Liraglutide for the treatment of type 2 diabetes

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 08/230/01. The assessment report began editorial review in October 2010 and was accepted for publication in November 2010. See the HTA programme website for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Declared competing interests of authors

NW is a member of the Scottish Study Group for the Care of Diabetes in the Young, whose educational meetings are part sponsored by Novo Nordisk.

Copyright statement

© Queen’s Printer and Controller of HMSO 2011. This work was produced under the terms of a commissioning contract issued by the Secretary of State for Health. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2011 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Type 2 diabetes mellitus is one of the most common chronic metabolic disorders found in both England and Wales. In England, it is estimated that > 2.1 million people have diabetes mellitus and the majority, i.e. about 90% of them, have type 2 diabetes. 3

Type 2 diabetes is treated first with lifestyle measures aiming at weight loss and increased physical activity, but most patients will need drug treatment as well, partly because most do not achieve sufficient weight loss. However, type 2 diabetes is a progressive disease because of loss over time of beta-cell capacity and falling insulin production. Standard therapy in the UK is to add metformin as first drug when lifestyle measures fail, and then to add a sulphonylurea. When dual therapy fails, triple therapy with insulin or a glitazone is next. 4 However, many patients fail to achieve good control on insulin, and weight gain is a common unwanted side effect.

Scope of the decision problem

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. Naturally occurring GLP-1 is released by the small intestine in response to food, and has a number of actions, including stimulating insulin release, inhibiting glucagon release, delaying gastric emptying and promoting a feeling of satiety. Liraglutide is taken once daily and has a plasma half-life of approximately 13 hours (compared with that of native GLP-1, 1.5–2.1 minutes). 5 Liraglutide (Victoza^®, Novo Nordisk) received marketing authorisation by the European Medicines Agency on 30 June 2009. It was subsequently launched in the UK on 6 July 2009. Liraglutide is licensed for treatment of adults with type 2 diabetes mellitus in combination with (1) metformin or a sulphonylurea in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin or sulphonylurea or (2) metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycaemic control despite dual therapy.

The Novo Nordisk submission provided data on the clinical effectiveness of liraglutide as a second- and third-line drug for type 2 diabetes, taken from a suite of trials known as the LEAD (Liraglutide Effects and Actions in Diabetes) trials. Two doses are available in the UK: 1.2 or 1.8 mg once daily. The trials compared liraglutide with glargine and exenatide in triple therapy, and with sitagliptin, rosiglitazone and glimepiride in dual therapy.

The annual costs are £954.84 for the 1.2-mg dose and £1432.26 for the 1.8-mg dose.

Summary of submitted clinical evidence

Of the six clinical trials8–12 included in the submission report, five were published in full and one was then unpublished. 9 All were sponsored by the manufacturer. The main evidence was from the LEAD phase III randomised controlled trials. All trials were multicentred and had glycated haemoglobin (HbA_1c) level as the primary outcome. Secondary outcomes measured included percentage of patients reaching HbA_1c level of 7%, percentage of patients reaching HbA_1c level of < 6.5%, changes in body weight, body mass index (BMI), fasting plasma glucose (FPG), systolic blood pressure (SBP) and lipids, and numbers of patients experiencing adverse events, such as hypoglycaemia and nausea. Patients aged 18–80 years were included and all trials had a duration of 26 weeks.

All studies analysed data for the intention-to-treat population for subjects who were exposed to at least one dose of the drug and had one postbaseline measurement of the parameter. Each end point was analysed using an analysis of covariance model with treatment, pretreatment and country as fixed effects and baseline as a covariate. Missing data were imputed as last observation carried forward.

One of the recommendations in the NICE guideline is that GLP-1 agonists should be used as a triple therapy only in people whose control is unsatisfactory on a combination of two oral agents, usually metformin and a sulphonylurea. Some people would be unable to tolerate these and might take a glitazone or a gliptin instead. Therefore, on the basis of this guideline, not all LEAD trials were relevant. Therefore, the ERG paid most attention to the studies that compared liraglutide in triple therapy, but studies that used liraglutide in dual therapy were reviewed in case NICE decided to approve it for such use.

The two trials that were most relevant were LEAD-5,7 in which liraglutide 1.8 mg was compared with the long-acting insulin glargine (in combination with metformin and glimepiride), and LEAD-6,8 in which liraglutide 1.8 mg was compared with another GLP-1 agonist, exenatide. Approximately 63% of patients in both arms were on metformin plus a sulphonylurea, with 27.5% on metformin only and ∼9.5% on sulphonylurea only. 8

In LEAD-5,7 liraglutide 1.8 mg daily reduced HbA_1c level by 0.24% (p = 0.0015) more than glargine 24 units/day. Liraglutide also resulted in statistically significant reductions in weight (3.4 kg) and SBP (4.51 mmHg) compared to glargine, but no difference in FPG. The ERG wondered if the dose of glargine had been sufficiently titrated, being only 24 units a day at study end.

In LEAD-6,8 liraglutide reduced HbA_1c level by 0.33% (p < 0.0001) more than exenatide twice daily. FPG was reduced by 1.01 mmol/l (p < 0.0001) in favour of liraglutide, but weight and SBP showed no significant difference. There was less nausea with liraglutide.

