Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care Published online ahead of print October 17, 2008
The results from this 26 week trial demonstrate that parenteral liraglutide once daily, in conjunction with metformin, was superior to metformin alone in reducing the surrogate outcome of glycated haemoglobin (HbA1c). Liraglutide doses of 1.2mg and 1.8mg daily appeared to be non-inferior to glimepiride, when both patient groups received metformin as background therapy. However, a per-protocol analysis is needed to confirm non-inferiority and unfortunately this was not reported.
Liraglutide is not covered in the draft NICE clinical guideline on newer agents for T2DM, publication date of which is anticipated as March 2009. Therefore, if liraglutide should receive a licence in 2009 local decision making bodies on medicines will need to consider where, or whether, it fits in the overall management of the condition, given that at this time there are no outcome data on prevention of cardiovascular (CV) events.
What is the background to this?
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, like exenatide (Byetta▼) and is given once daily by SC injection. The drug is currently in licensing with the EMEA; more information on the product can be found in our On the Horizon, Future Medicines review (NHSnet connection required).
Further information about the management of diabetes is available on the cardiovascular floors of NPC.
What does this study claim?
All doses of liraglutide decreased HbA1c levels by a mean of about 1%, similar to levels achieved in patients on glimepiride when all patients were receiving background therapy with metformin. Differences compared to placebo (95% confidence intervals, CI) for the liraglutide patients were -0.8% (-1.0; -0.6) for 0.6mg and -1.1% (-1.3; -0.9) for 1.2mg and 1.8mg. Differences compared to glimepiride were 0.0% (-0.2; 0.2) for the 1.2mg and 1.8mg doses. The higher doses of liraglutide were non-inferior to glimepiride in the intention-to-treat population (defined as all patients exposed to at least one dose of trial medication and with one post-baseline measurement). It is usual for non-inferiority trials to include two analyses: intention-to-treat and per-protocol analysis, but only the former has been quoted in this trial. Further information on this is available in a recent Drug and Therapeutics Bulletin.
How does this relate to other studies?
LEAD-2 Met is part of a series of Liraglutide Effect and Action in Diabetes trials where liraglutide is being used as monotherapy or added to other agents, such as rosiglitazone. The LEAD-3 study, blogged recently, demonstrated that monotherapy with once daily parenteral liraglutide was more effective than glimepiride monotherapy in reducing HbA1c.
Liraglutide is not currently included in the draft NICE clinical guideline on newer agents for T2DM, as it is unlikely to be licensed by the anticipated publication date of March 2009. Advice is provided in this draft guidance on the role of exenatide for patients fulfilling a particular set of criteria.
This study used a surrogate outcome, HbA1c. Controlling HbA1c may not necessarily lead to people with diabetes living longer or better. When choosing agents to control blood glucose consideration should be given to the presence or absence of data on patient oriented outcomes such as the effect on CV events, quality of life, and mortality for that intervention. Cardiovascular outcomes are especially important – we know that having diabetes significantly increases the risk of coronary heart disease (CHD). Women with T2DM have a three to fivefold greater annual risk of CHD and men a two to fourfold increase. Evidence-based interventions include smoking cessation, other lifestyle changes such as diet and exercise, blood pressure control, statins and metformin. The additional value of liraglutide in addition to those interventions remains uncertain at this time.
Design: phase III, double blind, double-dummy, active control, randomised, parallel-group study.
Patients: Adults aged 18 – 80 years with T2DM (n=1,087) treated with oral antidiabetic drugs for at least 3 months as monotherapy or in combination. Mean baseline HbA1c levels + standard deviation (SD) were 8.4% (+0.9), 8.3% (+ 1.0) and 8.4% (+ 1.0) in the 0.6mg, 1.2mg and 1.8mg liraglutide groups and 8.4% (+ 1.0) and 8.4% (+ 1.1) in the glimepiride and placebo patients, respectively.
Intervention: subcutaneous liraglutide 0.6mg (n=242), 1.2mg (n=240) or 1.8mg (n=242) daily plus metformin 2g per day.
Comparison: glimepiride 4mg daily (n=242) or placebo (n=121), both in combination with metformin 2g per day. Doses of all drugs were titrated to study levels over 2 to 3 weeks followed by 23 or 24 weeks of maintenance doses. Doses of metformin could be reduced to a minimum of 1500mg/day following unacceptable hypoglycaemia or other adverse events.
Outcomes and Results: primary, surrogate, endpoint of change in HbA1c levels between baseline and week 26. Change in body weight was a pre-specified secondary outcome. A dose-dependent decrease in body weight was reported in the liraglutide plus metformin patients (e.g. 2.8 + 0.2kg standard error [SE] with liraglutide 1.8mg). This was significantly different (P<0.0001) than the weight gain observed in the glimepiride group (1.0 +0.2kg).
Adverse events: as has been seen in other liraglutide trials, the most frequently reported adverse events were gastro-intestinal in nature (e.g. nausea, vomiting, diarrhoea). These were reported in about 40% of patients in the liraglutide groups and 17% in the placebo and glimepiride groups. The incidence of nausea declined over time. One patient in the liraglutide 1.2mg group and one in the glimepiride group withdrew due to acute pancreatitis.
No episodes of major hypoglycaemia were reported. The incidence of minor hypoglycaemia was less in the liraglutide groups at approximately 3%, as compared to 17% for those patients receiving glimepiride(P<0.001). More patients in the liraglutide/metformin groups withdrew due to adverse events: 5%, 10%, and 12% of patients on 0.6mg, 1.2mg and 1.8mg liraglutide respectively, compared to 3% of those receiving glimepiride and 2% of patients receiving placebo.
Sponsorship: Novo Nordisk