Zerilli Tina, Pyon Eunice Y
International Drug Information Center, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201, USA.
Clin Ther. 2007 Dec;29(12):2614-34. doi: 10.1016/j.clinthera.2007.12.034.
Sitagliptin phosphate, the first dipeptidyl peptidase 4 (DPP-4) inhibitor, provides a new treatment option for patients with type 2 diabetes.
The purpose of this article is to review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and cost of sitagliptin in adults with type 2 diabetes.
A literature search of MEDLINE (1966-May 10, 2007), Iowa Drug Information Service (1966-May 10, 2007), and International Pharmaceutical Abstracts (1970-May 10, 2007) was performed using the terms sitagliptin and MK-0431. English-language, original research and review articles were reviewed, as were citations from these articles. The 2005 and 2006 American Diabetes Association Scientific Abstracts were searched, and the US Food and Drug Administration review of the new drug application for sitagliptin and select information from the manufacturer were consulted.
By inhibiting DPP-4, sitagliptin enhances postprandial levels of active glucagon-like peptide-1 (GLP-1), leading to a rise in insulin release and decrease in glucagon secretion from pancreatic alpha-cells. Sitagliptin is 87% orally bioavailable, undergoes minimal hepatic metabolism, and is primarily excreted unchanged (approximately 79%) in the urine. At doses >or=100 mg QD, DPP-4 activity is inhibited by >80%, with a consequent 2-fold rise in active GLP-1 levels. The reduction in glycosylated hemoglobin (HbA(1c)) observed with 100 mg QD of sitagliptin in Phase III monotherapy trials ranged from approximately 0.5% to 0.6% (P <or= 0.001 vs placebo). In Phase III combination trials, HbA(1c) was reduced by approximately 0.7% when added to metformin and approximately 0.9% with pioglitazone (P < 0.001 vs placebo). Markers of beta-cell function, including proinsulin/insulin ratio and homeostasis model assessment of beta-cell function, were improved with sitagliptin treatment. In studies, sitagliptin has been well tolerated; significant hypoglycemia and weight gain have not been noted.
When used alone or in combination with metformin or pioglitazone, sitagliptin has been associated with significant reductions in HbA(1c) and has been well tolerated. Before its place in therapy can be firmly established, long-term studies evaluating the safety of prolonged DPP-4 inhibition are necessary.
磷酸西格列汀是首个二肽基肽酶4（DPP-4）抑制剂，为2型糖尿病患者提供了一种新的治疗选择。
本文旨在综述西格列汀在成年2型糖尿病患者中的药理学、药代动力学、药效学、临床疗效、不良反应及成本。
使用西格列汀和MK-0431检索MEDLINE（1966年至2007年5月10日）、爱荷华药物信息服务（1966年至2007年5月10日）和国际药学文摘（1970年至2007年5月10日）。对英文的原创研究和综述文章以及这些文章的参考文献进行了回顾。检索了2005年和2006年美国糖尿病协会科学文摘，并查阅了美国食品药品监督管理局对西格列汀新药申请的审评以及来自制造商的选定信息。
通过抑制DPP-4，西格列汀可提高餐后活性胰高血糖素样肽-1（GLP-1）水平，导致胰岛素释放增加，胰腺α细胞胰高血糖素分泌减少。西格列汀口服生物利用度为87%，肝脏代谢极少，主要以原形经尿液排泄（约79%）。剂量≥100mg每日一次时，DPP-4活性被抑制>80%，活性GLP-1水平随之升高2倍。在III期单药治疗试验中，每日一次100mg西格列汀使糖化血红蛋白（HbA1c）降低幅度约为0.5%至0.6%（与安慰剂相比，P≤0.001）。在III期联合试验中，与二甲双胍联用时HbA1c降低约0.7%，与吡格列酮联用时降低约0.9%（与安慰剂相比，P<0.001）。西格列汀治疗可改善β细胞功能标志物，包括胰岛素原/胰岛素比值和β细胞功能的稳态模型评估。在研究中，西格列汀耐受性良好；未观察到显著低血糖和体重增加。
单独使用或与二甲双胍或吡格列酮联合使用时，西格列汀可使HbA1c显著降低且耐受性良好。在其在治疗中的地位得以牢固确立之前，有必要进行长期研究以评估长期抑制DPP-4的安全性。
