TY - JOUR

T1 - 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

T2 - Results from the Liraglutide Effect and Action in Diabetes (LEAD) trials

AU - Buse, John B

AU - Garber, Alan

AU - Rosenstock, Julio

AU - Schmidt, Wolfgang E

AU - Brett, Jason H

AU - Videbæk, Nicoline

AU - Holst, Jens Juul

AU - Nauck, Michael

PY - 2011

Y1 - 2011

N2 - 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 A1c (HbA1c) 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 (HbA1c 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 HbA1c 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% HbA1c 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.

AB - 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 A1c (HbA1c) 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 (HbA1c 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 HbA1c 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% HbA1c 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.

KW - Antibody Formation

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Glucagon-Like Peptide 1

KW - Humans

KW - Male

KW - Peptides

KW - Radioimmunoassay

KW - Venoms

U2 - 10.1210/jc.2010-2822

DO - 10.1210/jc.2010-2822

M3 - Journal article

C2 - 21450987

VL - 96

SP - 1695

EP - 1702

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 6

ER -