Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes

A Review of Current Literature

Courtney Aavang Tibble; Tricia Santos Cavaiola; Robert R Henry


Expert Rev Endocrinol Metab. 2013;8(3):247-259. 

In This Article

Antibody Development in Subjects Treated With LA-GLP1 RA

As with all therapeutic peptides, there has been ongoing concern as to whether the development of antidrug antibodies when using GLP1-RAs could lead to decreased efficacy or increased hypersensitivity of the medication over time. This is especially true since tapsoglutide, another very promising once weekly GLP1-RA was pulled from development in 2010 after a small number of patients developed severe hypersensitivity reactions.[40] Multiple studies on exenatide b.i.d. have shown significant numbers of subjects, treated with the b.i.d. formulation, develop antidrug antibodies peaking at weeks 6–16 of therapy with titers declining over time.[41] By 30 weeks of therapy, approximately 35% of treated patients are antibody (Ab) positive, with a great majority of these having low titers (<125) and only 5% having high titers (>625). Liraglutide therapy resulted in less common development with LEAD trial subjects showing an average 8.6% of patients developing antidrug antibodies.[42] All trials to date on the LA GLP1-RAs have measured Ab levels. With EQW, albiglutide, dulaglutide and semaglutide trials, there are varying rates of Ab development, presumably due to the difference in immunogenicity of the varied formulations of each drug. With albigultide, only 2.5% of subjects developed antidrug antibodies, most of which were transient.[34] With dulaglutide, antibodies were tested at a variety of dosing strengths, and in contrast to other GLP1-RA, no patients showed emergence of any treatment-related antibodies.[37] One subject in the semaglutide study of T2D (given the highest dose of semaglutide, 1.6 mg) developed low-titer nonneutralizing antisemaglutide antibodies, which did not crossreact with native GLP-1.[39] With EQW, there were much higher rates of Ab formation. In the DURATION-1 trial, there was found to be a significantly greater prevalence of anti-exenatide Abs in the EQW-treated subjects than the exenatide b.i.d.-treated subjects (p = 0.0002).[12] Similar findings with regards to percent of subjects developing antidrug Abs were noted in all DURATION trials, with positive Ab development in approximately 43–54% of individuals receiving the weekly formulation.[11–17,24] There was not a significant difference in overall A1c reduction from baseline in subgroups of patient with positive versus negative Ab titers,[11,13] and all patients treated with EQW experienced clinically significant A1c reduction regardless of Ab status. However, in looking across multiple studies, it appears that the small percentage of patients (~10–12%) who develop high titers of antidrug antibodies to EQW had a significantly lower mean A1c response to the drug compared with low-titer and Ab-negative subjects.[41] No association was found between the development of positive antibodies in any study and also no significant differences in weightloss, GI side effects or other adverse events were observed.[15,27,41] There is one exception, and that being in the rate of local injection site reactions, which are more common in patients who develop antibodies. However, the majority of these reactions were mild and also transient, and generally did not result in the discontinuation of therapy.[41] There have been no severe hypersensitivity or anaphylactic reactions reported with any of the LA GLP1-RA currently in development.