Popular injected weight loss medications work better for one sex. Researchers want to know why

You’ve probably heard the stories: For every man who has cut carbs from his diet and dropped 10 pounds, there’s a woman who’s done exactly the same thing and lost 2. Research backs up this frustrating fact. Diet and exercise tend to benefit men much more than women when it comes to losing weight. That’s why the results of recent clinical trials were surprising — and welcome — for some: In study after study, injected GLP-1 weight loss medications appear to work better on average for women than they do for men. What’s not clear is why. And researchers say it’s important to understand so doctors can optimize the use of these powerful drugs for everyone. The latest study to see this effect was presented Sunday at the annual meeting of the European Congress on Obesity and published in the New England Journal of Medicine. It was the first head-to-head comparison of the injectable GLP-1 medications semaglutide and tirzepatide, which are sold under the brand names Wegovy and Zepbound for weight loss. Roughly 750 people with obesity were randomly split into two groups. Half were assigned to get the maximum dose of Wegovy they could tolerate; the other half used the maximum dose of Zepbound. Zepbound is newer medication than Wegovy. It stimulates two different gut hormones that affect appetite and blood sugar, while Wegovy primarily affects the action of one. Many doctors have observed that Zepbound seems to be a more powerful medication than Wegovy, so it was not surprising when this trial – which was sponsored by Eli Lilly, the manufacturer of Zepbound – arrived at the same conclusion. People in the study who were using Zepbound lost about 50% more weight those who got Wegovy, making it the superior drug in terms of weight loss. One curious thing about the study was that all the participants lost a little bit less weight, on average, than has been measured with the same medications in other trials. Researchers say that result was driven by men, who lost about 6% less weight than women. About 35% of participants in this study were men, while 20% to 25% of participants in previous trials have been male. “Why this works better in women, I can’t honestly tell you, but it’s great,” said Dr. Louis Aronne, who directs the Comprehensive Weight Control Center at Weill Cornell Medicine and who led the study. “It has been seen again and again.” For example, in long-term follow up of a trial that compared semaglutide to a placebo, women using semaglutide for two years lost an average of 11% of their starting weight, while men using the drug lost an average of 8%. Across trials of tirzepatide that compared it to a placebo, women on the drug lost up to 28% of their starting weight, while men lost up to 19% of their weight. Untangling sex-specific effects There could be a host of reasons for this, spanning numerous aspects of biology and culture, said Dr. Melanie Jay, an obesity expert and professor of medicine at New York University’s Grossman School of Medicine. The first has to do with drug dosing. Women tend to weigh a little bit less than men but are prescribed the same doses, so it may be that they’re getting more for their size. “So maybe they’re getting a higher dose,” Jay said. It might also have something to do with where women store fat. Jay said women tend to have more cutaneous fat, or fat under their skin, than visceral fat, or fat that’s packed around the internal organs like the liver. Perhaps the drugs are more effective on one type of fat than the other. Women also face more societal pressure to be thin, Jay said, and this could lead to greater motivation to stay on the medications, which aren’t always easy to take. Jay said she’s seen this in her own practice. Women seem to be more willing to tolerate and work through the significant side effects of the drugs, which can include regular nausea, vomiting and constipation. “I have had a few more men be like, ‘I can’t take the constipation or the nausea,’ whereas the women usually figure out how to get through it,” Jay said. She said the side effects tend to get better over time, as people learn how to eat differently and start to exercise more. Role of estrogen in weight loss One of the most intriguing clues to explain why women benefit more from the GLP-1 medications has to do with the hormone estrogen, which women have in higher amounts than men. Dr. Karolina Skibicka is a professor of molecular medicine at the University of Gothenberg in Sweden and has a lab in the nutrition department at Penn State University. “Overall, I’m a neuroscientist interested in gut-brain communication,” which is how she began studying GLP-1, a gut hormone that also works in the brain. Skibicka says scientists have known that estrogen plays a role in metabolism for about 30 years, but they didn’t really understand how. Her research in rats has shown that estrogen directly interacts with GLP-1 and other gut hormones, making them more potent in the brain. Several studies have shown that if you inject rats with GLP-1 and estrogen together, “you will see a very enhanced effect sort of across the board, on feeding behavior, motivated behavior, various other aspects of GLP-1 actions,” she said. You can test this interaction in a another way, she said. If you block the action of estrogen with a chemical inhibitor, it turns down the effect of GLP-1, too. “If we take it away, the effect is reduced, so the animals will eat a little bit more now, or GLP-1 is just not as effective as suppressing feeding or suppressing food reward behavior, maybe more specifically, when we take away estrogen,” she said. Estrogen appears to amplify the effects of GLP-1 by increasing the number of receptors — think of them as boat docks — on the surface of cells where this gut hormone can attach. In many tissues, she says, cells have receptors for both estrogen and GLP-1. “So then you sort of have an amplified effect inside the cell as well.” Although all of these theories are interesting, they are just educated guesses at this point. A push for more research “We’re really dealing with paucity of data compared to just sort of the baseline data that you have about what GLP-1 does,” Skibicka said. “Clinical studies don’t really ask and don’t really confirm why they see a difference.” Both Jay and Skibicka said sex differences typically go unexplored when it comes to drugs, and the GLP-1 medications are no exception. In studies that do report data by sex, women may lose 50% to 90% more weight than men, but they also seem to report more GI side effects, Skibicka said. Men seem to get more cardiovascular benefits from the medications than women. Although most studies don’t find that GLP-1 medications negatively affect mood, some have shown that this may differ by sex, with women being more likely to experience depression on the medications than men. Understanding the impacts of these sex differences could be important for all patients. If estrogen affects how strongly the medications work, that may have implications for the treatment of women before or after menopause, since estrogen levels fall in women as they age. It may also impact how well GLP-1 medications work for women on hormone-blocking therapies after breast cancer, for example. It may lead to strategies that help nonresponders, the people who don’t seem to lose weight on the drugs, and people who stop losing weight before they reach their weight loss goals. Jay said that understanding the mechanisms behind the sex differences could help with adherence to the medications, too. “I think those things are really important to know, because maybe there’s something else that we could give men alongside it that could enhance it … or we could change the dosing,” Jay said. “Men and women have different biologies, and we can’t treat them always the same.”