Diabetes Centre, Heart of England National Health Service Foundation Trust and University of Birmingham, Birmingham, UK.
Clin Drug Investig. 2013 Oct;33(10):707-17. doi: 10.1007/s40261-013-0107-8.
Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM).
The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin.
This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18-78 years with glycated hemoglobin (HbA1c) 7.5-11 % on a stable insulin regimen (30-150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52.
In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (-0.75 %) versus placebo (-0.38 %); the adjusted between-group difference was -0.37 % (95 % CI -0.55 to -0.19); between-group differences were similar in patients treated with metformin (-0.37 % [95 % CI -0.59 to -0.15]) and without metformin (-0.37 % [95 % CI -0.69 to -0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c <7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1-19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, -1.01 U [95 % CI -3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo.
Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.
实现血糖控制是 2 型糖尿病（T2DM）管理的重要目标。
本研究旨在评估二肽基肽酶-4 抑制剂沙格列汀与安慰剂作为胰岛素单药或胰岛素联合二甲双胍治疗控制不佳的 T2DM 患者的附加治疗的安全性和有效性。
这是一项为期 28 周的长期（28 周）扩展研究，在 24 周的短期（24 周）随机、双盲、平行组试验的基础上进行，沙格列汀 5mg 每日一次与安慰剂作为附加治疗，联合开放标签胰岛素或胰岛素联合二甲双胍治疗，共 52 周的治疗。与短期阶段维持稳定胰岛素剂量的目标相反，在扩展阶段，胰岛素剂量是灵活的，并由研究者根据需要进行调整。该研究在临床实践环境中进行，包括家庭实践和医院场所。筛选时接受稳定胰岛素方案（30-150U/天，有或没有二甲双胍）治疗 8 周以上且糖化血红蛋白（HbA1c）为 7.5-11%的 18-78 岁 T2DM 患者纳入研究。根据二甲双胍的使用情况进行分层，并随机分为 2:1 接受口服沙格列汀 5mg（n=304）或安慰剂（n=151），每日一次。所有完成初始 24 周治疗的患者无论是否需要挽救治疗，均有资格参加 28 周的扩展。主要观察指标为从基线到第 52 周的 HbA1c 变化。
一般来说，第 24 周的结果在第 52 周得到维持。第 52 周时，沙格列汀（-0.75%）与安慰剂（-0.38%）相比，HbA1c 从基线的调整平均变化更大；组间差异为-0.37%（95%CI -0.55 至 -0.19）；在接受二甲双胍治疗的患者（-0.37%[95%CI -0.59 至 -0.15]）和未接受二甲双胍治疗的患者（-0.37%[95%CI -0.69 至 -0.04]）中，组间差异相似。第 52 周时，接受沙格列汀治疗的患者中有更大比例的 HbA1c<7%，而接受安慰剂治疗的患者为 21.3%（95%CI 6.1-19.1）。第 52 周时，平均每日总胰岛素剂量从基线的增加在数值上较小，沙格列汀为 5.67U，安慰剂为 6.67U；差异为-1.01U（95%CI -3.24 至 1.22）。在 52 周的研究期间，报告≥1 次不良事件（AE）的患者比例为沙格列汀组 66.4%，安慰剂组 71.5%，大多数为轻度或中度强度。最常见的 AE（沙格列汀或安慰剂发生率≥5%）为尿路感染、鼻咽炎、上呼吸道感染、头痛、流感和四肢疼痛；两组的发病率相似。在沙格列汀和安慰剂组中，报告的低血糖发生率分别为 22.7%和 26.5%，分别为经证实的低血糖（手指血糖≤50mg/dL[≤2.77mmol/L]，伴有特征性症状）的发生率为 7.6%和 6.6%。从基线体重的调整平均变化分别为沙格列汀组增加 0.8kg，安慰剂组增加 0.5kg。
沙格列汀 5mg 每日一次作为胰岛素的附加治疗，联合或不联合二甲双胍，可在 52 周的治疗中持久改善血糖控制，并具有良好的耐受性。
