Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus
Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus
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DOI：
10.1111/j.1463-1326.2009.01040.x
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Goodman, M.
中科院分区：
文献类型：
--
作者：
Bosi, E.;Dotta, F.;Goodman, M.
目的：比较维达格列汀和二甲双胍初始联合治疗与单独单用治疗初治的2型糖尿病(T2 DM)患者的疗效和安全性。治疗--糖化血红蛋白(1c)为7.5-11%的T2 DM患者(N=1179)被随机分为三组，分别接受维格列汀联合治疗(50 mg+1000 mg，每日两次)、维达格列汀联合小剂量二甲双胍治疗(50 mg+500 mg，每日两次)、维达格列汀单一治疗(50 mg，每日两次)或大剂量二甲双胍联合治疗(1000 mg，每日两次)。研究的主要目的是证明在第24周的终点，用任何一种联合疗法降低HbA(1c)的效果优于两种单一疗法。未通过血糖筛查标准[HbA(1c)>；11%或空腹血糖15 mmol/L(270 mg/dl)]的患者可进入为期24周的单臂亚研究。这些患者(N=94)接受开放标签的维格列汀和大剂量二甲双胍联合治疗(100 mg+1000 mg，每日两次)。从可比的基线值(8.6-8.7%)来看，所有四个治疗组的HbA(1c)都有所下降，在维达格列汀和大剂量二甲双胍联合治疗中下降幅度最大。维格列汀联合大剂量二甲双胍治疗、维达格列汀联合小剂量二甲双胍治疗、维达格列汀联合小剂量二甲双胍治疗、维达格列汀联合小剂量二甲双胍治疗组、维达格列汀联合二甲双胍治疗组、维达格列汀联合治疗组、维格列汀联合二甲双胍治疗组的(SE)HbA(1c)较治疗前平均变化分别为-1.8%(0.06%)、-1.6%(0.06%)、-1.1%(0.06%)和-1.4%(0.06%)。维格列汀加大剂量二甲双胍联合疗法(P<；0.001比两种单一疗法)和维达格列汀加小剂量二甲双胍联合疗法(P<；0.001和p=0.004，分别比维达格列汀和二甲双胍单一疗法)组间差异更大。基线HbA(1c)值越高，HBA(1c)下降幅度越大，分别为-3.2%(0.22%)、-2.7%(0.22%)、-1.5%(0.24%)和-2.6%(0.26%)，发生在基线HbA(1c)和Gt；=10%的患者中。维格列汀联合大剂量二甲双胍治疗空腹血糖[基线变化-2.63(0.13)mmoL/L]优于两种单药治疗[分别为-1.26(0.13)mmo1/L和-1.92(0.13)mmo1/L；p<；0.001]。在任何一种联合治疗中，都没有低血糖或严重低血糖的发生率，也没有与体重增加相关。所有治疗耐受性良好，总体不良事件发生率相似。尽管维达格列汀和小剂量二甲双胍联合治疗可显著降低HbA(1c)，但与单用二甲双胍相比，维达格列汀加小剂量二甲双胍联合治疗组的胃肠道(GI)耐受性更好。在未接受治疗的患者中，维达格列汀与大剂量和小剂量二甲双胍的联合治疗提供了比单一治疗更好的疗效，总体耐受性相似，低血糖风险较低。在小剂量二甲双胍中加入维格列汀而不是上调二甲双胍的潜在剂量节约效应，可能允许患者实现同等或更高的HBA(1c)降低，而不会出现与高剂量二甲双胍相关的胃肠道耐受性问题。
To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment-naive patients with type 2 diabetes mellitus (T2DM).This was a 24-week, randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA(1c)) of 7.5-11% (N = 1179) were randomized equally to receive vildagliptin plus high-dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low-dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high-dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA(1c) reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic-screening criteria [HbA(1c) > 11% or fasting plasma glucose (FPG) > 15 mmol/l (270 mg/dl)] could enter a 24-week, single-arm substudy. These patients (N = 94) received open-label vildagliptin plus high-dose metformin combination therapy (100 mg + 1000 mg twice daily).From comparable baseline values (8.6-8.7%), HbA(1c) decreased in all four treatment groups, to the greatest extent with vildagliptin plus high-dose metformin combination therapy. Mean (SE) HbA(1c) change from baseline was -1.8% (0.06%), -1.6% (0.06%), -1.1% (0.06%) and -1.4% (0.06%) with vildagliptin plus high-dose metformin combination therapy, vildagliptin plus low-dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between-group difference was superior with vildagliptin plus high-dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low-dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA(1c) values were linked to greater HbA(1c) reductions, with changes of -3.2% (0.22%), -2.7% (0.22%), -1.5% (0.24%) and -2.6% (0.26%) respectively, occurring in patients with baseline HbA(1c) >= 10%. Reductions in FPG were superior with vildagliptin plus high-dose metformin combination therapy [change from baseline -2.63 (0.13) mmol/l] compared with both monotherapies [-1.26 (0.13) mmol/l and -1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA(1c) lowering, the vildagliptin plus low-dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy.In treatment-naive patients, combinations of vildagliptin and both high-dose and low-dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose-sparing effect of adding vildagliptin to low-dose metformin in preference to the up-titration of metformin may allow patients to achieve equivalent or superior HbA(1c) lowering without the GI tolerability issues associated with higher doses of metformin.