Liraglutide lowers A1C more than exenatide in 26-week head-to-head trial

A once-daily GLP-1 injection lowered blood sugar more than a twice-daily one in a 26-week head-to-head study, results published in The Lancet show. Among 464 adults with type 2 diabetes, liraglutide 1.8 mg once a day reduced A1C by 1.12 percentage points, compared with 0.79 points for exenatide 10 micrograms twice a day ^[1].

The trial, called LEAD-6, enrolled adults whose type 2 diabetes was not adequately controlled on the highest doses they could tolerate of metformin, a sulfonylurea, or both. Researchers randomly assigned 233 people to liraglutide and 231 to exenatide at sites in 15 countries. The average starting A1C was 8.2%. The main measure was change in A1C, analyzed by intention to treat. The study was open-label, meaning participants and their doctors knew which drug was being used, and it was funded by Novo Nordisk A/S, the maker of liraglutide. It is registered as NCT00518882 ^[1].

On the primary measure, the gap between the two drugs was 0.33 percentage points in favor of liraglutide (95% confidence interval -0.47 to -0.18; p<0.0001). More people taking liraglutide reached an A1C below 7%: 54% versus 43% (odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide also lowered fasting plasma glucose more, by 1.61 mmol/L versus 0.60 mmol/L. Post-meal glucose control, however, was less effective with liraglutide after breakfast and dinner ^[1].

Both drugs produced similar weight loss: 3.24 kg with liraglutide and 2.87 kg with exenatide. Nausea was less persistent with liraglutide (rate ratio 0.448, p<0.0001). Minor low blood sugar was less frequent with liraglutide, at 1.93 versus 2.60 events per patient per year, with 25.5% versus 33.6% of patients having at least one minor episode (rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131). Two patients taking exenatide along with a sulfonylurea had a major hypoglycemic episode. The authors described both drugs as well tolerated and concluded that liraglutide was generally better tolerated ^[1].

The report does not say how the two drugs compare beyond 26 weeks, and it does not compare either with later GLP-1 medicines such as semaglutide or tirzepatide. It also tested only one dose of each drug, so nothing is known from this trial about other doses ^[1].

Why it matters for patients

People weighing GLP-1 options often balance how much a drug lowers A1C against how often it must be injected and how tolerable the side effects are. In this trial, the once-daily drug produced the larger average A1C drop and less persistent nausea, while both drugs produced similar weight loss ^[1].

The A1C results are averages. Some people in each group did better or worse than the average, and the trial does not identify who is likely to respond to which drug ^[1].

The low blood sugar differences are worth noting for anyone also taking a sulfonylurea, a class of older diabetes pills. Two of the major hypoglycemic episodes in the trial occurred in patients taking exenatide plus a sulfonylurea ^[1]. How the two drugs compare in people taking other combinations of diabetes medicines has not been reported from this study.

Because the trial was open-label, patients and investigators knew which treatment was given. The published report does not describe how that was accounted for in measuring side effects such as nausea and low blood sugar ^[1].