瑞士诺华制药公司Stefano Del Prato课题组比较了早期联合使用维格列汀和二甲双胍与二甲双胍单药治疗新诊断的2型糖尿病的血糖耐久性。 该研究2019年9月19日在线发表于《柳叶刀》杂志。

VERIFY是一项随机、双盲、平行组研究，在34个国家的254个中心进行。2012年3月30日至2014年4月10日，研究组招募了2001名参与者，年龄为18-70岁，入组前2年内诊断出2型糖尿病，糖化血红蛋白（HbA1c）为6.5%-7.5%，体重指数为22-40 kg/m²。患者按1：1随机分配，998例接受二甲双胍+维格列汀的早期联合治疗，1003例接受二甲双胍+安慰剂的标准治疗。若连续相隔13周患者的HbA1c未降到7.0%以下，则接受联合治疗。

共有1598例（79.9%）患者完成了为期5年的研究，早期联合治疗组811例（81.3%），单一治疗组787例（78.5%）。联合治疗组首次治疗失败429例（43.6%），显著低于单一治疗组（614例，62.1%），风险比为0.51。单一治疗组治疗失败的中位观察时间为36.1个月，而早期联合治疗组由于超出了研究持续时间，只能估计其治疗失败的中位观察时间为61.9个月。两种治疗方法均安全，患者耐受性良好，没有意外或不良事件，也没有与治疗相关的死亡事件。

综上，与目前的标准治疗相比，维格列汀联合二甲双胍对新确诊的2型糖尿病患者进行早期干预可获得更大更持久的长期益处。

据悉，早期强化治疗控制血糖持续良好是延缓糖尿病并发症的关键。虽然大家都认为初始联合治疗比传统逐步疗法提供了更多的机会，但其有效性仍有待确定。

附：英文原文

Title: Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial

Author: David R Matthews, Pivi M Paldánius, Pieter Proot, YannTong Chiang, Michael Stumvoll, Stefano Del Prato

Issue&Volume: 19 September 2019

Summary:

Background

Early treatment intensification leading to sustained good glycaemic control is essential to delay diabetic complications. Although initial combination therapy has been suggested to offer more opportunities than a traditional stepwise approach, its validity remains to be determined.

Methods

Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) was a randomised, double-blind, parallel-group study of newly diagnosed patients with type 2 diabetes conducted in 254 centres across 34 countries. The study consisted of a 2-week screening visit, a 3-week metformin-alone run-in period, and a 5-year treatment period, which was further split into study periods 1, 2, and 3. Patients aged 18–70 years were included if they had type 2 diabetes diagnosed within 2 years prior to enrolment, and centrally confirmed glycated haemoglobin A1c (HbA 1c) of 48–58 mmol/mol (6·5–7·5%) and a body-mass index of 22–40 kg/m 2. Patients were randomly assigned in a 1:1 ratio either to the early combination treatment group or to the initial metformin monotherapy group, with the help of an interactive response technology system and simple randomisation without stratification. Patients, investigators, clinical staff performing the assessments, and data analysts were masked to treatment allocation. In study period 1, patients received either the early combination treatment with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and placebo twice daily. If the initial treatment did not maintain HbA 1c below 53 mmol/mol (7·0%), confirmed at two consecutive scheduled visits which were 13 weeks apart, patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of the placebo and entered study period 2, during which all patients received the combination therapy. The primary efficacy endpoint was the time from randomisation to initial treatment failure, defined as HbA 1c measurement of at least 53 mmol/mol (7·0%) at two consecutive scheduled visits, 13 weeks apart from randomisation through period 1. The full analysis set included patients who received at least one randomised study medication and had at least one post-randomisation efficacy parameter assessed. The safety analysis set included all patients who received at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, NCT01528254.

Findings

Trial enrolment began on March 30, 2012, and was completed on April 10, 2014. Of the 4524 participants screened, 2001 eligible participants were randomly assigned to either the early combination treatment group (n=998) or the initial metformin monotherapy group (n=1003). A total of 1598 (79·9%) patients completed the 5-year study: 811 (81·3%) in the early combination therapy group and 787 (78·5%) in the monotherapy group. The incidence of initial treatment failure during period 1 was 429 (43·6%) patients in the combination treatment group and 614 (62·1%) patients in the monotherapy group. The median observed time to treatment failure in the monotherapy group was 36·1 (IQR 15·3–not reached [NR]) months, while the median time to treatment failure time for those receiving early combination therapy could only be estimated to be beyond the study duration at 61·9 (29·9–NR) months. A significant reduction in the relative risk for time to initial treatment failure was observed in the early combination treatment group compared with the monotherapy group over the 5-year study duration (hazard ratio 0·51 [95% CI 0·45–0·58]; p<0·0001). Both treatment approaches were safe and well tolerated, with no unexpected or new safety findings, and no deaths related to study treatment.

Interpretation

Early intervention with a combination therapy of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care initial metformin monotherapy for patients with newly diagnosed type 2 diabetes.

DOI: 10.1016/S0140-6736(19)32131-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32131-2/fulltext