Tuesday September 9 2008
Exenatide is given as an injection under the skin
“A weekly treatment for type 2 diabetes has proved safe and effective for patients”, The Guardian reported. It said the treatment, exenatide, is already available, but currently needs to be self-injected by patients twice daily. The newspaper added that the new once-weekly injection controlled glucose levels better, and had fewer side effects. It said that none of the currently available type 2 diabetes treatments could be given this infrequently, but that more trials will be needed before this formulation can be licensed for general use.
This trial gives encouraging results for the once-weekly exenatide formulation. Further long-term studies will be needed to investigate the long-term efficacy and safety of this treatment compared with other forms of treatment for type 2 diabetes. It should be pointed out that exenatide is currently not licensed for use on its own in type 2 diabetes, and is only taken alongside first-line diabetes medications which have controlled blood sugar levels poorly.
Where did the story come from?
Dr Daniel Drucker and colleagues from the University of Toronto, the University of North Carolina School of Medicine, and the companies Amylin Pharmaceuticals Inc. and Eli Lilly and Company carried out the research. The study was funded by Amylin Pharmaceuticals Inc. and Eli Lilly and Company. The funders were involved in the design, conduct, and analysis of the study. The study was published in the peer-reviewed medical journal: the Lancet.
What kind of scientific study was this?
This was a special form of randomised controlled trial called a ‘non-inferiority trial’. This type of trial compares a new treatment with an established one to show that the new treatment is not inferior. It is often used when a new treatment is thought to be more convenient than an established one, and researchers want to show that it performs just as well for important health outcomes. This trial compared two different formulations of the drug exenatide, a glucose-regulating drug for type 2 diabetes. The established twice-daily formulation was compared with a new, long-acting formulation that is given only once a week. Both of these formulations are given as injections under the skin.
The researchers enrolled people aged 16 or over with type 2 diabetes. The participants had been treated for at least two months and had been prescribed a diet and exercise plan, or one or more oral diabetes medications (metformin, a sulphonylurea, or a thiazolidinedione). The researchers did not include anyone taking insulin, meglitinides, α-glucosidase inhibitors, weight loss drugs, corticosteroids, drugs affecting gastrointestinal motility, or any other investigational drugs as part of another trial. Participants had to have a stable weight (less than 10% change in the past six months), and no abnormal blood test results or significant medical problems. Participants were only included if they had never taken exenatide or other drugs of the same type (GLP-1 analogues).
After exclusions there were 295 eligible participants. These were randomly assigned to either a group that received standard formulation exenatide twice daily or a group that received the long acting formulation once-weekly for 30 weeks. At the beginning and end of the study, the participants monitored and recorded their blood glucose levels seven times daily, for three days. Over this period, standard methods were used to measure how well the participants’ blood sugar levels were being controlled. This involved measuring the amount of haemoglobin in their blood that was attached to sugar molecules (called glycated haemoglobin or HbA1c). The treatment aimed to keep levels of HbA1c to 7% or less. The researchers also monitored the participants for any side effects of treatment.
After 30 weeks, the researchers compared the two groups for changes in HbA1c throughout the study and the proportion of people who achieved target HbA1c levels (≤7%). Although the trial was not blinded and therefore both participants and researchers knew who was taking which formulation, the participants’ HbA1c and glucose readings were anonymised during the analysis.
In non-inferiority trials, researchers need to set limits on how much worse one drug has to be than the other before it is described as inferior to the other drug. In this study, the researchers decided that if once-weekly exenatide reduced HbA1c by up to 0.4% less than twice-daily exenatide, it would be considered “non-inferior”. The analyses took into account what medication the participants were taking and their HbA1c measurement when the study began.
What were the results of the study?
The researchers found that at 30 weeks, the once-weekly exenatide formulation had reduced HbA1c levels more than the twice-daily formulation (a reduction of about 1.9% compared to a reduction of about 1.5%). This represented a greater reduction of HbA1c levels by about 0.3% with the once-weekly exenatide, (95% confidence intervals 0.54% to 0.12%). Based on the criteria set by the researchers before the study began, this meant that once-weekly exenatide was not inferior to the twice-daily formulation, and was in fact better for controlling HbA1c levels.
When the researchers looked at the 259 participants who completed at least 26 weeks of the study, they found that the once-weekly exenatide formulation increased the proportion of participants who were able to achieve target HbA1c levels of ≤7% compared to the twice-daily formulation. In the once-weekly exenatide group, 77% of participants achieved this target, compared with 61% of participants in the twice-daily exenatide group. There was no difference in change in bodyweight between the groups. There was also no difference between the groups in episodes of hypoglycaemia (low blood sugar), with no major (serious) episodes in either group.
Fewer participants in the once-weekly group experienced nausea associated with treatment than in the twice-daily group (about 26% compared to about 35%). More participants in the once-weekly group experienced injection site itching than in the twice-daily group (about 18% compared with about 1%), but this itching was generally mild and decreased over time. About 6% of the once-weekly group withdrew from the study due to side effects, compared with 5% in the twice-daily group.
What interpretations did the researchers draw from these results?
The researchers concluded that a once-weekly formulation of exenatide improved blood sugar control more than the standard twice-daily formulation, and resulted in similar decreases in body weight, without increasing the risk of hypoglycaemia.
What does the NHS Knowledge Service make of this study?
This study provides encouraging results for the once-weekly exenatide injections, which may eventually provide a more convenient treatment regimen for patients with type 2 diabetes than the current standard twice-daily regimen. There are a few limitations to consider:
- This study’s findings should not be interpreted to mean that once-weekly exenatide injections could be used as an isolated treatment that replaces all other diabetes treatments. Exenatide is currently not licensed for isolated use, and is indicated only when blood sugar is poorly controlled by first-line diabetes medications (such as sulphonylureas, metformin, or both), which continue to be taken alongside the daily injections. Other randomised controlled trials will be needed to compare once-weekly exenatide against other types of treatment.
- The study was not blinded, and this may have introduced bias.
- The researchers found that the once-weekly treatment increased the level of anti-exenatide antibodies in the blood. Further studies may be needed to determine whether this affects the long-term efficacy of the once-weekly treatment.
It is also important to point out that this treatment is not in any way comparable to insulin. The two drugs have different modes of action. Exenatide increases insulin secretion from the pancreas, slows stomach emptying and also suppresses hormones that would increase glucose production, while insulin is given as a last resort treatment for type 2 diabetes when the body can no longer manufacture sufficient insulin.
Sir Muir Gray adds...
For the moment, and forever, people with type 2 diabetes can rely on one treatment - 30 minutes of extra walking a day.