Department of Clinical Research, Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA.
Diabetes Obes Metab. 2012 Jan;14(1):67-76. doi: 10.1111/j.1463-1326.2011.01492.x. Epub 2011 Nov 3.
To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β-cell function in patients with type 2 diabetes.
The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI.
At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β-cell function relative to their respective monotherapy groups.
After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β-cell function were found with treatments for up to 2 years.
研究西他列汀和二甲双胍单独及联合应用对 2 型糖尿病患者β细胞功能模型参数的影响。
本分析中使用的数据来自一项为期 104 周的研究，该研究包括 24 周的安慰剂和活性对照期、30 周的活性对照延续期和另外 50 周的活性对照扩展期。患者被随机分配至 6 种盲法治疗组之一：西他列汀 50mg+二甲双胍 1000mg 每日 2 次、西他列汀 50mg+二甲双胍 500mg 每日 2 次、二甲双胍 1000mg 每日 2 次、二甲双胍 500mg 每日 2 次、西他列汀 100mg 每日 1 次或安慰剂。安慰剂组患者在第 24 周时以盲法方式换用二甲双胍 1000mg 每日 2 次。部分患者自愿在基线和第 24、54 和 104 周时进行频繁取样的餐耐量试验。用 C 肽最小模型评估β细胞反应性。静态成分（Φ(s)）估计与基础葡萄糖浓度以上相关的胰岛素分泌率。动态成分（Φ(d)）与葡萄糖变化率相关。总指数（Φ(total)）代表对血糖刺激的整体反应，是根据 Φ(s)和 Φ(d)计算的。胰岛素敏感性用 Matsuda 指数（ISI）估计。根据 Φ(total)和 ISI 计算评估胰岛素分泌相对于现有胰岛素敏感性的处置指数。
与安慰剂组相比，所有活性治疗组在第 24 周时餐后血糖均显著降低。与安慰剂相比，所有活性治疗组在第 24 周时，Φ(s)、Φ(total)和处置指数均较基线显著改善。与单药治疗组相比，西他列汀和二甲双胍初始联合治疗通常具有更大的效果。以基线百分比变化的中位数表示，低剂量和高剂量联合组的Φ(s)分别增加了 137%和 177%，高剂量二甲双胍、低剂量二甲双胍、西他列汀单药和安慰剂组分别增加了 85%、54%、73%和-9%。在第 54 和 104 周时，联合治疗组相对于各自的单药治疗组继续表现出更大的β细胞功能改善。
与安慰剂相比，西他列汀或二甲双胍单药治疗 24 周后β细胞功能得到改善；此外，初始联合治疗比单药治疗有更大的改善。治疗 2 年以上仍可改善β细胞功能。
