ESPE Abstracts

Background: While research demonstrated successful weight and BMI reduction in response to recent obesity drugs in adults and adolescents, there are significant limitations of current drugs targeting single receptors, such as problems maintaining a reduced weight status, and the high rates of gastrointestinal adverse events, which can lead to discontinuation of treatment. Based on this, we hypothesized that a more effective and better tolerated obesity intervention will be targeting multiple receptors of body weight regulating neurocircuits.

Methods: We created a single molecule dual glucagon-like peptide-1 receptor (GLP-1R)/ melanocortin-4 receptor (MC4R) coagonist, which resembles GLP-1RA exendin-4 at the N-terminal and α-melanocyte stimulating hormone (α-MSH - an MC4R agonist) on the C-terminal end. The resulting chimeric sequence was termed KCEM1, which was tested in vitro on receptor binding and in vivo in diet-induced obese (DIO) rats on reduction of food intake, body weight and blood gucose levels by intraperitoneal glucose tolerance tests (IPGTT) at baseline, 2 and 7 weeks of treatment.

Results: Receptor binding studies demonstrated, that, KCEM1 is a weaker agonist than exendin-4 at GLP-1R, and a weaker agonist than α-MSH at MC4R. KCEM1 resulted in significant reductions of food intake and body weight. While after 7 weeks the body weight reduction compared to vehicle was similar in response to KCEM1 (-14.5%), and equimolar doses of active controls semaglutide (-14.1%) and tirzepatide (-12.7%), blood glucose levels during IPGTT testing were significantly lower in KCEM1 treated rats vs. all other groups (7 min peak glucose: KCEM1 208±19, semaglutide 301±32, tirzepatide 339±23, vehicle 357±43 mg/dL, one-way ANOVA P = 0.0011). 15-min peak insulin was significantly stimulated by KCEM1.

Conclusion: KCEM1 is a weaker agonist compared to semaglutide or tirzepatide, while it offered superior glycemic control. The GLP-1R/MC4R coagonism might be suitable to achieve weight loss and improvement of glucose tolerance at doses that might be subthreshold for side-effects on both receptors.