Xu L, Man C Dalla, Charbonnel B, Meninger G, Davies M J, Williams-Herman D, Cobelli C, Stein P P
Merck Research Laboratories, Rahway, NJ 07065, USA.
Diabetes Obes Metab. 2008 Dec;10(12):1212-20. doi: 10.1111/j.1463-1326.2008.00887.x. Epub 2008 May 12.
The purpose of this exploratory analysis was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on pancreatic beta-cell function using a model-based analysis.
Data for this analysis were from three large, placebo-controlled clinical studies that examined sitagliptin 100 mg q.d. as add-on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine-point meal tolerance test performed at baseline and study end-point. Blood samples were collected at -10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C-peptide concentrations. Parameters for beta-cell function were calculated using the C-peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Phi(b); ISR at basal glucose concentrations), static (Phi(s); ISR at above basal glucose concentrations following a meal) and dynamic (Phi(d); ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Phi(total); average ISR over the average glucose concentration) is calculated as a function of Phi(s), Phi(d )and Phi(b. )Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Phiand ISI.
When administered in combination with ongoing metformin therapy or as monotherapy, sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Phi(s )and Phi(total), regardless of treatment regimen (add-on to metformin or as monotherapy). For Phi(d), there was a numerical, but not statistically significant, improvement with sitagliptin relative to placebo. Treatment with sitagliptin increased Phi(b), but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with sitagliptin treatment relative to placebo.
In this model-based analysis, sitagliptin improved beta-cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.
本探索性分析旨在使用基于模型的分析方法评估二肽基肽酶-4抑制剂西他列汀对胰腺β细胞功能的影响。
该分析的数据来自三项大型、安慰剂对照的临床研究，这些研究考察了每日一次100mg西他列汀作为二甲双胍治疗的附加治疗或作为单药治疗18或24周的情况。在这些研究中，部分患者同意在基线和研究终点进行作为九点餐耐量试验一部分的广泛血液采样。在相对于进餐开始的-10、0、10、20、30、60、90、120和180分钟采集血样，随后测定血浆葡萄糖和血清C肽浓度。使用C肽最小模型计算β细胞功能参数，该模型估计胰岛素分泌率（ISR）并将ISR分为基础部分（Phi(b)；基础葡萄糖浓度下的ISR）、静态部分（Phi(s)；进餐后基础葡萄糖浓度以上的ISR）和动态部分（Phi(d)；进餐后基础葡萄糖浓度以上葡萄糖浓度增加速率的反应性ISR）。总反应性指数（Phi(total)；平均葡萄糖浓度下的平均ISR）作为Phi(s)、Phi(d)和Phi(b)的函数进行计算。用经过验证的综合指数（ISI）评估胰岛素敏感性。处置指数（DI）评估胰岛素敏感性变化情况下的胰岛素分泌，计算为Phi和ISI的乘积。
与正在进行的二甲双胍治疗联合使用或作为单药治疗时，与安慰剂相比，西他列汀在进餐挑战后餐后血糖波动显著降低。无论治疗方案（二甲双胍附加治疗或单药治疗）如何，西他列汀均使Phi(s)和Phi(total)有显著改善（与安慰剂相比，p<0.05）。对于Phi(d)，与安慰剂相比，西他列汀有数值上的改善，但无统计学意义。西他列汀治疗可增加Phi(b)，但与安慰剂相比的差异仅在单药治疗时显著。西他列汀和安慰剂之间的ISI无显著差异。与安慰剂相比，西他列汀治疗使静态、动态和总测量的DI显著增加（p<0.05）。
在这项基于模型的分析中，与安慰剂相比，西他列汀在2型糖尿病患者的空腹和餐后状态下均改善了β细胞功能。
