DeFronzo Ralph A, Okerson Ted, Viswanathan Prabhakar, Guan Xuesong, Holcombe John H, MacConell Leigh
University of Texas Health Science Center, Department of Medicine, Diabetes Division (MSC 7886), 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Curr Med Res Opin. 2008 Oct;24(10):2943-52. doi: 10.1185/03007990802418851. Epub 2008 Sep 10.
This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.
This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 +/- 5 kg/m(2); HbA(1c): 8.5 +/- 1.2%; 2-h PPG: 245 +/- 65 mg/dL. Patients received exenatide (5 microg BID for 1 week, then 10 microg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).
After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 +/- 6 mg/dL versus 208 +/- 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 +/- 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by -76 +/- 10 mg/dL. Postprandial glucose parameters (AUC, C(ave), C(max)) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (-15 +/- 4 mg/dL vs. -19 +/- 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 +/- 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 +/- 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 +/- 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 +/- 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (-134 +/- 97 kcal vs. +130 +/- 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.
Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.
本研究评估了胰高血糖素样肽-1（GLP-1）受体激动剂艾塞那肽和二肽基肽酶-4（DPP-4）抑制剂西他列汀对2型糖尿病（T2D）患者餐后2小时血糖（PPG）、胰岛素和胰高血糖素分泌、胃排空及热量摄入的影响。
本双盲、随机交叉、多中心研究纳入接受二甲双胍治疗的T2D患者：女性占54%；体重指数（BMI）：33±5kg/m²；糖化血红蛋白（HbA1c）：8.5±1.2%；餐后2小时血糖：245±65mg/dL。患者接受艾塞那肽（5μg，每日两次，共1周，然后10μg，每日两次，共1周）或西他列汀（100mg，每日上午一次）治疗2周。2周后，患者交叉接受另一种治疗。通过标准餐试验评估餐后血糖指标；通过随意晚餐（部分患者）评估热量摄入。通过对乙酰氨基酚吸收评估胃排空情况（临床试验注册号：NCT00477581）。
治疗2周后，与西他列汀相比，艾塞那肽治疗后餐后2小时血糖更低：133±6mg/dL 对比 208±6mg/dL，p<0.0001（可评估，N = 61）。从艾塞那肽换用西他列汀使餐后2小时血糖升高73±11mg/dL，而从西他列汀换用艾塞那肽使餐后2小时血糖进一步降低76±10mg/dL。艾塞那肽治疗后的餐后血糖参数（曲线下面积、平均浓度、最大浓度）低于西他列汀（p<0.0001）。艾塞那肽和西他列汀降低空腹血糖的幅度相似（-15±4mg/dL 对比 -19±4mg/dL，p = 0.3234）。与西他列汀相比，艾塞那肽改善了胰岛素分泌的胰岛素生成指数（艾塞那肽与西他列汀的比值：1.50±0.26，p = 0.0239），降低了餐后胰高血糖素水平（艾塞那肽与西他列汀的曲线下面积比值：0.88±0.03，p = 0.0011），降低了餐后甘油三酯水平（艾塞那肽与西他列汀的曲线下面积比值：0.90±0.04，p = 0.0118），并减慢了胃排空（对乙酰氨基酚曲线下面积比值：艾塞那肽与西他列汀为0.56±0.05，p<0.0001）。与西他列汀相比，艾塞那肽降低了总热量摄入（-134±97kcal 对比 +130±97kcal，p = 0.0227，N = 25）。两种治疗的常见不良事件强度为轻至中度，性质为胃肠道反应。
尽管本研究受限于2周的暴露时间，但这些数据表明，艾塞那肽：（i）在降低餐后血糖方面比西他列汀效果更显著；（ii）在增加T2D患者胰岛素分泌和降低餐后胰高血糖素分泌方面作用更强。与西他列汀不同，艾塞那肽减慢了胃排空并降低了热量摄入。这些关键发现区分了两种基于肠促胰岛素的治疗方法的治疗作用，可能具有重要的临床意义。
