Lixisenatide is a novel glucagon-like peptide 1 receptor agonist (GLP-1RA) recently licensed in the UK for use in adults with type 2 diabetes, in combination with oral glucose-lowering drugs and /or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control. Although two other GLP-1RAs are also currently licensed in the UK (exenatide and liraglutide), neither is currently licensed for use in addition to insulin therapy.
The purpose of the current double-blind, placebo-controlled study was to evaluate the effect of adding lixisenatide to basal insulin in patients with type 2 diabetes who have relatively acceptable control of fasting plasma glucose (FPG) after initiating and titrating basal insulin, but have glycosylated haemoglobin (HbA1c) levels remaining persistently elevated (≥7%), presumably due to postprandial hyperglycaemia. Although the addition of mealtime rapid-acting insulin has traditionally been the next therapeutic option in this setting, it is not always effective and has some disadvantages (e.g. weight gain; hypoglycaemia).
After an initial 12-week run-in phase, during which insulin glargine was added to pre-existing oral therapy and titrated, those with a FPG ≤7.8 mmol/L and HbA1c 7–9% (446/825) were randomised to receive additional lixisenatide (20mcg; n=223) or placebo (n=223) injected one hour before breakfast. HbA1c reduced during the run-in period (8.6% to 7.6%) and then reduced further in the lixisenatide group following randomisation, by -0.32% (95% CI -0.46 to -0.17%; p<0.0001) compared to placebo at 24 weeks.
The authors suggest from these results that a single daily injection of lixisenatide could provide similar improvements in glycaemic control to the addition of short-acting insulin and a modest beneficial effect on weight (difference vs. placebo –0.89kg; P=0.0012), while avoiding the need for additional glucose testing. The two strategies were not however compared directly in this trial, which is a limitation of this study. Lixisenatide was associated with an increased risk of confirmed hypoglycaemia (0.80 events per participant-year versus 0.44 for placebo) with one severe event (0.4%) reported. Nausea and vomiting were the most commonly reported adverse events and led to discontinuation in 4% of participants.
As well as its placebo-controlled nature, the authors note the following further limitations of their study:
• Around 40% of patients randomised to lixisenatide did not achieve HbA1c levels <7% and it is not known what further measure could help achieve this goal
• The run-in period was short; a longer period may have permitted further glargine dose increases prior to randomisation
• It is not known if different timing of basal insulin and lixisenatide administration could alter efficacy
NICE published an evidence summary on lixisenatide in January 2013 which can be accessed via the link below. This focused on the two Phase III trials that had been fully published at the time, and it will be updated when full data become available.