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24th June 2009, updated 16th July 2009 (action and what is the background to this)
The open-label LEAD-6 study compared once daily liraglutide▼ to twice daily exenatide▼ in 264 people with type 2 diabetes mellitus. After 26 weeks, liraglutide produced a greater change in HbA1c from baseline and was generally better tolerated.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
The role of hypoglycaemic agents (apart from metformin) in the management of type 2 diabetes (T2DM) is controversial, as we have previously blogged. Local decision making bodies will need to consider the place in therapy of new agents such as liraglutide alongside other interventions for T2DM. We should bear in mind that recent NICE guidance (see our blog) advised a third-line role for exenatide, and only in certain people with T2DM – as yet, there is no evidence that these agents reduce the risk of cardiovascular events.
Update:
Liraglutide has been marketed in the week commencing 6th July. A black triangle (▼) has been added to this blog to indicate that all suspected adverse reactions to liraglutide should be reported to the CHM via the yellow card system.
What is the background to this?
Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue that is recommended for use in the treatment of T2DM in combination with other antidiabetic agents. It is administered as a once-daily subcutaneous injection.
Update:
Further details can be found in the Summary of Product Characteristics. The product is formulated as a pre-filled pen available in a 2x3ml pen pack, £78.48 or a 3x3ml pen pack, £117.72.
What does this study claim?
Liraglutide was more effective than exenatide at reducing HbA1c from baseline to week 26. The estimated treatment difference was –0.33; 95% confidence interval [CI] –0.47 to –0.18, P<0.0001. Adverse events mainly affected the gastro-intestinal system, and included nausea and diarrhoea.
How does this relate to other studies?
A NICE clinical guideline on the management of T2DM was published in May 2009. This covered newer agents such as exenatide but not liraglutide which did not receive a positive opinion in time to be included. The guidance recommends that if exenatide is used, it should be continued only if the patient has a beneficial metabolic response (reduction of at least 1% in HbA1c and a weight loss of at least 3% of initial body weight at six months).
A NICE 20th wave appraisal is proposed for liraglutide, but no timelines are available currently.
We have previously blogged two other LEAD studies (LEAD-2 and LEAD-3). and information is also available in our On the Horizon review (NHSnet connection required).
So what?
The LEAD-6 study, in common with many previously published diabetes trials, used a disease-oriented or surrogate outcome, HbA1c, rather than a patient-oriented outcome such as the effect on cardiovascular events and mortality. The role of tight control of blood glucose and the use of hypoglycaemic agents is controversial in people with type 2 diabetes, as we have previously blogged. As NICE suggest, once any symptoms of hyperglycaemia are controlled, addressing cardiovascular risk factors such as smoking cessation, lifestyle modification and the use of drug interventions such as blood pressure lowering agents, as well as statins and metformin should be the priority for people with type 2 diabetes.
In both treatment groups in this small study, HbA1c reached its lowest point at 12 weeks and then started to climb (but remained below baseline) so it is not known if the treatment effect is sustained. The study was not powered to assess rare adverse events and additional data are required to assess the long-term benefits of liraglutide.
Although once daily liraglutide appears to be more effective than twice daily exenatide in lowering HbA1c in this six month, open-label trial it is not known how liraglutide would compare to the once weekly formulation of exenatide which is in development. We have discussed this latter preparation previously.
Exenatide is licensed for use in combination with metformin and/or sulphonylureas in patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies. Liraglutide has received authorisation for use in combination with metformin or a sulphonylurea, and in combination with metformin and a sulphonylurea or metformin and a thiazolidinedione (glitazone) in patients with insufficient glycaemic control despite dual therapy.
The NICE clinical guideline suggests a third-line position for exenatide in patients with:
- a body mass index (BMI) = 35.0kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific problems associated with high body weight, or
- a BMI < 35.0kg/m2, and where therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related co-morbidities.
More information on T2DM can be found on the cardiovascular floors of NPC.
Design: phase III, open-label, randomised, non-inferiority trial.
Patients: aged 18–80 years with T2DM which was stable on maximally tolerated doses of metformin, sulphonylurea or both for three months or more. Patients were required to have an HbA1c of between 7–11% and a BMI of 45.0kg/m2 or less at entry into the study. Mean baseline HbA1c for both groups was 8.2%. The patient population for efficacy analysis was by intention to treat (ITT).
Intervention and comparison: subcutaneous (s/c) liraglutide (n=233) was compared to s/c exenatide (n=231). The trial started with a dose escalation period of two weeks for liraglutide and four weeks for exenatide. This was followed by 22–24 weeks of maintenance treatment at doses of 1.8mg once daily for liraglutide and 10 micrograms twice daily for exenatide.
Outcomes and results: the primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a secondary outcome. The mean change in HbA1c with liraglutide was –1.12% [standard error, SE 0.08] versus –0.79% [SE 0.08] for exenatide. The estimated treatment difference was –0.33; 95% CI –0.47 to –0.18, P<0.0001.
In non-interiority studies it is acceptable to check for superiority if non-inferiority is proven in the intention-to-treat and per protocol populations. In this trial, liraglutide was shown to be both non-inferior and superior to twice daily exenatide.
Weight loss was similar in each group (about 3kg over six months). Patient satisfaction, as measured by the Diabetes Treatment Satisfaction Questionnaire, was better in the liraglutide group.
Safety: similar numbers of patients withdrew from each group, mainly due to adverse events. 74.9% of liraglutide and 78.9% of exenatide patients reported adverse events. Nausea was the most commonly reported adverse event (25.5% liraglutide versus 28.0% exenatide) but this was less persistent in the liraglutide patients. One episode of severe hypoglycaemia requiring medical attention was reported in the exenatide group.
No episodes of acute pancreatitis were reported in either group. However, acute pancreatitis has been reported previously with GLP-1 analogues and the authors of a Comment linked to the LEAD-6 trial’s online publication suggest that GLP-1 analogues should not be given to patients at risk of pancreatitis.
Although more liraglutide patients experienced serious adverse events, these were judged unlikely to be related to study medication. However, one such report concerned a thyroid neoplasm. Increased levels of calcitonin have been observed with liraglutide, although in the LEAD-6 study they decreased. The effect on calcitonin concentration and the risk of thyroid tumours may become clearer when longer term data are available.
Sponsorship: Novo Nordisk A/S.
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