Phase III trial tests addition of twice-daily exenatide to insulin glargine in patients with type 2 diabetes
23 February 2012
A randomised, double-blind, 30-week, phase III trial (n = 261) found that adding twice-daily exenatide to basal insulin therapy with insulin glargine improved HbA1c levels in patients with sub-optimally controlled type 2 diabetes. The reduction of HbA1c level from baseline at week 30 was 1.74% in the exenatide plus glargine group and 1.04% in the placebo plus glargine group (p < 0.001).
The addition of exenatide did not lead to more hypoglycaemia but was associated with more gastro-intestinal side effects. A total of 9% of the exenatide recipients withdrew due to adverse events compared to 1% of the placebo group (p < 0.010).
Level of evidence
Level 3 (other evidence) according to the SORT criteria.
Healthcare professionals should follow NICE guidance on the management of type 2 diabetes. This recommends involving individuals in decisions about their treatment and agreeing individual HbA1c targets taking into account each patient’s particular risk factors, preference and the balance of likely benefits and burden of treatment.
Twice-daily exenatide has recently received a Positive Opinion for use as adjunctive therapy to basal insulin. Commissioners and local specialists would need to identify those patients for whom such a regimen might be appropriate. They may wish to consider whether such prescribing should be initiated by secondary care until experience with the combination is gained.
This study represents the best available evidence relating to this treatment regimen. These data, together with their limitations, should be taken into account by local decision-makers when planning the entry of this new indication and the commissioning of appropriate services. Local decision-makers may need to consider additional published data about this product as they emerge.
What is the background to this?
Managing type 2 diabetes requires a multifactorial approach including smoking cessation, changes to diet and exercise, and management of blood pressure, lipids and blood glucose. Control of blood glucose is important, but pursuing intensive blood glucose control may be inappropriate, especially in older patients with long-standing disease, when other cardiovascular risk factors are being managed actively.
Summary of NICE recommended treatment options for blood glucose lowering in type 2 diabetes
Exenatide, an incretin mimetic is available as a twice-daily injection (Byetta). NICE guidance recommends the twice-daily formulation of exenatide added to metformin plus a sulfonylurea as a possible alternative to the usual third-line therapy of NPH insulin if control of blood glucose remains or becomes inadequate (HbA1c ≥ 7.5% [59 mmol/mol], or other higher level agreed with the individual), and the person has:
- a body mass index (BMI) ≥ 35.0 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight,
- or a BMI < 35.0 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities.
Treatment with exenatide should continue only if a beneficial response has occurred, defined by a reduction of at least 1.0 percentage point in HbA1c (about 11mmol/mol) and also a weight loss of at least 3% of initial body weight at six months.
Following a consultation, NICE has decided to update Clinical Guideline 87. Exenatide in combination with basal insulin for the treatment of type 2 diabetes is under consideration to be included in the guideline update.
The twice-daily formulation of exenatide has recently received a Positive Opinion from the European licensing agency (EMA) for use as adjunctive therapy to basal insulin with or without metformin and/or pioglitazone in adults who have not achieved adequate glycaemic control with these agents.
A prolonged-release suspension of exenatide (Bydureon) for once weekly injection is licensed for the treatment of type 2 diabetes mellitus in combination with certain oral treatments. NICE guidance is available for the use of the prolonged-release suspension as second-line therapy (dual therapy) or third-line therapy (triple therapy).
What does this study claim?
Patients were randomised to exenatide (n = 138), starting with 5 micrograms twice daily for four weeks and then 10 micrograms twice daily thereafter, or matching placebo (n = 123), in addition to structured titration of basal insulin glargine. Mean baseline HbA1c levels were 8.32% (standard deviation [SD] 0.85) in the exenatide group and 8.50% (SD 0.96) in the placebo group.
The primary outcome was change in HbA1c at week 30 (least squares means) in all patients who had received a study drug and had measurements at post-baseline visits. The change in HbA1c at week 30 in the exenatide group was −1.74% (95% confidence interval [CI] −1.91 to −1.56) and −1.04% (95% CI −1.22 to −0.86) in the placebo group; a difference of −0.69% (95% CI −0.93 to −0.46), p < 0.001.
Body weight, a secondary outcome, decreased by 1.78 kg (95% CI 1.08 to 2.48) in the exenatide group and increased by 0.96 kg (95% CI 0.23 to 1.70) in the placebo group a between-group difference of –2.74 kg (95% CI -3.74 to –1.74, p < 0.001).
Gastro-intestinal adverse events were more commonly reported in the exenatide group. For example, nausea was reported by 41% of the exenatide group compared to 8% of the placebo group; diarrhoea by 18% versus 8% and vomiting by 18% versus 4%, respectively. The proportion of participants who had minor hypoglycaemia was similar between exenatide and placebo, 25% and 29%, respectively. More patients in the exenatide group withdrew due to adverse events (9% compared to 1% in the placebo group, p < 0.010).
