Elsevier

The Lancet

Volume 394, Issue 10208, 26 October–1 November 2019, Pages 1519-1529
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(19)32131-2Get rights and content

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 (HbA1c) of 48–58 mmol/mol (6·5–7·5%) and a body-mass index of 22–40 kg/m2. 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 HbA1c 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 HbA1c 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.

Funding

Novartis.

Introduction

Guidelines for the management of hyperglycaemia in type 2 diabetes recommend metformin as first-line pharmacological therapy,1, 2 with sequential intensification and second-line therapy only when glycaemic control (glycated haemoglobin A1c [HbA1c] ≤53 mmol/mol or ≤7·0%) is not achieved. However, with clinical inertia, treatment intensification is often delayed, resulting in loss of glycaemic control3 and exposure to avoidable hyperglycaemia. The UK Prospective Diabetes Study4 established that early treatment to lower glycaemia using metformin was associated with reduction in myocardial infarction, diabetes-related deaths, and all-cause mortality, and a legacy of continued benefit after 10 years. Recent studies5 have highlighted the importance of achieving early glycaemic control within the first 12 months of diagnosis, as this improves long-term glycaemic durability and reduces the risk of associated complications.

One potential strategy to improve the achievement and maintenance of glycaemic control is to introduce combination therapy with two or more agents as early as possible. The rationale for this approach is based on the multiple pathophysiologic mechanisms underlying chronic hyperglycaemia,6 and the complementary mechanisms of action of available glucose-lowering agents.7, 8 In a recent meta-analysis of 15 randomised clinical trials evaluating initial combination therapy with metformin versus metformin monotherapy in patients with untreated type 2 diabetes, Phung and colleagues9 reported that combination therapy with metformin significantly reduced HbA1c, increased attainment of HbA1c below 53 mmol/mol (7·0%), and reduced fasting plasma glucose compared with metformin alone.

Despite these encouraging results, the most recent American Diabetes Association and European Association for the Study of Diabetes consensus statement1 for the treatment of hyperglycaemia in type 2 diabetes noted that although there is some support for early combination therapy because of the greater initial reduction of HbA1c compared with metformin alone, evidence for the superiority of the strategy of early combination therapy over later combination therapy for maintaining glycaemic control is scarce.

The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) study was therefore designed as a 5-year efficacy and safety study, comparing an early combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor vildagliptin with standard-of-care metformin monotherapy, defined as a traditional stepwise approach with metformin as initial therapy and vildagliptin added at the time of metformin failure. The choice of exploring the combination of a dipeptidyl peptidase-4 inhibitor with metformin is supported by glucose-dependent β-cell stimulation by vildagliptin7 and concomitant insulin sensitisation by metformin,10 as well as the established favourable safety profile of both drugs.7, 11

Section snippets

Study design and participants

The VERIFY study design has been previously reported.12 Briefly, 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. During the 5-year treatment period, treatment was initially intensified when loss of glycaemia occurred

Results

Trial enrolment began on March 30, 2012, and was completed on April 10, 2014. The last trial visit was on April, 2019. Of the 4524 participants screened, 2001 eligible participants15 were randomly assigned to either the early combination treatment group (n=998) or the initial metformin monotherapy group (n=1003; figure 2). The most common reasons for study exclusion were HbA1c outside the protocol-defined range and metformin intolerance prior to up-titration. A total of 1598 (79·9%) patients

Discussion

The VERIFY study has shown that early combination treatment with metformin and vildagliptin improves glycaemic durability in patients with type 2 diabetes compared with standard-of-care initial metformin monotherapy followed by sequential combination with vildagliptin. Early combination treatment significantly reduced the probability of initial treatment failure, the time to second treatment failure, and the time to treatment failure compared with monotherapy throughout the 5-year study

Data sharing

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymised to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The criteria and process for trial data availability are described online.

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