低的現(xiàn)象，所以注射GLP-1受體激動劑和口服DPP-4抑制劑能夠促進(jìn)胰島素分泌和維持血糖水平穩(wěn)定[2]。本文簡要介紹這兩類基于腸促胰島素的抗糖尿病藥物的發(fā)展概況。

1 GLP-1受體激動劑

1.1 艾塞那肽（exenatide）

艾塞那肽是人工合成的含有39個氨基酸的exendin-4類似物，是美國批準(zhǔn)的第一個GLP-1受體激動劑。exendin-4是自希拉毒蜥（Gila monster）的唾液中分離得到的，與人GLP-1在氨基酸序列上具有53%的同源性[3]。exendin-4不是DPP-4的底物，不會被迅速降解。艾塞那肽能夠激活GLP-1受體、由此發(fā)揮類似人GLP-1的作用，但因其N端不能被DPP-4降解，故血漿半衰期更長。皮下給予艾塞那肽后約2 h達(dá)血藥濃度峰值，半衰期為2.4 h，降血糖時間超過8 h，主要由腎小球?yàn)V過清除[4]。研究證實(shí)，艾塞那肽能改善2型糖尿病患者的第一時相胰島素分泌[3]和抑制餐后胰高血糖素分泌，顯著降低空腹和餐后血糖水平、顯著延緩胃排空時間[5]。與安慰劑相比，每日2次皮下注射艾塞那肽5或10 μg可降低糖化血紅蛋白A1C（glycosylated hemoglobin A1C, HbA1C）值1.0個百分點(diǎn)且長期治療有效（3年后降低HbA1C值仍為1.0個百分點(diǎn)）[6]，同時明顯減輕患者的體重（最多減輕3.1 kg）[7]并能使患者發(fā)生心血管事件的風(fēng)險較不使用艾塞那肽治療者降低16%[8]。歐盟最近還批準(zhǔn)了艾塞那肽的一種新劑型，即艾塞那肽每周1次用長效劑型。

艾塞那肽的常見不良反應(yīng)為惡心和嘔吐，通常發(fā)生在治療早期。根據(jù)患者個體差異調(diào)整艾塞那肽的劑量、注射時間以及選擇非工作日開始首次注射有助于減少此藥的惡心、嘔吐發(fā)生率；采用逐漸加大用藥劑量的方法能改善患者的耐受性[9]。

1.2 利拉魯肽（liraglutide）

利拉魯肽是另一個已被批準(zhǔn)用于臨床的GLP-1受體激動劑，其結(jié)構(gòu)與人GLP-1具有97%的同源性，故也被稱為人GLP-1類似物。利拉魯肽可與血清白蛋白結(jié)合、然后緩慢釋放到循環(huán)中，能抵抗DPP-4的分解、延遲吸收和減少腎臟清除，半衰期長達(dá)12 h[10-11]。因此，利拉魯肽僅需每天注射1次。無論是單用還是聯(lián)用其他抗糖尿病藥物，利拉魯肽均能有效降低HbA1C值（1.0個百分點(diǎn)左右）和減輕患者體重[12-14]，并顯著改善2型糖尿病患者的餐后血糖水平、抑制餐后胰高血糖素分泌以及顯著改善胰島素原/總胰島素比值和胰島β細(xì)胞分泌功能指數(shù)（homeostasis model assemsment of islet beta-cell function, HOMA-β）[15]。

利拉魯肽的常見不良反應(yīng)是惡心，但發(fā)生率較艾塞那肽低并會隨用藥時間延長而降低。

1.3 他司魯肽（taspoglutide）

他司魯肽是長效人GLP-1類似物，與人GLP-1具有93%的同源性。他司魯肽因結(jié)構(gòu)中第8和第35位氨基酸被替換為氨基異丁酸、同時還含有一種能保證其緩釋性能的成分[16]，故僅需每周注射1次。他司魯肽現(xiàn)尚處于臨床試驗(yàn)階段，但已完成的II期和III臨床試驗(yàn)顯示，每周注射10或20 mg、或每2周注射20 mg他司魯肽均能有效降低HbA1C值和體重，尤以降低空腹血糖水平的作用最為顯著[17-18]。他司魯肽的不良反應(yīng)主要是惡心、嘔吐以及注射部位的過敏反應(yīng)[18]。

