NPC Archive Item: Top-line results from the DURATION-6 study show that once-weekly formulation of exenatide failed to achieve non-inferiority to liraglutide&#9660

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21 April 2011

According to a press release, results from the DURATION-6 study show that once weekly exenatide 2mg s.c. did not achieve the primary endpoint of non-inferiority  to 1.8mg once daily s.c. liraglutide in reducing HbA1c levels.

As yet, there are no data that shows exenatide reduces the risk of macrovascular or microvascular events. A market application has been made for this new long-acting formulation of the drug. Although the dosing regimen may have some advantages for patients, these top-line results suggest it does not appear to have any advantage over daily liraglutide in terms of HbA1C reduction.

A NICE appraisal of this weekly formulation as either dual or triple therapy is likely to start mid-April 2011. Local decision making bodies need to plan for the managed introduction of the product; they may wish to take into account that the existing NICE Clinical Guideline advises a third-line role for exenatide twice daily for people who meet specific criteria.

What is the background to this?
Exenatide, an incretin-based therapy for T2DM, is currently available as a twice daily subcutaneous injection (Byetta®). A long-acting once weekly subcutaneous formulation is now in development and has recently received a Positive Opinion from the European Medicines Agency (EMA) for use in dual or triple therapy regimens.

The NICE Clinical Guideline on newer agents for T2DM recommends the twice-daily formulation of exenatide as a third-line option in patients who remain poorly controlled despite metformin and a sulphonylurea and have:

  • 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.

Treatment with the drug should only continue if a beneficial response occurs as measured by a reduction of at least 1.0 percentage point in HbA1c and a weight loss of at least 3% of initial body weight at six months.

What does this press release say?
The DURATION-6, open-label superiority study enrolled patients with type 2 diabetes who were unable to achieve adequate glycaemic control with diet and exercise in conjunction with metformin, a sulfonylurea, metformin plus a sulfonylurea or metformin plus pioglitazone. Patients were randomised to once weekly 2mg exenatide subcutaneous injection (n=461) or subcutaneous liraglutide, with forced titration to 1.8mg per day (n=451). The pre-specified primary endpoint was non-inferiority to liraglutide in terms of reduction in HbA1C from baseline to week 26. Patients in the weekly exenatide group achieved a reduction of 1.3% compared to 1.5% in the liraglutide group and failed to demonstrate non-inferiority to liraglutide.

Despite gastrointestinal adverse events, including nausea in 20% of liraglutide and 9% of weekly exenatide patients, more than 85% of patients in both groups completed the study. Liraglutide was dosed at the maximum licensed dose of 1.8mg daily, and therefore a high incidence of nausea and vomiting could have been expected. Nausea was reported by 40% of patients on this dose of liraglutide in the LEAD-4 Met+TZD trial. Current NICE guidance recommends use of a 1.2mg liraglutide once daily dose in treatment regimens. Injection site nodules were reported by 10% of exenatide and 1% of liraglutide patients. No major hypoglycaemic events were reported in either group.

No other details are available in the press release and statistical significance of data is not stated. The manufacturer plans to submit the results for full publication in due course.

The once weekly formulation of exenatide has been the subject of a series of DURATION trials. Details of the DURATION 1 trial are available here. We have discussed DURATION 2 previously and a Rapid Review of DURATION 3 is also available.

Further information on the management of type 2 diabetes is available in the NPC’s eLearning materials.

Please comment on this rapid review in the NPC discussion rooms, or using our feedback form.

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