Garber A, Henry R, Ratner R et al for the LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. The Lancet DOI:10.1016/S0140-6736(08)61246-5
The results from this 52 week trial in patients with type 2 diabetes, demonstrated that monotherapy with once daily parenteral liraglutide was more effective than glimepiride monotherapy in reducing the surrogate outcome of glycated haemoglobin (HbA1c).
If liraglutide receives a marketing authorisation for monotherapy, based on the LEAD-3 trial, it will have a broader indication than the twice-daily formulation of exenatide. The DURATION-1 trial of once weekly exenatide, blogged recently, included a small number of patients who received monotherapy (about 15% of each group). Area Prescribing Committees will need to consider where, or whether, these newer agents fit in the overall management of type 2 diabetes mellitus (T2DM), given that 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?
The primary outcome of this phase III, double blind randomised controlled trial was defined as the change in HbA1c from baseline to week 52. The results demonstrated that two different doses of liraglutide daily produced greater reductions in HbA1c than glimepiride. The change with liraglutide 1.2mg was –0.84% (standard deviation [SD] 1.23), for liraglutide 1.8mg –1.14% (SD 1.24) and with glimepiride 8mg –0.51% (SD 1.20). The differences between the liraglutide and glimepiride groups were statistically significant: liraglutide 1.8mg vs. glimepiride –0.62% (95% confidence interval [CI] –0.83 to –0.42, P <0.0001), liraglutide 1.2mg vs. glimepiride –0.33% (95% CI –0.53 to –0.13, P=0.0014).
At the end of 52 weeks, 28% of patients in the liraglutide 1.2mg group and 38% of the 1.8mg liraglutide group reached HbA1c levels of 6.5% or less vs. 16% of those on glimepiride (P=0.0025 and P <0.0001 for 1.2mg and 1.8mg respectively).
How does this relate to other studies?
A NICE clinical guideline on newer agents for T2DM is anticipated in March 2009. Comments on the draft may be sent to NICE until 5th November. Advice is provided on the role of exenatide for patients fulfilling a particular set of criteria, however as liraglutide does not have a Product Licence yet it is not included.
This study used a surrogate outcome, HbA1c, rather than a patient oriented outcome such as the effect on CV events and mortality. A recent posting on once-weekly exenatide, highlighted that a US advisory committee has recommended that long-term studies for new drugs for diabetes should measure cardiovascular events. This conclusion was reached after a meta-analysis suggested that patients on rosiglitazone were at increased risk of cardiovascular events, despite known favourable effects on blood glucose.
Design: phase III, double blind, double-dummy, active control, randomised, parallel-group study
Patients: Adults aged 18 – 80 years with T2DM (n=746) treated with diet plus exercise or up to half the maximum dose of oral antidiabetic drug monotherapy for at least 2 months. Previous treatment was stopped at randomisation. Mean baseline HbA1c levels were 8.3% (SD 1.0%), 8.3% (SD 1.1%) and 8.4% (SD 1.2) in the 1.2mg, 1.8mg liraglutide groups and the glimepiride patients respectively.
Intervention: subcutaneous liraglutide 1.2mg (n=251) or 1.8mg (n=247) daily for 52 weeks.
Comparison: glimepiride 8mg daily (n=248) for 52 weeks (the maximum dose in the UK is 6mg). Doses of all drugs were titrated up at the beginning of the trial.
Outcomes and Results: primary, surrogate, endpoint of change in HbA1c levels at 52 weeks.
Pre-specified secondary outcomes included changes in body weight and blood pressure. Body weight decreased in patients on both doses of liraglutide but increased in patients on glimepiride (P<0.0001 for either dose vs. glimepiride).
Adverse events: gastro-intestinal disorders were more common in liraglutide patients. Nausea occurred in 27% of patients on liraglutide 1.2mg, 29% on 1.8mg and 8% in glimepiride patients. Similarly, diarrhoea occurred in 16%, 19% and 9%, respectively. Pancreatitis, which has also been reported with exenatide (particularly in the US), was seen in one patient in each liraglutide group.
No episodes of major hypoglycaemia were reported. Minor hypoglycaemia was seen in 12% of liraglutide 1.2mg patients, 8% on 1.8mg and 24% of patients on glimepiride (P<0.0001 for both doses of liraglutide vs. glimepiride).
Sponsorship: Novo Nordisk