Head-to-head comparison of the safety and efficacy of once-weekly exenatide versus once-daily liraglutide for the treatment of type 2 diabetes

Example of a scientific summary written for a physician audience

Achieving optimal glycemic control is an important clinical objective during the management of type 2 diabetes. There are many types of anti-hyperglycemic drugs currently available. Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new class of injectable anti-hyperglycemic agents. Exenatide was the first GLP-1 receptor agonist to be approved as a once-weekly formulation. Exenatide is a synthetic version of exendin-4, a peptide agonist of the GLP-1 receptor. Another GLP-1 receptor agonist, liraglutide, is an analogue of human GLP-1. Liraglutide is approved for once-daily use in patients with type 2 diabetes. Multiple head-to-head comparisons have shown improved glycemic control after administration of once-weekly exenatide or once-daily liraglutide compared with oral anti-hyperglycemic agents or twice-daily exenatide.1-5

DURATION-6 was the first study to directly compare the efficacy and safety of once-weekly exenatide to once-daily liraglutide in patients with type 2 diabetes.6 A 26-week, randomized, open-label, parallel-group investigation was performed at 105 sites in 19 countries. Participants were adults with type 2 diabetes and suboptimal glycemic control despite lifestyle changes and treatment with oral anti-hyperglycemic agents. Patients were randomly assigned by a computer-based method to receive daily injections of liraglutide (titrated up to 1.8 mg) or weekly injections of exenatide (2 mg). An intention-to-treat analysis was performed on 911 patients enrolled in the trial. There were 450 patients in the liraglutide group and 461 patients in the exenatide group. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to the end of the trial.

Both treatments were associated with significant reductions in HbA1c. Liraglutide reduced HbA1c levels by 1.48%, whereas exenatide reduced HbA1c levels by 1.28%. Exenatide was initially hypothesized to be non-inferior to liraglutide. However, based on relative changes in HbA1c, exenatide did not meet the predefined criterion of non-inferiority to liraglutide. Body weight and fasting serum glucose levels were also significantly decreased in both groups. Patients treated with liraglutide showed more significant changes in body weight and fasting glucose compared with those in the exenatide group. Both groups showed similar levels of improvement in blood pressure, markers of cardiovascular health, and patient-reported health outcomes.

Nausea, vomiting, and diarrhea were the most common adverse effects of both treatments and were generally mild to moderate. These gastrointestinal events occurred more frequently at the beginning of the trial and were more common in the liraglutide group. Fifteen patients in the liraglutide group withdrew from the trial during the first month due to adverse gastrointestinal effects. By contrast, none of the patients in the exenatide group experienced gastrointestinal complications that required treatment discontinuation during the first four weeks. The most common adverse event in the exenatide group was the development of injection-site nodules. Major hypoglycemic events were not observed. However, minor hypoglycemic events occurred in a similar number of patients in each group. Minor hypoglycemia was more common in patients who received concomitant treatment with oral anti-hyperglycemic agents.

This head-to-head comparison of two long-acting GLP-1 receptor agonists demonstrated that both treatment regimens offer clinical benefit. Once-weekly exenatide and once-daily liraglutide effectively reduced HbA1c and fasting blood glucose levels in patients with inadequately controlled type 2 diabetes. Glycemic control and weight loss were significantly greater in the liraglutide group. However, gastrointestinal side effects were also more common in patients treated with liraglutide. The relative risks and benefits should be carefully considered for each patient when deciding between a once-weekly formulation of exenatide and a once-daily injection of liraglutide.


1. Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 376: 431–39.

2. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240–50.

3. Blevins T, Pullman J, Malloy J, et al. DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301–10.

4. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39–47.

5. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 473–81.

6. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117-24.