Comparative Effects of the Long‐Acting GLP‐1 Receptor Ligands, Liraglutide and Exendin‐4, on Food Intake and Body Weight Suppression in Rats

Abstract

The glucagon-like-peptide-1 receptor (GLP-1R) agonists, liraglutide (Victoza) and the synthetic product of exendin-4 (Byetta), are approved for type II diabetes mellitus (T2DM) treatment and may be efficacious in obesity treatment as well, in part, due to the drugs' resistance to enzymatic degradation and prolonged half-life relative to endogenous GLP-1. To address the need to directly compare the food intake- and body weight-suppressive effects of these two GLP-1R ligands, acute and chronic dosing experiments were performed. Once-daily (q.d.) exendin-4 (0, 0.33, 1.5, and 3.0 µg/kg) and liraglutide (0, 50, 100, and 300 µg/kg, q.d.) both reduced the chow intake in nonobese rats in a dose-dependent fashion following either intraperitoneal (IP) or subcutaneous (SC) administration, whereas only liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats. Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following IP compared to SC delivery, whereas for exendin-4, the magnitude of intake-suppression was similar for IP and SC administration. The effects of chronic delivery (7 consecutive days; IP) of liraglutide (25 and 50 µg/kg; q.d.) and exendin-4 (3 µg/kg; q.d. and twice-daily (b.i.d.)) on food intake and body weight were also examined in diet-induced obese (DIO) rats. Liraglutide (50 µg/kg q.d.) and exendin-4 (3 µg/kg b.i.d.) were comparable in suppressing overall high fat/sucrose diet (HFS; 60% kcal from fat) intake. Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period. In conclusion, administration of the GLP-1R ligands, exendin-4 (b.i.d.) and liraglutide (q.d.), lead to comparable and pronounced suppression of food intake and body weight in DIO rats, suggesting a potential role for these drugs as a clinical tool for obesity treatment.