1.4 lixisenatide

lixisenatide是經(jīng)對exendin-4結(jié)構(gòu)中C末端的6個賴氨酸殘基進(jìn)行修飾后得到的一個GLP-1類似物，能耐受DPP-4的降解，可一日1次皮下注射用藥。與安慰劑相比，lixisenatide能顯著降低HbA1C值、尤其是降低餐后2 h時的血糖水平，但不會引起低血糖反應(yīng)[19-20]。lixisenatide已完成III期臨床試驗(yàn)，主要不良反應(yīng)是胃腸道癥狀如惡心、嘔吐等。

1.5 其他GLP-1受體激動劑

如阿必魯肽（albiglutide）、(Val8)GLP-1、(His7)GLP-1和BMI51077等，目前也都處在臨床前研發(fā)或臨床試驗(yàn)階段。

2 DPP-4抑制劑

DPP-4抑制劑通過抑制DPP-4活性而提高人體內(nèi)天然GLP-1和GIP的濃度，由此刺激胰島素分泌和抑制胰高血糖素分泌并最終達(dá)到控制血糖水平的目的。

2.1 西格列?。╯itagliptin）

西格列汀是首個獲準(zhǔn)上市的DPP-4抑制劑，是含三氮唑并哌嗪環(huán)的β-氨基酸衍化物[21]，人口服后吸收迅速、1～4 h達(dá)血藥濃度峰值，主要以原形從腎臟代謝，血漿半衰期為11.8～14.4 h，可每日1次用藥[22]。無論單用還是聯(lián)用雙胍類、磺酰脲類或噻唑烷二酮類抗糖尿病藥物，西格列汀均能顯著降低2型糖尿病患者的HbA1C值（降低0.5～0.79個百分點(diǎn)）以及空腹血糖和餐后2 h時的血糖水平[23-25]，且低血糖發(fā)生率低、無體重增加風(fēng)險。

西格列汀的不良反應(yīng)包括超敏反應(yīng)、肝酶水平升高、上呼吸道感染、鼻咽炎和頭痛等。

2.2 維格列?。╲ildagliptin）

維格列汀是α-氨基?；杌量┩檠苌铮且环N選擇性的DPP-4競爭性抑制劑，具有較高的酶抑制活性。維格列汀被人口服后吸收迅速，約1.1 h達(dá)血藥濃度峰值，主要從腎臟代謝，血漿半衰期為1.7～2.5 h，需每日2次用藥。維格列汀能促進(jìn)葡萄糖刺激的胰島素分泌和抑制餐后胰高血糖素分泌，進(jìn)而降低血糖、特別是餐后血糖水平[26-27]。維格列汀聯(lián)用二甲雙胍能提高2型糖尿病患者的β細(xì)胞功能及餐后胰島素的敏感度[28]，聯(lián)用吡格列酮能更有效地降低HbA1C值且不會提高低血糖的發(fā)生率[29]。

維格列汀的最常見不良反應(yīng)是頭痛、鼻咽炎、咳嗽、便秘、頭暈和出汗量增加等。維格列汀在動物實(shí)驗(yàn)中見有皮膚壞死和腎損害等不良反應(yīng)，但在臨床研究中未出現(xiàn)過。

2.3 沙格列?。╯axagliptin）

沙格列汀是在維格列汀的氰基吡咯烷結(jié)構(gòu)上引入環(huán)丙基、從而提高了氰基吡咯烷的穩(wěn)定性后得到的，人口服后吸收迅速、約2 h達(dá)血藥濃度峰值，主要從腎臟和肝臟代謝，血漿半衰期為2.1 h，但其抑制DPP-4活性的時間可達(dá)24 h，故僅需每日1次用藥。沙格列汀的臨床療效與西格列汀相當(dāng)，每日1次口服5 mg沙格列汀可降低HbA1C值0.45～0.63個百分點(diǎn)[30]，聯(lián)用二甲雙胍則可使HbA1C值降低0.69個百分點(diǎn)[31]。

