Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials

Abstract

Context: Therapeutic proteins/peptides can produce immunogenic responses that may increase the risk of adverse events or reduce efficacy.

Objective: The objectives were to measure and characterize antibody formation to liraglutide, a glucagon-like peptide-1 receptor agonist, to investigate the impact on glycemic control and safety, and to compare it with exenatide, an agent in the same class.

Design: Antibody data were collected during six Liraglutide Effect and Action in Diabetes (LEAD) trials (26-104 wk duration).

Setting: Samples for determination of antibody formation were collected at LEAD trial sites and analyzed at central laboratories.

Participants: Antibodies were measured in LEAD trial participants with type 2 diabetes.

Interventions: Interventions included once-daily liraglutide (1.2 or 1.8 mg) or twice-daily exenatide (10 μg).

Main outcome measures: The main outcome measures included the proportion of patients positive for anti-liraglutide or anti-exenatide antibodies, a glucagon-like peptide-1 cross-reacting effect, and an in vitro liraglutide- or exenatide-neutralizing effect. Change in glycosylated hemoglobin A(1c) (HbA(1c)) by antibody status and magnitude [negative, positive (high or low level)].

Results: After 26 wk, 32 of 369 (8.7%) and 49 of 587 (8.3%) patients had low-level antibodies to liraglutide 1.2 and 1.8 mg, respectively [mean 3.3% antibody-bound radioactivity out of total radioactivity (%B/T), range 1.6-10.7%B/T], which did not attenuate glycemic efficacy (HbA(1c) reductions 1.1-1.3% in antibody-positive vs. 1.2% in antibody-negative patients). In LEAD-6, 113 of 185 extension patients (61%) had anti-exenatide antibodies at wk 26 (range 2.4-60.2%B/T). High levels of anti-exenatide antibodies were correlated with significantly smaller HbA(1c) reductions (P = 0.0022). After switching from exenatide to liraglutide, anti-exenatide antibodies did not compromise a further glycemic response to liraglutide (additional 0.4% HbA(1c) reduction).

Conclusions: Liraglutide was less immunogenic than exenatide; the frequency and levels of anti-liraglutide antibodies were low and did not impact glycemic efficacy or safety.

Trial registration: ClinicalTrials.gov NCT00294723 NCT00331851 NCT00333151 NCT00395746 NCT00518882 NCT00614120.