Elsevier

The Lancet

Volume 373, Issue 9662, 7–13 February 2009, Pages 473-481
The Lancet

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Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial

https://doi.org/10.1016/S0140-6736(08)61246-5Get rights and content

Summary

Background

New treatments for type 2 diabetes mellitus are needed to retain insulin–glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder.

Methods

In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1·2 mg [n=251] or 1·8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA1c). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723.

Findings

At 52 weeks, HbA1c decreased by 0·51% (SD 1·20%) with glimepiride, compared with 0·84% (1·23%) with liraglutide 1·2 mg (difference −0·33%; 95% CI −0·53 to −0·13, p=0·0014) and 1·14% (1·24%) with liraglutide 1·8 mg (−0·62; −0·83 to −0·42, p<0·0001). Five patients in the liraglutide 1·2 mg, and one in 1·8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so.

Interpretation

Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA1c, weight, hypoglycaemia, and blood pressure than does glimepiride.

Funding

Novo Nordisk A/S.

Introduction

Type 2 diabetes mellitus is a progressive disease; many treatments work early in the course of disease but do not remain effective.1, 2 Glucagon-like peptide 1 (GLP-1) stimulates glucose-dependent insulin secretion, suppresses glucagon secretion, and moderates appetite by delaying gastric emptying and reducing hunger.3 Endogenous GLP-1 has a very short half-life (1·5 min) because of rapid degradation by dipeptidyl peptidase 4,3 which restricts its therapeutic usefulness. Liraglutide is an analogue of human GLP-1 with 97% homology to the endogenous protein4 and a half life of 13 h, which gives it a pharmacokinetic profile suitable for once daily treatment.5

Liraglutide restores glucose-dependent insulin secretion after one injection in patients with type 2 diabetes mellitus.6 In a 14 week monotherapy trial,7 treatment with liraglutide produced substantial and clinically significant reductions in fasting and postprandial glucose concentrations and glycosylated haemoglobin (HbA1c), resulted in moderate weight loss, and had a very low risk of hypoglycaemia. Common side-effects of liraglutide treatment include gastrointestinal side-effects, such as nausea, diarrhoea, and vomiting.

We investigated the safety and efficacy of two doses of liraglutide versus glimepiride over 52 weeks for treatment of type 2 diabetes mellitus. We studied patients thought to be in the early stages of disease because they were either drug-naive, treated with lifestyle modifications, or had failed to achieve control with a single oral drug at less than 50% of maximum approved dose.

Section snippets

Participants and study design

Participants were aged 18–80 years, had body-mass index of 45 kg/m2 or less, and were diagnosed with type 2 diabetes mellitus. Eligible patients had been treated with diet and exercise (36·5% of patients randomised) or up to half the highest dose of oral antidiabetic drug monotherapy (63·5%) including sulphonylureas, meglitinides, aminoacid derivatives, biguanides, α-glucosidase inhibitors, and thiazolidinediones (1500 mg metformin or 30 mg pioglitazone were allowed) for at least 2 months.

Results

The three treatment groups were well balanced at baseline (figure 1, table 1). In the liraglutide treatment groups, most participants who withdrew did so because of other reasons or adverse events, whereas in the glimepiride group, other or ineffective therapy were the most common reasons for withdrawal. Mean baseline HbA1c and fasting plasma glucose values were 8·2% and 9·5 mmol/L, respectively. Mean baseline weight was 92·6 kg and mean blood pressure was 129/79 mm Hg.

HbA1c values decreased

Discussion

Treatment with liraglutide as monotherapy provided better glycaemic control for 52 weeks than did glimepiride, a traditional first-line secretagogue therapy for type 2 diabetes mellitus, in participants previously treated with either diet and exercise or oral antidiabetic monotherapy. Liraglutide improved glycaemic control with a low rate of hypoglycaemia.

Liraglutide led to decreases in both fasting and postprandial plasma glucose, and its 13 h half-life makes it suitable for once-daily use.

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