沙格列汀的最常見不良事件為上呼吸道感染、尿路感染和頭痛。

2.4 利格列汀（linagliptin）

利格列汀是首個主要經(jīng)膽道和胃腸道代謝的DPP-4抑制劑，用藥劑量中僅有5%由腎臟代謝，用于腎功能損害患者時不需調(diào)整劑量。利格列汀每日1次5 mg治療可降低HbA1C值0.4～0.7個百分點(diǎn)[32]，聯(lián)用二甲雙胍可使HbA1C值額外再降低0.4～0.6個百分點(diǎn)[33]。

2.5 阿格列汀（alogliptin）

阿格列汀現(xiàn)僅在日本獲準(zhǔn)上市，口服后1～2 h達(dá)血藥濃度峰值，主要由腎臟代謝。阿格列汀可顯著改善2型糖尿病患者的血糖控制水平[34]，但長期安全性尚有待臨床實(shí)踐和臨床研究的考察。阿格列汀的最常見不良反應(yīng)包括鼻咽炎、泌尿道感染、頭痛、上呼吸道感染和外周水腫。

2.6 其他DPP-4抑制劑

如地格列?。╠enagliptin）、卡格列汀（carmegliptin）、美格列汀（melogliptin）和度格列?。╠utogliptin）等，但目前還都處在不同的研發(fā)階段。

3 結(jié)語

綜上所述，GLP-1受體激動劑和DPP-4抑制劑因能有效降低血糖水平、改善胰島細(xì)胞功能、安全性和耐受性良好并有可減輕或不增加體重、極少導(dǎo)致低血糖和嚴(yán)重不良反應(yīng)等優(yōu)點(diǎn)，為2型糖尿病治療提供了新的手段。另有一些研究發(fā)現(xiàn)，這兩類藥物也有對心血管的潛在益處。但是，由于目前基于腸促胰島素的抗糖尿病藥物在臨床應(yīng)用的時間尚短，期待有更多的臨床研究證實(shí)其長期的治療效果和安全性。

參考文獻(xiàn)

[1] Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes [J]. Diabetes Care, 2003, 26(10): 2929-2940.

[2] Nauck M, Stockmann F, Ebert R,et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes [J]. Diabetologia,1986, 29(1): 46-52.

[3] Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes [J]. Regul Pept,2004, 117(2): 77-88.

[4] Kolterman OG, Kim DD, Shen L,et al. Pharmacokinetics,pharmacodynamics，and safety of exenatide in patients with type 2 diabetes mellitus [J]. Am Health Syst Pharm, 2005,62(2): 173-181.

[5] Kolterman OG, Buse JB, Fineman MS,et al. Synthetic exendin-4 (exenatide) signi fi cantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes [J]. J Clin Endocrinal Metab, 2003, 88(7): 3082-3089.

[6] Klonoff DC, Buse JB, Nielsen LL,et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years [J]. Curr Med Res Opin, 2008, 24(1): 275-286.

[7] Moretto TJ, Milton DR, Ridge TD,et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study [J]. CIin Ther, 2008, 30(8): 1448-1460.

[8] Best JH, Hoogwerf BJ, Herman WH,et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the lifeline database [J].Diabetes Care, 2011, 34(1): 90-95.

[9] Fineman MS, Shen LZ, Taylor K,et al. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes [J]. Diabetes Metab Res Rev, 2004, 20(5): 411-417.

[10] Vilsboll T. Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus [J]. Expert Opin lnvestig Drugs, 2007, 16(2): 231-237.

[11] 褚建平. 腸促胰島素類制劑及二肽基肽酶抑制物的研究與臨床應(yīng)用進(jìn)展[J]. 現(xiàn)代實(shí)用醫(yī)學(xué), 2009, 21(12): 1276-1279.

[12] Marre M, Shaw J, Brandle M,et al. Liraglutide, a oncedaily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU) [J]. Diabet Med, 2009, 26(3): 268-278.

[13] Nauck M, Frid A, Hermansen K,et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes mellitus(LEAD-2 Met) [J]. Diabetes Care, 2009, 32(1): 84-90.

[14] Zinman B, Gerich J, Buse JB,et al. Efficacy and safety ofthe human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus(LEAD-4 Met + TZD) [J]. Diabetes Care, 2009, 32(7): 1224-1230.

