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?，是一種選擇性的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

如地格列汀（denagliptin）、卡格列?。╟armegliptin）、美格列?。╩elogliptin）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。

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