Elsevier

The Lancet

Volume 374, Issue 9683, 4–10 July 2009, Pages 39-47
The Lancet

Articles
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

https://doi.org/10.1016/S0140-6736(09)60659-0Get rights and content

Summary

Background

Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.

Methods

Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1·8 mg once a day (n=233) or exenatide 10 μg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA1c). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882.

Findings

Mean baseline HbA1c for the study population was 8·2%. Liraglutide reduced mean HbA1c significantly more than did exenatide (−1·12% [SE 0·08] vs −0·79% [0·08]; estimated treatment difference −0·33; 95% CI −0·47 to −0·18; p<0·0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (−1·61 mmol/L [SE 0·20] vs −0·60 mmol/L [0·20]; estimated treatment difference −1·01 mmol/L; 95% CI −1·37 to −0·65; p<0·0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide −3·24 kg vs exenatide −2·87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.

Interpretation

Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.

Funding

Novo Nordisk A/S.

Introduction

Type 2 diabetes is an increasingly common chronic disease. Although diagnosed on the basis of hyperglycaemia, it is associated with broad metabolic abnormalities that contribute to microvascular and macrovascular complications. Importantly, unmet pharmacological needs remain despite great advances in diabetes care and treatment, and availability of ten different antihyperglycaemic medication classes.

To reach glycaemic targets, various antihyperglycaemic drugs—alone or in combination—are commonly required in addition to lifestyle interventions. Some agents are eventually combined with insulin in complex regimens that need daily titration based on glucose monitoring. Careful selection of therapies and follow-up is crucial to achieve glycaemic control while avoiding other substantial problems, particularly weight gain and hypoglycaemia.1

Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells, mainly in response to food intake. It has broad physiological effects, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner, and resulting in reduced hepatic glucose production. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety with reduced food intake. In animal models, it promotes β-cell proliferation and probably neogenesis, while reducing apoptosis.2, 3, 4 Because GLP-1 is rapidly degraded by dipeptidyl peptidase-4,5 GLP-1 receptor agonists based on exendin or human analogues resistant to dipeptidyl peptidase-4 have been developed.

The current consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) about the medical management of hyperglycaemia in type 2 diabetes suggests that comprehensive lifestyle management combined with metformin should be initiated at diagnosis, except in cases of severely uncontrolled hyperglycaemia.1 Subsequently, treatment should be intensified promptly if glycosylated haemoglobin (HbA1c) values exceed the ADA target of less than 7%. Recently, the consensus panel added GLP-1 receptor agonists as options when weight loss or risk of hypoglycaemia are major considerations. This decision was based on clinical data for the exendin-based GLP-1 receptor agonist exenatide, a molecule with 53% aminoacid identity with human GLP-1. Exenatide causes a decrease in HbA1c values of 0·5–1·0%, and treatment is associated with weight loss1 and with frequent gastrointestinal side-effects that tend to subside over time but can lead to treatment discontinuation. With elimination by glomerular filtration and a half-life of 2·4 h, administration of exenatide twice a day 0–60 min before meals is recommended.6 The drug's predominant effect is the reduction of postprandial glucose concentration, especially after breakfast and dinner.7

Liraglutide is a human GLP-1 analogue with one aminoacid substitution (Arg34Lys) and a C-16 palmitic-acid side chain attached via a glutamyl spacer. These modifications result in slower absorption from subcutaneous tissue, reversible albumin binding, and resistance to GLP-1 inactivation by dipeptidyl peptidase-4. Unlike exenatide, liraglutide is 99% bound to albumin, with free liraglutide degraded by endogenous peptidases, and not via renal elimination.8 Liraglutide injection produces maximal concentrations within 10–14 h after administration, with a half-life of 13 h.9 Liraglutide has been developed as a once-a-day treatment for type 2 diabetes, as an adjunct to lifestyle therapy and in combination with oral antidiabetic drugs.7

Because the molecular structure, aminoacid sequence identity shared with human GLP-1, metabolism, and pharmacokinetics of exenatide and liraglutide differ, we designed the liraglutide effect and action in our diabetes (LEAD-6) study to compare their efficacy and safety. We report the results of the 26-week randomised comparator trial.

Section snippets

Participants

Participants aged 18–80 years with type 2 diabetes were eligible if their HbA1c value was 7–11% and if they had a body-mass index (BMI) of 45·0 kg/m2 or less on stable treatment with maximally tolerated doses of metformin, sulphonylurea, or both, for 3 months or more. Exclusion criteria included previous insulin treatment (except short-term treatment for intercurrent illness), previous exposure to exenatide or liraglutide, impaired liver or renal function, clinically significant cardiovascular

Results

464 participants were randomly assigned to treatment (figure 1). Three participants received treatment without randomisation (2 in the liraglutide group, 1 in exenatide group), and they were included in the safety but not intention-to-treat populations. 33 of 235 participants withdrew from liraglutide and 45 of 232 from exenatide treatment; withdrawal rates were not significantly different between groups. Adverse events were the most common reason for withdrawal in both groups. The

Discussion

This trial provides a direct comparison of efficacy and safety between liraglutide and exenatide, both of which interact with the GLP-1 receptor but differ in aminoacid identity with human GLP-1, frequency and timing of administration, clearance, and especially pharmacokinetics. The results show that liraglutide provides superior overall glycaemic control on the basis of HbA1c data.

We show HbA1c reductions that are consistent with those from other studies with liraglutide and exenatide.

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