The latest buzzy diabetes drug semaglutide—better known by brand names Ozempic, Wegovy, and Rybelsus—is drawing attention for its ability to both control blood sugar and cause weight loss. But doctors and patients are anticipating that the most powerful of these drugs is yet to come, since the U.S. Food and Drug Administration is considering approving Eli Lilly’s drug tirzepatide (brand name: Mounjaro) for weight loss later this year.
In studies Lilly submitted to the FDA, the company showed that Mounjaro—which is already approved for treating Type 2 diabetes—can lower body mass among users at its highest dose by up to 15%. While semaglutide targets one molecule, glucagon-like peptide-1 (GLP-1), involved in insulin secretion, tirzepatide is the first to target two: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).
In a new study published in Nature Metabolism, an international group of researchers, in collaboration with scientists from Eli Lilly and Novo Nordisk (the maker of Ozempic and Wegovy), tried to understand how tirzepatide produces its robust effects on blood sugar and weight. Working with both mice and cultures of human insulin-making cells from the pancreas, the team conducted a series of experiments to better understand the drivers behind the drug’s dual actions.
“The historical narrative in the field has been that GIP is doing everything that GLP-1 is doing, just not as well,” says Jonathan Campbell, associate professor of medicine at Duke University and senior author of the study. Researchers have known that GLP-1 acts on cells in the pancreas and stimulates the production of insulin, which breaks down glucose in the body. It also works on the digestive system, suppressing hunger signals sent to the brain and curbing appetite. GIP has similar effects, but they’re generally not as powerful.
The scientists therefore expected to find that tirzepatide worked mainly by activating GLP-1 receptors in the body—and they questioned whether GIP would have any additional impact. Because the molecules are very similar, targeting both wouldn’t necessarily lead to an additive effect. Instead, the two entities could compete to bind to the same cell receptors, “both trying to go through the same door at the same time,” says Campbell.
But to their surprise, the team found that tirzepatide in fact triggers a powerful GIP response. “GIP was indispensable,” says Campbell. In fact, in experiments on insulin-producing pancreatic cells donated from eight volunteers, the researchers found that if GIP was blocked in these cells, preventing the drug from binding to GIP receptors, the drug had no effect on stimulating insulin production. When GIP receptors were not blocked, the cells produced insulin.
“That was surprising to us, and the opposite of what we thought,” he says.
The reason might have something to do with differences between mice and men. Scientists rely heavily on mouse models to understand how things like GIP and GLP-1 work in living organisms, but it turns out that GIP receptors are different in human cells. While the genetic sequences for the GLP-1 receptors in mice and humans are identical, the sequences for GIP receptors in the two species are not. That’s an issue, since the most efficient way to understand how GIP works is to study human versions of the receptors in mice. “All of the data looking at tirzepatide from a mechanistic standpoint has been done mostly in mouse models,” says Campbell. “So we thought it was important for researchers to know that there are confounding variables.”
The studies are an intriguing first step to answering questions about whether the latest class of GLP-1-based diabetes and weight-loss drugs could be more effective if combined with GIP-based medicines. More studies would be needed to explore whether targeting not just one, but several processes involved in insulin production and weight might be more effective. If that were the case, then “physicians would have different tools that give them more options to treat people,” says Campbell.
“This study shows that for insulin secretion, which is a major biological action for glucose control, it looks like GIP is very, very important,” he says. Taking that scientific hint, Campbell hopes to build on these findings by studying GLP-1 and GIP in a larger number of human cell samples. And because the volunteers in the current trial represented a range of BMIs but did not have diabetes, he says it’s important to also include cells from people with that condition to better isolate the most efficient way to control blood sugar and weight.
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