[Digital Today reporter Jinju Hong] Eli Lilly's next-generation obesity treatment retatrutide, now in development, may reduce fatigue, which has been cited as a major side effect of existing GLP-1 treatments. Its key distinction is drawing attention for going beyond appetite suppression to regulating energy metabolism itself.

On May 18 (local time), online media outlet Gigazine reported that retatrutide adopts a "triple agonist" structure that simultaneously stimulates GLP-1, GIP and glucagon receptors.

In the current obesity drug market, semaglutide and tirzepatide have emerged as representative medicines. Semaglutide works by activating only the GLP-1 receptor. Tirzepatide adds GIP receptor activity to that. Retatrutide, by contrast, goes a step further by also stimulating the glucagon receptor at the same time.

The human body regulates blood sugar and energy storage through a hormone network that includes insulin, glucagon, GLP-1 and GIP. GLP-1 is secreted after food intake. It sends the brain a signal that a person has already eaten, suppresses appetite and glucagon secretion, and increases insulin secretion. Glucagon, meanwhile, promotes the breakdown of glycogen stored in the liver and the use of fat, raising blood sugar and energy levels.

Retatrutide uses both pathways together. It promotes fat and glycogen breakdown by stimulating the glucagon receptor. At the same time, it activates the GLP-1 receptor to increase insulin secretion and curb sharp rises in blood sugar.

This mode of action is also linked to the fatigue issue associated with existing GLP-1 drugs. Existing GLP-1 treatments have dominated the market with strong appetite suppression and weight-loss effects, but criticism has continued that some users experience fatigue and lethargy symptoms.

Gigazine said retatrutide's glucagon action may help offset such fatigue or boost energy by promoting energy use. It added that relevant clinical data have not yet been sufficiently accumulated.

Retatrutide's design also reflects the binding mechanism between hormones and receptors. Hormones generally bind to specific receptors like a key and a lock, but even without a perfect match, they can act on other receptors if they have a certain level of affinity. Retatrutide was introduced as an example designed to leverage this trait to target multiple receptors at once.

The market is focusing on the point that obesity treatments are evolving beyond simple appetite suppressants toward regulating overall human energy metabolism. Retatrutide is assessed as an approach that aims for a balance between weight-loss effects and side-effect management by inducing not only appetite suppression but also fat and glycogen breakdown.

Elizabeth Van Nostrand, who wrote the article, assessed retatrutide's mechanism by saying, "The mechanism to offset the side effects of GLP-1 drugs is very sophisticated and beautiful."

Still, its real clinical significance and long-term safety are expected to become clearer through additional data and large-scale clinical results in the future.