Can Liraglutide Antibodies Affect Its Efficacy?

Dr. John B. Buse from the University of North Carolina School of Medicine in Chapel Hill stated that, "With exenatide treatment, a small proportion of patients develop high levels of antibodies associated with decreased effectiveness."

When patients taking exenatide don't have good blood sugar control, he said, "it is possible that high levels of antibodies are the cause and that switching to liraglutide would result in improved control."

Liraglutide is a recombinant once-daily glucagon-like peptide-1 (GLP-1) receptor agonist. Exenatide belongs to the same class of drugs; it is synthetic exendin-4, a xenopeptide from the saliva of the Gila monster with significant amino acid sequence identity to human GLP-1.

"Animal peptides generally do result in antibodies to the foreign protein," Dr. Buse explained. "Human analogs generally do not result in antibody formation presumably because of their minimal modification of the native human structure."

Dr. Buse and colleagues used LEAD-6 trial data to assess immunogenicity to liraglutide and its impact on glycemic control and safety. LEAD-6 also included data for exenatide.

After 26 weeks of treatment with liraglutide, 8.7% of patients taking 1.2 mg and 8.3% of patients taking 1.8 mg had low-level anti-liraglutide antibodies.

Results were similar at the end of 1 year (7.1% at 1.2 mg; 5.4% at 1.8 mg). By 2 years, the prevalence of antibodies had fallen off (3.1% at 1.2 mg; 3.5% at 1.8 mg).

Anti-liraglutide antibody formation did not attenuate the glycemic response to liraglutide, and no patients with anti-liraglutide antibodies had serious or systemic immunologic adverse events.

In marked contrast, 61% of exenatide patients had anti-exenatide antibodies at week 26 of treatment, and high levels of exenatide antibodies were associated with significantly smaller mean reductions in hemoglobin A1c.

After switching to liraglutide at week 26, exenatide patients continued to have anti-exenatide antibodies at week 40 (50%) and week 78 (17%), but the presence of these antibodies did not compromise their glycemic response to liraglutide.

"I do not think that the frequency of antibody formation should be a major consideration for prescribing one drug versus the other," Dr. Buse said. "Bigger issues are effectiveness in glucose lowering, frequency and severity of side effects, and acceptability of the schedule and method of administration."

In particular, liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors in both genders of rats and mice. A black box warning states, "It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors."

In conclusion, unlike exenatide (Byetta), liraglutide (Victoza) only rarely induces antibody formation, and when it does, those antibodies have no impact on glycemic efficacy or safety, according to findings.

J Clin Endocrinol Metab  March 30,2011.