Purdue University, College of Pharmacy, Indianapolis, Indiana, USA.
Clin Ther. 2011 Aug;33(8):1005-22. doi: 10.1016/j.clinthera.2011.06.016. Epub 2011 Jul 28.
Some conventional therapies for type 2 diabetes mellitus (T2DM) fail to address the progressive nature of the disease, and as a result, they may become ineffective in maintaining normoglycemia. Antihyperglycemic agents have been developed to target incretin hormones, specifically glucagon-like peptide (GLP)-1. Incretin analogues and agents that delay GLP-1 degradation, the dipeptidyl peptidase (DPP)-4 inhibitors, offer mechanisms of action that may improve T2DM management. Saxagliptin was approved by the US Food and Drug Administration in July 2009 and by the European Medicines Evaluation Agency in October 2009 for use as monotherapy or in combination regimens for the treatment of T2DM.
The aim of this article was to review the mechanism of action, pharmacology, clinical efficacy, and tolerability associated with the use of saxagliptin in patients with T2DM.
MEDLINE, BIOSIS, International Pharmaceutical Abstracts, and Google Scholar were searched for English-only clinical trials and therapeutic reviews published between 1966 and June 15, 2011 (search term: saxagliptin). Additional trials and reviews were identified from the reference lists of published articles.
Findings on efficacy and tolerability were obtained from 11 completed Phase III clinical trials. In trials in saxagliptin-naive patients, changes from baseline in glycosylated hemoglobin (HbA(1c)) ranged from -0.72% to -0.90% in the saxagliptin treatment arms compared with -0.27% with placebo (all, P < 0.007). When saxagliptin was used in combination with metformin for 24 weeks, the adjusted mean reductions from baseline in HbA(1c) and the proportions of patients achieving target HbA(1c) (<7.0%) were significantly greater with saxagliptin + metformin compared with monotherapy with either drug (all, P ≤ 0.0001). When saxagliptin was used in combination with a sulfonylurea or a thiazolidinedione, the changes in HbA(1c) ranged from -0.54% to -0.64% and -0.66% to -0.94%, respectively, in a dose-dependent manner (P ≤ 0.0007 vs monotherapies). Based on changes in HbA(1c), saxagliptin + metformin was reported to be noninferior to sitagliptin + metformin (-0.52% and -0.62%, respectively; difference, 0.09% [95% CI, -0.01% to 0.20%]). Saxagliptin was reported to have been well tolerated, with the most common adverse events being upper respiratory infection, urinary tract infection, headache, and nasopharyngitis. A systematic review of cardiovascular events in pooled trial results of saxagliptin use reported no increased cardiovascular risk compared with metformin, glyburide, or placebo (relative risk, 0.24 [0.09-0.63]).
Saxagliptin, used as monotherapy and in combination regimens, has been associated with significant reductions in HbA(1c) and significant increases in the rate of achieving target HbA(1c) in patients with T2DM. It has been reported to be well tolerated compared with other oral antihyperglycemic agents. Based on the findings from the studies in this review, the primary role of saxagliptin is expected to be in combination therapy with other antihyperglycemic agents.
一些 2 型糖尿病（T2DM）的常规治疗方法未能解决疾病的进展性，因此，它们可能无法有效维持血糖正常。为了靶向作用于肠促胰岛素激素，特别是胰高血糖素样肽（GLP）-1，开发了抗高血糖药物。肠降血糖素类似物和可延缓 GLP-1 降解的二肽基肽酶（DPP）-4 抑制剂提供了可能改善 T2DM 管理的作用机制。沙格列汀于 2009 年 7 月获得美国食品和药物管理局（FDA）的批准，于 2009 年 10 月获得欧洲药品管理局（EMA）的批准，可作为单药或与其他药物联合用于治疗 T2DM。
本文旨在综述沙格列汀在 T2DM 患者中的作用机制、药理学、临床疗效和耐受性。
检索了 1966 年至 2011 年 6 月 15 日（检索词：沙格列汀）期间发表的英文临床研究和治疗性综述，检索数据库包括 MEDLINE、BIOSIS、国际药学文摘和 Google Scholar。从已发表文章的参考文献中还确定了其他试验和综述。
从 11 项已完成的 III 期临床试验中获得了疗效和耐受性方面的发现。在沙格列汀初治患者中，与安慰剂组（所有，P < 0.007）相比，沙格列汀治疗组的糖化血红蛋白（HbA（1c））自基线的变化范围为-0.72%至-0.90%。当沙格列汀与二甲双胍联合使用 24 周时，与单药治疗相比，HbA（1c）的调整平均降低幅度和达到目标 HbA（1c）（<7.0%）的患者比例在沙格列汀+二甲双胍组显著更大（所有，P ≤ 0.0001）。当沙格列汀与磺酰脲类药物或噻唑烷二酮类药物联合使用时，HbA（1c）的变化范围分别为-0.54%至-0.64%和-0.66%至-0.94%，呈剂量依赖性（P ≤ 0.0007 与单药治疗相比）。根据 HbA（1c）的变化，沙格列汀+二甲双胍被报道与西格列汀+二甲双胍相比不劣效（分别为-0.52%和-0.62%；差异，0.09%[95%CI，-0.01%至 0.20%]）。沙格列汀被报道具有良好的耐受性，最常见的不良反应是上呼吸道感染、尿路感染、头痛和鼻咽炎。对沙格列汀使用的汇总试验结果进行的心血管事件的系统评价报告称，与二甲双胍、格列吡嗪或安慰剂相比，沙格列汀没有增加心血管风险（相对风险，0.24[0.09-0.63]）。
沙格列汀，无论是作为单药治疗还是联合治疗方案，都与 T2DM 患者的 HbA（1c）显著降低和达到目标 HbA（1c）的比例显著增加相关。与其他口服抗高血糖药物相比，它被报道具有良好的耐受性。根据本综述中研究的结果，沙格列汀的主要作用预计是与其他抗高血糖药物联合治疗。
