ADA 2011: Combo Treatment Increases Proportion of Diabetes Patients Achieving A1C Target

LEAD-6 trial results show improved glycemic control with weight loss and a low risk of hypoglycemia with liraglutide and exenatide.

Improved glycemic control with weight loss and a low risk of hypoglycemia can be obtained with two drugs approved for use in type 2 diabetes (T2D).

Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analog. Exenatide is a twice-daily xenopeptide with GLP-1 receptor agonist activity.

In an extension of the 26-week LEAD-6 (Liraglutide Effect and Action in Diabetes) trial, post-hoc results showed liraglutide to increase the percent of T2D patients achieving A1c targets after being switched from exenatide. John B. Buse, MD, from the Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, NC, presented results from the study at a poster session at the ADA 71st Annual Meeting in San Diego.

Three main comparisons were made in this presentation: 1) percent of patients achieving A1c target (<7% per ADA or ≤6.5% per AACE) after treatment with exenatide versus liraglutide in the 26-week LEAD-6 trial, 2) percent of exenatide-responding patients achieving target after switching to liraglutide in the 14-week extension, and 3) percent of exenatide non-responders achieving target after switching to liraglutide in the 14-week extension.

In the 26-week LEAD-6 trial, patients were randomized to 1.8 mg liraglutide or exenatide, both in combination with metformin and/or sulfonylurea. At the end of the 26 weeks, patients treated with liraglutide (n=233) had greater reductions in A1c compared to those treated with exenatide (n=231). In addition, more liraglutide patients met A1c targets compared to exenatide patients (54% versus 43% for ADA target, respectively, and 35% versus 21% for AACE target, respectively). Statistical significance of these differences was not reported.

Patients who had completed the 26-week trial (n=389) entered the 14-week extension, where those treated with exenatide were switched to liraglutide 1.8 mg daily.

After switching to liraglutide, 89% of those previously responding to exenatide achieved A1c target versus 32% of those not previously responding to exenatide. That is, liraglutide maintained target in the majority of exenatide-responders, but improved response in exenatide non-responders. Reductions in A1c after switching to liraglutide were -0.3% for exenatide responders and -0.8% for exenatide non-responders.

Overall, there was greater variation in response to liraglutide in exenatide non-responders compared to responders. Statistical significance was not reported in this study. However, there does appear to be some mechanism accounting for the difference in response to liraglutide between exenatide-responders and non-responders. “One sub-group that does very well when switching from exenatide to liraglutide is patients with high-titer anti-exenatide antibodies,” said Buse.

Study investigators reported a meta-analysis from the LEAD studies showing liraglutide to be associated with a lower frequency of antibody formation compared to exenatide (8.3-8.7% versus 61%).

If patients are responding to exenatide, one may wonder why switch to liraglutide? The main impetus, said Buse, is patients who prefer one daily injection over two. In addition, patients who achieve target with exenatide may experience additional benefits by switching to liraglutide. Although all of the results are compelling, perhaps more important is the idea that patients not achieving A1c target on exenatide may have better success with liraglutide.