title: 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: BACKGROUND
  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.
  
  
  METHODS
  Antibody data were collected during six Liraglutide Effect and Action in Diabetes (LEAD) trials (26-104 wk duration).
  
  
  METHODS
  Samples for determination of antibody formation were collected at LEAD trial sites and analyzed at central laboratories.
  
  
  METHODS
  Antibodies were measured in LEAD trial participants with type 2 diabetes.
  
  
  METHODS
  Interventions included once-daily liraglutide (1.2 or 1.8 mg) or twice-daily exenatide (10 μg).
  
  
  METHODS
  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.
authors: Division of Endocrinology, University of North Carolina School of Medicine, CB 7172, 8027 Burnett-Womack Building, Chapel Hill, North Carolina 27599, USA. jbuse@med.unc.edu
authors: John B
authors: JB
authors: Buse
authors: Alan
authors: A
authors: Garber
authors: Julio
authors: J
authors: Rosenstock
authors: Wolfgang E
authors: WE
authors: Schmidt
authors: Jason H
authors: JH
authors: Brett
authors: Nicoline
authors: N
authors: Videbæk
authors: Jens
authors: J
authors: Holst
authors: Michael
authors: M
authors: Nauck
mesh_terms: D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology*; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D000069450:Liraglutide; D008297:Male; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D011863:Radioimmunoassay; D014688:Venoms / Q000276:immunology / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D010455:Peptides; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide