LEAD-6 shows liraglutide beats twice-daily exenatide

The Lancet has published LEAD-6, the first large head-to-head comparison of two injected GLP-1 receptor agonists. In 464 adults with type 2 diabetes, liraglutide 1.8 mg once a day lowered A1C by 1.12 percentage points over 26 weeks, compared with 0.79 percentage points for exenatide 10 micrograms twice a day ^[1].

The trial enrolled adults whose diabetes was not adequately controlled on maximally tolerated doses of metformin, a sulfonylurea, or both. Participants were stratified by their prior oral diabetes therapy and randomly assigned to add either liraglutide (n=233) or exenatide (n=231) in an open-label, parallel-group study run in 15 countries. The primary outcome was change in A1C, analyzed by intention to treat. The trial is registered as NCT00518882 and was funded by Novo Nordisk A/S, which makes liraglutide ^[1].

What the numbers showed

Mean baseline A1C was 8.2% ^[1]. The estimated treatment difference favored liraglutide by 0.33 percentage points (95% CI −0.47 to −0.18; p<0.0001). More people on liraglutide reached an A1C below 7%: 54% versus 43% (odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015) ^[1].

Fasting plasma glucose fell more with liraglutide, by 1.61 mmol/L versus 0.60 mmol/L — roughly 29 mg/dL versus about 11 mg/dL — an estimated difference of 1.01 mmol/L (95% CI −1.37 to −0.65; p<0.0001). But the pattern reversed after meals: post-meal glucose control was less effective with liraglutide after breakfast and dinner ^[1].

Weight loss was similar between the two drugs: 3.24 kg with liraglutide and 2.87 kg with exenatide, or roughly 7 pounds versus a little over 6 pounds ^[1].

On tolerability, the authors reported both drugs were generally well tolerated, but nausea was less persistent with liraglutide (estimated treatment rate ratio 0.448, p<0.0001). Minor hypoglycemia was less frequent as well: 1.93 versus 2.60 events per patient per year (rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131), with 25.5% of the liraglutide group and 33.6% of the exenatide group experiencing at least one minor low. Two patients taking exenatide together with a sulfonylurea had a major hypoglycemic episode ^[1].

The authors concluded that once-daily liraglutide provided significantly greater improvements in blood sugar control than twice-daily exenatide and was generally better tolerated, and that it "might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations" ^[1].

Why it matters for patients

Until now, people considering a GLP-1 medicine and their clinicians had mostly indirect comparisons to work from — separate trials against placebo or insulin, run in different populations. LEAD-6 puts two of these drugs against each other in the same study, which makes the differences easier to interpret ^[1].

The practical trade-offs are visible in the numbers. Liraglutide is injected once a day; exenatide in this trial was injected twice a day ^[1]. Liraglutide did more for fasting glucose, while exenatide did more for glucose after breakfast and dinner ^[1]. Weight change was close to a wash ^[1]. The lower rate of minor hypoglycemia with liraglutide is notable because most participants were also on metformin, a sulfonylurea, or both, and sulfonylureas are associated with lows — the two major hypoglycemic episodes in the trial both occurred in people taking exenatide plus a sulfonylurea ^[1].

Several things are not answered here. The trial ran 26 weeks, so longer-term durability, cardiovascular outcomes and rare safety signals were not addressed by this report ^[1]. The study was open-label, meaning participants and investigators knew which drug was being used, which can influence reporting of side effects like nausea ^[1]. And because Novo Nordisk funded the trial of its own product, independent replication matters ^[1].

What happens next

The Lancet published an accompanying commentary on GLP-1 receptor agonists for type 2 diabetes in the same July 4, 2009 issue ^[1]. A letter questioning adverse event reporting in the trial, with an author reply, appeared in the October 3, 2009 issue ^[1]. A separate commentary asking "Is liraglutide or exenatide better in type 2 diabetes?" was published in Expert Opinion on Pharmacotherapy in November 2009 ^[1].