How does this relate to other studies?
The NICE Clinical Guideline (CG87) lists a research recommendation concerning the clinical and cost-effectiveness of insulin and GLP-1 mimetics used in combination to manage blood glucose control. The document states (as of May 2009) that ‘this combination does not currently have UK marketing authorisation but does appear logical and appropriate. There is also some anecdotal evidence that this combination is being used in current practice. Evidence on its effectiveness and safety is therefore needed’.
Limited data for the use of exenatide with insulin is available from small clinical trials and observational analyses demonstrating reductions in HbA1c levels, insulin dose and body weight.
This study had a number of limitations, for example the trial lasted for only 30 weeks, hence the long-term efficacy and safety of adding twice-daily exenatide to insulin glargine are not known. The study used a disease-oriented outcome (HbA1c) and no data are available on quality of life or cardiovascular events.
There were some imbalances in the groups at baseline, due to block randomisation by site. For example, more patients in the exenatide group than in the placebo group were previously receiving both metformin and pioglitazone (17% compared to 7%). After adjustment for this variable, the primary outcome was not affected.
Patients in the exenatide group had modest weight loss, which may have been related to gastro-intestinal side effects. The authors of the paper state that there was no apparent relationship between the weight change and such adverse events, but this was not formally tested.
Study details: Buse JB, Bergenstal RM, Glass LC et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154:103-12
Design: Randomised, double-blind, placebo-controlled trial with concealed allocation. Randomisation was stratified according to HbA1c (< 8.0% or > 8.0%; equivalent to < 64 mmol/mol or > 64 mmol/mol).
Patients: Adults with type 2 diabetes who were receiving insulin glargine alone, or in combination with metformin or pioglitazone (or both). The minimum glargine dose was 20 units per day and patients had to be on stable doses of oral medication for at least three months. Patients were excluded if they had significant co-morbidities (such as clinically significant cardiac, renal, hepatic or gastro-intestinal disease), a history of pancreatitis, had experienced more than one episode of major hypoglycaemia within the six months before the study, had been part of a weight-loss programme in the three months before the study or received systemic glucocorticoid treatment in the eight weeks before the study.
Included patients had a mean age of 59 years, had had diabetes for a mean of 12 years and a mean body weight of 94.4kg. Baseline HbA1c in the exenatide group was 8.32% (SD 0.85) and 8.50% (SD 0.96) in the placebo group. 66% of the exenatide patients were taking metformin, 2% pioglitazone and 17% were taking both medicines; the figures for the placebo group were 75%, 5% and 7%, respectively.
Intervention and comparison: Patients received exenatide injection 5 microgram twice daily for four weeks followed by 10 microgram twice daily (n = 138) or matching placebo (n = 123) within 60 minutes prior to morning and evening meals. Patients with HbA1c levels of more than 8.0% at randomisation continued on their previous glargine dose. If HbA1c was 8.0% or less, the glargine dose was reduced by 20%. The starting dose was continued for five weeks until patients began an insulin dose titration phase to achieve a fasting glucose level of less than 5.6 mmol/litre. Treatment was continued for a total of 30 weeks.
Outcomes and results: The primary outcome was change in HbA1c at week 30 (least squares means) in all patients who had received a study drug and had measurements at post-baseline visits. Two randomised patients withdrew before receiving medication and so were excluded from analyses. The change in HbA1c in the exenatide group was −1.74% (95% CI −1.91 to −1.56) and −1.04% (95% CI −1.22 to −0.86) in the placebo group; a difference of −0.69% (95% CI −0.93 to −0.46), p < 0.001.
In the secondary outcomes, body weight changed from 95.4 kg to 93.6 kg in the exenatide group, a decrease of 1.78 kg (95% CI 1.08 to 2.48) and in the placebo group from 93.8 kg to 94.8 kg, an increase of 0.96 kg (95% CI 0.23 to 1.70), a between-group difference of −2.74 kg (95%CI −3.74 to −1.74, p < 0.001). The dose of insulin increased from baseline by 20 units per day in the placebo group and 13 units in the exenatide group (p = 0.030).
A total of 9% of the exenatide recipients withdrew from the trial due to adverse events compared to 1% in the placebo group (p < 0.010).
The number of minor hypoglycaemic events was similar in both groups and occurred in 25% of patients in the exenatide group and 29% of the placebo group; minor nocturnal hypoglycaemia was observed in 17% and 26% of patients, respectively. One patient in the placebo group experienced two episodes of major hypoglycaemia.
Gastro-intestinal adverse events were more commonly reported in the exenatide group. Nausea was reported by 41% of the exenatide group compared to 8% of the placebo group; diarrhoea by 18% and 8%, respectively; vomiting by 18% and 4%, respectively; and constipation by 10% and 2%, respectively.
This study was sponsored by Eli Lilly and Company and Amylin Pharmaceuticals.
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