Three trials9–11 examined liraglutide in dual therapy. LEAD-110 compared liraglutide 1.2 and 1.8 mg with rosiglitazone 4 mg daily, added to existing sulphonylurea in both arms. Liraglutide showed a significant improvement in HbA_1c level, but no difference in weight and SBP.

LEAD-211 investigated patients who were inadequately controlled on metformin alone, and compared liraglutide 1.2 and 1.8 mg daily with glimepiride (a sulphonylurea) as the second drug. There was no difference in HbA_1c level between the drugs, but liraglutide showed a favourable difference in weight of 3.7 kg and SBP of 3.2 mmHg compared with glimepiride.

Pratley and colleagues9 compared the efficacy and safety of liraglutide 1.2 or 1.8 mg once daily with sitagliptin 100 mg once daily. All groups continued on metformin therapy. Compared with sitagliptin, liraglutide 1.2 mg showed a reduction in HbA_1c level of 0.34%, a reduction in weight of 1.9 kg and an increase in SBP of 0.39 mmHg.

Because of the significant cost difference between the two doses of liraglutide, the ERG compared the relative benefits between the two in the meta-analyses shown in Figures 1–4. Data used in the meta-analyses come from a fully published paper. 9–12 There were no significant differences in changes in HbA_1c, in proportions achieving HbA_1c level or in SBP. There was a statistically significant difference in weight, of 0.48 kg, where the clinical significance is doubtful.

FIGURE 1.

Change in HbA_1c level (%) from baseline liraglutide 1.2 versus 1.8 mg.

FIGURE 2.

Patients reaching HbA_1c level of < 7% liraglutide 1.2 versus 1.8 mg.

FIGURE 3.

Change in weight (kg) from baseline liraglutide 1.2 versus 1.8 mg.

FIGURE 4.

Change in SBP (mmHg) from baseline liraglutide 1.2 versus 1.8 mg.

As the trials were of short duration, there was a lack of data on the long-term safety of liraglutide. Concerns have been raised about the risk of pancreatitis with GLP-1 agonists.

The ERG concluded that liraglutide was effective in lowering blood glucose, while avoiding weight gain and hypoglycaemia, and was a useful addition to the therapeutic options available for type 2 diabetes.

Summary of submitted cost-effectiveness evidence

The manufacturer based cost-effectiveness analysis on data from LEAD-57 (liraglutide 1.8 mg vs glargine), LEAD-68 (liraglutide 1.8 mg vs glargine) and a trial by Pratley and colleagues9 (liraglutide 1.2 and 1.8 mg vs sitagliptin). The ERG re-ran the base cases in the CORE model, using the manufacturer’s assumptions, and the results matched with those reported in the submission. The measure of health benefits was quality-adjusted life-years (QALYs). The manufacturer estimated the incremental cost-effectiveness ratios to be £15,130 per QALY for liraglutide 1.8 mg compared with glargine, £10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin and £9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. It was also reported that liraglutide was more cost-effective for patients with higher BMI; however, the cost-effectiveness for patients with lower BMI was not reported.

The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were:

• in the comparison with glargine, the direct utility effects of BMI changes and SBP, with some additional contribution from HbA_1c

• in the comparison with exenatide, HbA_1c, with some additional effects from cholesterol and triglycerides

• in the comparison with sitagliptin, HbA_1c and direct utility effects of BMI changes.

Because the trials were of short duration, the costs and outcomes in the CORE model had to be modelled far beyond the duration of the trials.

Commentary on the robustness of submitted evidence

The manufacturer gives an accurate description of type 2 diabetes and of the current treatments available, correctly noting that existing treatments are not wholly satisfactory and that patients often suffer from adverse events, such as hypoglycaemia and weight gain. However, the manufacturer did not report the findings of a trial that compared insulin against an intensive lifestyle intervention in patients poorly controlled by combination oral glucose-lowering agents. Aas and colleagues13 reported that intensive life modification was better than starting insulin. However, the findings of Aas and colleagues13 were not confirmed in the TULIP (Testing the Usefulness of gLargine when Initiated Promptly) study. 14 The latter,14 sponsored by the manufacturer of glargine, reported that adding glargine early in the conventional treatment with oral glucose-lowering drugs and lifestyle interventions resulted in better glycaemic control than intensifying lifestyle interventions.

The LEAD studies are of good quality. The trials were conducted in multiple settings in multiple countries, therefore increasing the generalisability of the results, though only a few patients were from the UK.

NICE recommends neutral protamine Hagedorn (NPH) as the first-choice basal insulin in type 2 diabetes, and none of the liraglutide trials provides a comparison with NPH. This might be justified on the grounds that glargine is now the most commonly used long-acting insulin,15 but NPH is considerably cheaper. The advantages of glargine over NPH in type 2 diabetes are slight. 16

One weakness was the short durations of the trials. We do not have data on how long the GLP-1 agonists will be effective for in this progressive disease. The ERG and the manufacturer assumed a mean duration of use of 5 years.

Disclaimers

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.