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18 November 2010
We have previously discussed the 30-week DURATION-1 trial of long-acting exenatide 2mg once weekly versus 10micrograms exenatide▼ twice daily in adults with type 2 diabetes (T2DM). In a subsequent extension (n=258), improvements in HbA1c with once weekly exenatide were maintained, by an average of 2%, through to 52 weeks.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
A licence application has been made for this new long-acting formulation of exenatide and a NICE appraisal is planned for exenatide weekly as either dual or triple therapy. No timelines are available currently for this guidance, therefore local decision making bodies need to plan for the managed introduction of the product. They may wish to take into account that existing NICE guidance advises a third-line role for exenatide twice daily, and only in certain people with T2DM. As yet, there are no data that shows exenatide reduces macrovascular or microvascular events in people with type 2 diabetes mellitus.
What is the background to this?
Exenatide is an incretin-based therapy for T2DM. It is currently available as a twice daily subcutaneous injection (Byetta®). A long-acting once weekly subcutaneous formulation is now in development and has been submitted to the European Medicines Agency (EMA). These two formulations have been compared in the DURATION-1 study, the first 30 weeks of which were the subject of a previous review. We now discuss the 22-week extension to this trial.
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 6 months.
NICE guidance on this long-acting formulation for second-line (dual therapy) or third-line (triple therapy) is in progress, but no timeline for final guidance is available currently.
A Drug Safety Update issued in March 2009 by the MHRA and CHM highlights that suspected adverse reaction reports of necrotising and haemorrhagic pancreatitis have been received in association with the twice daily formulation of exenatide. Some of these have had a fatal outcome. If pancreatitis is suspected, treatment with exenatide should be suspended immediately. If pancreatitis is diagnosed, exenatide should be permanently discontinued. Reports of renal impairment, including acute renal failure and worsened chronic renal failure have also been received. Therefore, exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment.
Further information on the management of T2DM is available on the diabetes section of NPC and a recent MeReC Extra has looked at blood glucose lowering and mortality in T2DM.
What does this study claim?
After the first 30 weeks, patients were either switched from twice daily to once weekly exenatide or continued on weekly exenatide. Those who continued on weekly exenatide maintained improvements in HbA1c seen during the first 30 weeks. The change from baseline (least squares mean) was –2.1% (95% confidence interval [CI] –2.2 to –1.9%) at week 30 and –2.0% (-2.1 to –1.8%) at week 52. For patients who switched formulations the change was –1.8% (-1.9 to –1.6%) at week 30 and a similar –2.0% (no CI quoted) at week 52. 54% of all patients achieved an HbA1c of < 6.5% at 52 weeks.
In the secondary outcomes, reductions in body weight were similar in both groups: those patients remaining on exenatide weekly experienced a change (least square mean) of –4.1kg (95%CI ‑5.3 to –2.9kg) at 52 weeks and for those who switched formulations the change was –4.5kg (-5.7 to –3.3kg).
The adverse events reported included nausea (in approximately 7% in each group), vomiting and diarrhoea. No episodes of major hypoglycaemia or cases of pancreatitis occurred.
How does this relate to other studies?
Exenatide once weekly has been the subject of a series of DURATION trials. In DURATION-2 (n=514), exenatide once weekly, once daily sitagliptin or once daily pioglitazone were added to stable metformin therapy. Details are here.
In DURATION-3 (n=456), once weekly exenatide was more effective than daily insulin glargine (dose adjusted according to fasting blood glucose concentrations) in patients on maximum tolerated doses of metformin or metformin plus sulphonylurea.
Details are here.
DURATION-4 is comparing exenatide once weekly with metformin, sitagliptin or pioglitazone in drug-naïve patients. The primary outcome is change in HbA1c from baseline to week 26. No data are yet available from this study.
The 24 week DURATION-5 study is comparing the effects on HbA1c of twice daily and once weekly formulations of exenatide in patients whose T2DM was managed with diet and exercise alone or with oral antidiabetic drugs. Currently data has been presented only in poster format – at the American Diabetes Association June 2010.
A further GLP-1 analogue, liraglutide▼ (Victoza®) is administered once daily as a subcutaneous injection and NICE has advised on its place in therapy.
We have previously discussed the results from the open-label LEAD-6 trial (n=264) which compares daily liraglutide with twice daily exenatide. Liraglutide was more effective than twice daily exenatide at reducing HbA1c from baseline to week 26. The estimated treatment difference was –0.33; 95%CI –0.47 to –0.18, P<0.0001. Adverse events mainly affected the gastro-intestinal system, and included nausea and diarrhoea.
