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One molecule, three receptors
Why one drug fits several
The receptors involved are evolutionarily related and look kind of similar, so a drug can be tweaked slightly to fit several of them instead of one. GLP-1 receptors on their own already sit in multiple parts of the body, and sometimes a drug that attaches to only one thing is better, while sometimes acting on several things brings several benefits.
The tradeoff
Hitting more targets can dial up efficacy, but it also adds risk, because the drug touches things that have a function in keeping the body normal. One molecule acting on three receptors is a statistical bet on how much it interacts with each of them, which medicinal chemists favor because it gives better control than three separate molecules.
The results
The new drugs are more effective partly because they act on more receptors. In trials, semaglutide produced about 15% weight loss, tirzepatide about 21%, and retatrutide in its phase three trial a 28% reduction in body weight over roughly 18 months.
Why do these receptors resemble each other?
The GLP-1, GIP, and glucagon receptors all belong to the class B family of G protein-coupled receptors, which respond to peptide hormones. Their hormones are related too: glucagon and GLP-1 are both cut from the same precursor protein, proglucagon. Tirzepatide is a chain of 39 amino acids built on the sequence of GIP, with changes that let it also activate the GLP-1 receptor. A natural gut hormone, oxyntomodulin, already activates both the GLP-1 and glucagon receptors.
Why add glucagon to a weight loss drug?
Glucagon is best known for raising blood sugar, but it also increases the body's energy expenditure and the burning of fat in the liver. The rise in blood sugar would be a drawback on its own, which GLP-1's effect on insulin helps offset. Together, the combination aims to reduce food intake and raise energy use at once. Retatrutide's phase two trial in obesity was published in the New England Journal of Medicine in 2023.
How did tirzepatide fare against semaglutide directly?
The SURMOUNT-5 trial, published in the New England Journal of Medicine in 2025, compared the two drugs head to head in adults with obesity. After 72 weeks, people on tirzepatide had lost about 20 percent of their body weight, and people on semaglutide about 14 percent. The study was open label, so participants and doctors knew which drug was being given.
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