“I had three chairs in my house; one for solitude, two for friendship, three for society.”— Henry David Thoreau, Walden
Nature is all about balance. Push one biological lever and another often moves with it — usually in the opposite direction. Biology also hates waste. Why invent a new molecule for every job when the same one can take on multiple roles? Nowhere is this more apparent than in the control of metabolism.
Take glucagon, for example. We’re taught that it’s insulin’s counterweight. Insulin lowers blood glucose and glucagon tips the balance the other way, raising it. A perfectly balanced system designed to maintain homeostasis.
Eat too little and the body responds by trying to conserve energy. Eat too much and another complex interplay of hormonal signals comes into play. Hunger and fullness, energy storage and energy expenditure, rising and falling blood sugar — each carefully balanced against the other. But glucagon doesn’t just sit on one side of the blood-sugar seesaw. As with many biological processes, it has much more going on below the surface. And it is the exploration and engineering of this hidden world that ultimately led to retatrutide.1
It turns out that glucagon also influences how much energy we use and encourages the metabolism and burning of stored fat. For scientists at Eli Lilly, this presented a challenge: could they harness this side of glucagon without tipping the blood-sugar balance too far the other way?
But weight loss is a team game, and glucagon wasn’t entering the field alone. Two other hormones were already very much in play: GLP-1 and GIP. Semaglutide showed us that activating a single hormone receptor (GLP-1) could reduce appetite and body weight. Tirzepatide then brought GIP into the team, activating both GIP and GLP-1 receptors to influence appetite, glucose regulation and body weight. A powerful duo.2
And here lay a possible answer to Lilly’s glucagon question. What if glucagon could be added to the mix, its effects on energy expenditure and fat metabolism working alongside the appetite- and glucose-regulating effects of GLP-1 and GIP?
Retatrutide was engineered to do exactly that: a single peptide with agonist (activating) activity at three different receptors — GLP-1, GIP and the glucagon receptor. It’s hard to overstate what an achievement this is. Engineering this kind of activity into a single molecule is a testament to human ingenuity and creativity. Nature provided the triumvirate; the clever part was learning how to bring all three under the control of one molecule.
Enough theory — what does it do in the real world? In a Phase 2 obesity trial, people receiving the highest dose of retatrutide lost an average of 24.2% of their starting body weight after 48 weeks — almost a quarter of their body weight in less than a year. In Lilly’s TRIUMPH-1 trial, participants receiving 12 mg of retatrutide lost an average of 28.3% after 80 weeks, while in an extension involving people with a starting BMI of at least 35, average weight loss reached 30.3% after two years. It is remarkable that these kinds of numbers can be achieved with a drug. For decades, bariatric surgery could achieve a degree of weight loss that medicines simply couldn’t approach. The clinical trial results with retatrutide suggest that this may no longer be a one-horse race.3,4
And what about the question we started with — would adding glucagon send blood glucose spiralling out of control? So far, the answer appears to be no. Quite the opposite: studies have reported improvements in glycaemic control, including in people with type 2 diabetes. Retatrutide is now being studied specifically for diabetes in Lilly’s Phase 3 TRANSCEND-T2D programme.5
Of course, there is no such thing as a free biological lunch. Like other drugs acting on the incretin system, retatrutide can cause gastrointestinal side effects including nausea, diarrhoea and vomiting, and the dose needs to be increased gradually. It’s important to remember that retatrutide remains an experimental medicine and, at the time of writing, has not been approved by any regulatory authority anywhere in the world. Longer-term safety and efficacy are still being established in ongoing clinical trials.3 It’s not over the finish line yet. And it may never get there.
Which leaves one question weighing on me: where does all this go next? We have spent centuries trying to defeat our biology in the battle against weight gain. Retatrutide suggests that perhaps the answer was never to fight it at all, but to understand its competing signals well enough to rebalance them. Nature provided the orchestra. We are only just learning how to conduct it.
References:
1) Ansari S, Khoo B, Tan T. Targeting the incretin system in obesity and type 2 diabetes mellitus. Nature Reviews Endocrinology. 2024;20:447–459. doi:10.1038/s41574-024-00979-9.
2) Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nature Reviews Endocrinology. 2023;19:201–216. doi:10.1038/s41574-022-00783-3.
3) Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. 2023;389:514–526. doi:10.1056/NEJMoa2301972.
4) Eli Lilly and Company. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial: TRIUMPH-1 topline results. Company news release, 21 May 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss.
5) Eli Lilly and Company. Lilly’s triple agonist, retatrutide, drove substantial improvements in weight, A1C, knee osteoarthritis pain, and obstructive sleep apnea: TRANSCEND-T2D-1 topline results. Company news release, 6 June 2026. Further Information.