The extension to the LEAD-6 trial also featured a switch, this time from twice daily exenatide to once daily liraglutide injections. After 26 weeks, patients continued into a 14-week extension trial. Exenatide patients were switched to escalating doses of liraglutide and patients originally randomised to liraglutide 1.8mg daily continued on that treatment. In those who switched, mean HbA1c levels decreased from 7.2% achieved at week 26 to 6.9% at week 40, P<0.0001. HbA1c levels remained similar in those who continued on liraglutide (7.0 to 6.9%).
A trial comparing weekly exenatide to daily liraglutide is expected to finish in April 2011. Several other trials of the long-acting exenatide formulation are being carried out. For example, a 26-week trial in comparison to insulin detemir is examining change in HbA1c and weight loss.
So what?
The primary outcome of DURATION-1 was the disease-oriented measure of HbA1c, a surrogate outcome, rather than a patient-oriented outcome such as the effect on macrovascular or microvascular events, diabetes-related mortality or total mortality. The FDA in the United States has issued guidance for the pharmaceutical industry concerning the development of new agents for T2DM; sponsors are advised to undertake studies to demonstrate that the therapy is not associated with an unacceptable cardiovascular risk. Similar guidance is being developed in Europe.
The marketing of the weekly formulation in the US has been delayed due to a FDA request for a study to investigate if exposures to higher concentrations of exenatide than typical therapeutic levels are associated with a prolongation of the QT interval in electrocardiograms, a condition that could predispose to potential cardiac arrhythmias.
A long-term clinical trial (EXSCEL) of once weekly exenatide looking at cardiovascular outcomes is currently recruiting patients (a similar study for liraglutide has recently started). Until such data are available, local decision makers may wish to follow NICE guidance on the place in therapy of GLP-1 analogues.
Design: 22-week extension to the open-label, randomised 30-week DURATION-1 study.
Patients: Adult patients with T2DM treated with diet/exercise or oral drugs. After the 30-week stage, 258 of the 295 intention-to-treat patients continued into the extension phase. Of these, 243 completed 52 weeks of treatment, and 241 were evaluable. They had had diabetes for a mean of 6.5 years with a mean HbA1c at baseline of 8.3% and weighed a mean of 103kg.
Intervention and comparison: Initially in DURATION-1, half the patients received exenatide 5 micrograms subcutaneously twice a day for the first 28 days followed by 10 micrograms twice daily for a further 26 weeks. The remaining patients received 2mg of the once weekly formulation continually for 30 weeks. For the extension phase, patients either continued to receive the weekly formulation or switched from twice daily to once weekly exenatide.
Outcomes and results: The primary outcome was glucose control at week 30. The second phase of the study examined glucose control during the transition from twice daily to weekly dosing, in addition to efficacy, safety and tolerability of 52 weeks of the weekly formulation.
Results at 52 weeks are for patients who completed visits to at least week 48. Patients who continued to receive weekly exenatide (n=128) maintained improvements in HbA1c. The change from baseline (least square mean) was –2.1% (95%CI –2.2 to –1.9%) at week 30 and –2.0% (-2.1 to –1.8%) at week 52. For patients who switched formulations (n=130) the change was –1.8% (-1.9 to –1.6%) at week 30 and a similar –2.0% (no CI quoted) at week 52. 54% of all patients achieved an HbA1c of < 6.5% at 52 weeks.
Patients who switched to weekly exenatide at week 30 experienced a short-lived increase in mean fasting plasma glucose concentration followed by a rapid decrease within two weeks of the switch. By three to four weeks after the switch the mean FPG had returned to levels observed before the switch occurred. Patients in this group who were concomitantly receiving a sulphonylurea (n=44) reduced their dose at the time of the transition and this may have contributed to the transient rise in FPG concentration.
Reductions in body weight (a secondary outcome) were similar in both groups: those patients remaining on exenatide weekly experienced a change (least square mean) of –4.1kg (95%CI ‑5.3 to –2.9kg) at 52 weeks and for those who switched formulations the change was –4.5kg (-5.7 to –3.3kg).
Adverse events: These were similar to those reported during the 30-week phase and included nausea (in approximately 7% in each group), vomiting and diarrhoea. Injection site bruising was reported by 5.4% of patients who switched, and by none of those who continued on the weekly formulation, but did not lead to withdrawal from the trial. No episodes of major hypoglycaemia or cases of pancreatitis were reported.
Sponsorship: Amylin Pharmaceuticals Inc, Eli Lilly and Company.
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