Elsevier

The Lancet

Volume 373, Issue 9675, 9–15 May 2009, Pages 1607-1614
The Lancet

Articles
Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance

https://doi.org/10.1016/S0140-6736(09)60222-1Get rights and content

Summary

Background

The increased prevalence of type 2 diabetes mellitus is a major concern for health providers. We therefore assessed whether voglibose, an α-glucosidase inhibitor, could prevent the development of type 2 diabetes in high-risk Japanese individuals with impaired glucose tolerance.

Methods

1780 eligible patients on a standard diet and taking regular exercise with impaired glucose tolerance were randomly assigned to oral voglibose 0·2 mg three times a day (n=897) or placebo (n=883) in a multicentre, double-blind, parallel group trial. Treatment was continued until participants developed type 2 diabetes (primary endpoint) or normoglycaemia (secondary endpoint), or for a minimum of 3 years, subject to the findings of an interim analysis. Analysis was by full analysis set. This trial is registered with the University Hospital Medical Information Network (UMIN) clinical trials registry, number UMIN 000001109.

Findings

In the interim analysis, voglibose was better than placebo (p=0·0026) in individuals treated for an average of 48·1 weeks (SD 36·3). Patients treated with voglibose had a lower risk of progression to type 2 diabetes than did those on placebo (50 of 897 vs 106 of 881; hazard ratio 0·595, 95% CI 0·433–0·818; p=0·0014). More people in the voglibose group achieved normoglycaemia than did those in the placebo group (599 of 897 vs 454 of 881; 1·539, 1·357–1·746; p<0·0001). 810 (90%) of 897 patients in the voglibose group had adverse events versus 750 (85%) of 881 in the placebo group. Serious adverse events (all one each) in the voglibose group were cholecystitis, colonic polyp, rectal neoplasm, inguinal hernia, liver dysfunction, and subarachnoid haemorrhage, and in the placebo group were cerebral infarction and cholecystitis.

Interpretation

Voglibose, in addition to lifestyle modification, can reduce the development of type 2 diabetes in high-risk Japanese individuals with impaired glucose tolerance.

Funding

Takeda.

Introduction

Metabolic disorders with a predisposition towards impaired glucose intolerance and ultimately type 2 diabetes mellitus are a major health problem.1, 2 In 2002, the Japanese Ministry of Health, Labour and Welfare estimated that 7·4 million patients in Japan had diabetes and, more worryingly, 8·8 million people were considered to be possibly diabetic on the basis of HbA1c levels that were between 5·6% and 6·1%. The number of individuals with diabetes had increased by almost 2 million since the 1997 survey.3

Although type 2 diabetes has a genetic basis, evidence supports a key part played by modifiable behavioural risk factors such as obesity and physical inactivity.4 Disorders such as impaired glucose intolerance and metabolic syndrome seem to be intermediate stages between normal glucose tolerance and overt diabetes, and greatly increase the risk of type 2 diabetes and its attendant macroangiopathy.5, 6, 7 The International Diabetes Federation Taskforce on Prevention and Epidemiology convened a consensus workshop in Lisbon, Portugal, and recommended a three-step approach—identification of those at risk, measurement of the risk, and appropriate intervention—to prevent or delay the development of type 2 diabetes.8 At the core of this strategy is lifestyle modification—ie, dietary control and increased exercise, but the International Diabetes Federation recognises that pharmacotherapy might be needed in some individuals who cannot maintain such behavioural changes.

The European DECODE study,5, 9 a meta-analysis of 13 prospective cohort studies, some in Asian individuals,10 reported that impaired glucose tolerance is a prognostic factor for both all-cause and cardiovascular death. Thus, impaired glucose tolerance not only increases the likelihood of developing diabetes, but also exacerbates macrovascular pathological changes. Treatment strategies designed to slow or delay the progression of impaired glucose tolerance therefore have the potential to reduce cardiovascular morbidity and mortality, and some of the burden on health-care resources. Indeed, results of large, well designed trials have suggested that intensive diet and exercise programmes,11, 12, 13 and pharmacological intervention,13, 14, 15, 16, 17, 18, 19, 20 help prevent or delay the development of diabetes in high-risk individuals with impaired glucose tolerance.

Diabetes is a global problem, and its prevalence in Asia is predicted to increase substantially over the next 25 years. Studies specifically involving Asian people include the Da Qing study in China,11 the Indian Diabetes Prevention Programme,21 and a Japanese lifestyle intervention trial.22 Until now, no active drug intervention trial in Japanese individuals with impaired glucose tolerance has been reported. We therefore investigated the effectiveness of voglibose, an α-glucosidase inhibitor that reduces diurnal insulin secretion,23, 24, 25 for prevention of the development of type 2 diabetes in Japanese patients with impaired glucose tolerance.

Section snippets

Study design

This study was a multicentre, randomised, double-blind, parallel group comparison of voglibose and placebo in Japanese individuals with impaired glucose tolerance. From April, 2003, we aimed to treat people until type 2 diabetes or normoglycaemia was diagnosed, or for at least 3 years. The Independent Data Monitoring Committee planned an interim analysis to investigate whether or not to continue the study on the basis of efficacy and safety findings.

Procedure

We recruited individuals from 103 Japanese

Results

The Independent Data Monitoring Committee did an interim analysis in March, 2007, with data from 1778 individuals that had been gathered by October, 2006. The cumulative number of cases of type 2 diabetes in the interim analysis was 84 in the placebo group and 40 in the voglibose group. The HR was 0·577 (two-sided 95% CI 0·404–0·825; p=0·0026), verifying the efficacy of voglibose compared with placebo and, accordingly, the Independent Data Monitoring Committee made the decision to terminate the

Discussion

In our trial, even though we reinforced diet and exercise programmes, individuals remained at risk of developing diabetes. Voglibose significantly reduced the risk of individuals with impaired glucose tolerance developing type 2 diabetes and significantly increased the proportion of people who achieved normoglycaemia compared with placebo. Because of the high normalisation rate and the early termination of the trial, the average duration of treatment was about 1 year. Thus, the clinically

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