[15] Degn KB, Juhl CB, Sturis J,et al. One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide(NN2211) markedly improves 24h glycemia and alpha- and betacell function and reduces endogenous glucose release in patients with type 2 diabetes [J]. Diabetes, 2004, 53(5): 1187-1194.

[16] Dong JZ, Shen Y, Zhang J,et al. Discovery and characterization of taspoglutide, a novel analogue of human glucagon-like peptide-1, engineered for sustained therapeutic activity in type 2 diabetes [J]. Diabetes Obes Metab, 2011,13(1): 19-25.

[17] Nauck MA, Ratner RE, Kapitza C,et al. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone:a double-blind placebo-controlled study [J]. Diabetes Care,2009, 32(7): 1237-1243.

[18] Henry RR, Mudaliar S, Kanitra L,et al. Ef fi cacy and safety of taspoglutide in patients with type 2 diabetes inadequately controlled with metformin plus pioglitazone over 24 weeks:T-Emerge 3 Trial [J]. J Clin Endocrinol Metab, 2012, 97(7):2370-2379.

[19] Fonseca VA, Alvarado-Ruiz R, Raccah D,et al. Ef fi cacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono) [J].Diabetes Care, 2012, 35(6): 1225-1231.

[20] Seino Y, Min KW, Niemoeller E,et al. Randomized, doubleblind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia) [J]. Diabetes Obes Metab, 2012, 14(10): 910-917.

[21] Kim HJ, Kwak WY, Min JP,et al. Discovery of DA-1229:a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes [J]. Bioorg Med Chem Lett, 2011,21(12): 3809-3812.

[22] Bergman AJ, Stevens C, Zhou Y,et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin,a dipeptidyl peptidase-IV inhibitor: a doubleblind, randomized, placebo-controlled study in healthy male volunteers [J]. Clin Ther, 2006, 28(1): 55-72.

[23] Aschner P, Kipnes MS, Lunceford JK,et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes [J]. Diabetes Care, 2006, 29(12): 2632-2637.

[24] Hermansen K, Kipnes M, Luo E,et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled glimepiride alone or on glimepiride and metformin [J].Diabetes Obes Metab, 2007, 9(5): 733-745.

[25] Rosenstock J, Brazg R, Andryuk PJ,et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin add to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week,multicenter, randomized, double-blind, placebo-controlled,parallel-group study [J]. Clin Ther, 2006, 28(10): 1556-1568.

[26] Ahren B, Landin-Olsson M, Jansson PA,et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels,and reduces glucagon levels in type 2 diabetes [J]. J Clin Endocrinol Metab, 2004, 89(5): 2078-2084.

[27] Pratley R, Galbreath E. Twelve-week monotherapy with the DPP-4 inhibitor, LAF237 improves glycemic control in patients with type 2 diabetes [J]. Diabetes, 2004, 53(Suppl 2): A8.

[28] Ahren B, Gomis R, Standl E,et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase-4 inhibitor LAF237 in metformin-treated patients with type 2 diabetes [J]. Diabetes Care, 2004, 27(12): 2874-2880.

[29] Richter B, Bandeira-Echtler E, Bergerhoff K,et al.Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus [J/OL]. Cochrane Database Syst Rev, 2008, (2):CD006739 [2010-02-24]. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006739.pub2/pdf.

[30] Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-na?ve patients with type 2 diabetes [J]. Diabetes Obes Metab, 2008,10(5): 376-386.

[31] DeFronzo RA, Hissa MN, Garb AJ,et al. The efficacy and safety of saxagliptin when add on to metformin therapy in patients with inadequately controlled type 2 diabetes with mefformin alone [J]. Diabetes Care, 2009, 32(9): 1649-1655.

[32] Karen W, Sando KR. Linagliptin (Tradjenta) for the treatment of diabetes mellitus [J]. Am Fam Physician, 2012, 86(12):1144-1148.

[33] Lajara R. Use of the dipeptidyl peptidase-4 inhibitor linagliptin in combination therapy for type 2 diabetes [J].Expert Opin Pharmacother, 2012, 13(18): 2663-2671.

[34] Fleck P, Christopher R, Covington P,et al. Ef fi cacy and safety of alogliptin monotherapy over 12 weeks in patients with type 2 diabetes [J]. Diabetes, 2008, 57(Suppl 1): A143.