2057-LB: Amino Acids Plasma Levels Do Not Correlate with Lean Mass Loss in Weight-Matched DIO Mice Treated with Survodutide or Semaglutide

Concomitant with beneficial fat mass loss, anti-obesity therapies lead to detrimental lean mass loss. It is known that amino acids are essential for muscle mass maintenance, growth, and repair. Moreover, it is recognized that glucagon promotes skeletal muscle wasting to supply amino acids for gluconeogenesis. Given that survodutide is a dual glucagon/glucagon like peptide 1 (GLP1) receptor agonist, and semaglutide acts solely as GLP1 receptor agonist, it could be hypothesized that survodutide leads to greater lean mass loss. Hence, we investigated plasma amino acids levels, body composition and energy expenditure (EE) of DIO (diet induced obesity) mice (8 mice/group) treated with either survodutide or semaglutide (both at 20 nmol/kg s.c. q.d. 3 weeks). Similar weight loss was achieved with survodutide (17.7±3.3%) and semaglutide (15.6±3.7%) vs. baseline, mean±SD, p<0.0001. While the weight loss for semaglutide was due to its anorexigenic effect, survodutide additionally increased EE (p=0.0081, d21) due to its glucagon component. Both compounds showed ~40% decrease in fat mass (40.4±1.7% and 40.8±3.7%, mean±SD, survodutide and semaglutide respectively, p=0.0006 vs. vehicle). Importantly, lean mass loss was not significantly different when comparing survodutide (8.3±0.8%) and semaglutide (5.3±0.9%), mean±SD, p=0.9071. Interestingly, both essential and non-essential plasma amino acids were decreased when comparing semaglutide with survodutide: L-lysine decreased from 180.5±32.7 µmol/L to 90.3±16.6 µmol/L and L-alanine from 336.4±121.4 µmol/L to 117.8±32.2 µmol/L when comparing semaglutide and survodutide respectively, mean±SD. In summary, we showed that the glucagon component of survodutide increased EE and reduced plasma amino acids levels when compared to semaglutide. However, these results did not translate into a different lean mass loss, indicating that the reduction in plasma amino acids did not correlate with lean mass loss.