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18 November 2010
Exenatide 2mg once weekly injection was more effective at reducing HbA1c than maximum oral doses of either sitagliptin▼ or pioglitazone▼, when added to metformin, in the 26 week DURATION-2 trial (n=514). Exenatide and sitagliptin were associated with decreases in body weight of 2.3 and 0.8kg respectively, compared to an increase of 2.8kg for those patients on pioglitazone.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
As yet, there are no data that show that exenatide reduces the risk of macrovascular or microvascular events in people with type 2 diabetes mellitus. A market application has been made for this new long-acting formulation of exenatide and a NICE appraisal of this formulation as either dual or triple therapy is planned. 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 the existing NICE Clinical Guideline advises a third-line role for exenatide▼ twice daily in 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 been submitted to the European Medicines Agency (EMA). A once-monthly suspension formulation is also in development.
NICE guidance on exenatide once weekly is in progress, for second-line (dual therapy) or third-line (triple therapy), but no timeline for final guidance is available currently. 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.
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?
In DURATION-2 (n=514), exenatide once weekly, once daily sitagliptin or once daily pioglitazone were added to stable metformin therapy in adults with T2DM. Between baseline and week 26, reduction in HbA1c (least squares mean) was greater with exenatide: -1.5% (95% confidence interval [CI] –1.7 to –1.4) compared with -0.9% (‑1.1 to –0.7) with sitagliptin (P<0.0001 for exenatide vs. sitagliptin) and –1.2% (-1.4 to -1.0) with pioglitazone (P=0.0165 exenatide vs. pioglitazone).
Patients on exenatide achieved statistically significant greater reductions in body weight (a secondary endpoint) by week 26. The mean change with exenatide was ‑2.3kg (95%CI –2.9 to –1.7), a difference of -1.5kg over sitagliptin (95%CI -2.4 to ‑0.7, P=0.0002) and of -5.1kg (95%CI -5.9 to -4.3), P<0.0001) over pioglitazone.
Nausea was experienced by 24% of exenatide, 10% of sitagliptin and 5% of pioglitazone patients and diarrhoea by 18%, 10% and 7% of patients, respectively. Peripheral oedema was more common in pioglitazone patients: 8% compared to 1% on exenatide and 3% on sitagliptin.
How does this relate to other studies?
The once weekly formulation of exenatide has been the subject of a series of DURATION trials. Details of DURATION 1 and outlines of the DURATION 4 and 5 trials are here. A Rapid Review of DURATION 3 is here.
NICE guidance on another GLP-1 analogue liraglutide▼ (Victoza®) was published in October 2010. We have previously discussed trial data for daily liraglutide compared to twice daily exenatide here. A trial comparing weekly exenatide to daily liraglutide is expected to finish in April 2011.
So what?
The primary outcome of the trial 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: Double-blind, double-dummy, randomised 26-week study with concealed allocation.
Patients: Adult T2DM patients not sufficiently controlled on stable doses of metformin for at least two months were included. At baseline, patients had had diabetes for a mean of 6 years, had a mean HbA1c of 8.5% and a mean body weight of 88kg.
Intervention and comparison: 170 patients were randomised to weekly 2mg exenatide subcutaneous injections, 172 to sitagliptin 100mg daily and 172 to pioglitazone 45mg daily, in addition to stable doses of metformin.
Outcomes and results: The primary outcome was change in HbA1c at week 26 compared to baseline. Change in body weight and patient-reported quality of life (QOL) assessments were included in the secondary outcomes. Results are for the modified intention-to-treat population, defined as randomised patients who received at least one dose of study drug. The reduction in HbA1c (least squares mean) with exenatide (n=160) was −1·5% (95% CI −1·7 to −1·4) and was significantly greater than with sitagliptin (n=166, −0·9%, −1·1 to −0·7) or pioglitazone (n=165, −1·2%, −1·4 to −1·0). Treatment differences were −0·6% (95%CI −0·9 to −0·4, adjusted P<0·0001) for exenatide versus sitagliptin, and −0·3% (−0·6 to −0·1, adjusted P=0·0165) for exenatide versus pioglitazone.
Patients on exenatide achieved statistically significantly greater reductions in body weight by week 26. The mean change with exenatide was –2.3kg (95%CI –2.9 to ‑1.7), with sitagliptin –0.8kg (-1.4 to –0.1) and 2.8kg (2.2 to 3.4) with pioglitazone. 28% of patients on exenatide lost at least 5% of their body weight compared to 10% of patients on sitagliptin and 2% of those on pioglitazone.
Adverse events: Treatment emergent adverse events leading to withdrawal from treatment were seen in 6.3% of exenatide patients (10/160) compared with 3.0% of sitagliptin patients (5/166) and 3.6% of pioglitazone patients (6/165). Gastrointestinal events (such as nausea and diarrhoea) were most frequently reported in exenatide and sitagliptin patients. Nausea was experienced by 24% of exenatide, 10% of sitagliptin and 5% of pioglitazone patients and diarrhoea by 18%, 10% and 7% of patients, respectively. Upper respiratory tract infection and peripheral oedema were most likely in pioglitazone patients.
One patient in the sitagliptin group died, following uncontrolled hypertension. Two serious adverse events led to withdrawal from treatment: cryptogenic organising pneumonia on exenatide and necrotising pancreatitis on pioglitazone. No patients experienced major hypoglycaemia and minor hypoglycaemia was reported rarely.
Sponsorship: Amylin Pharmaceuticals and Eli Lilly.
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