It’s not clear why some people on these drugs lose a lot of weight while others don’t lose any. “We still don’t understand most of the variation in response,” says Ewan Pearson, professor of diabetic medicine at the University of Dundee in Scotland. There are a few known predictors of how patients will fare, though. For instance, women tend to lose more weight than men on GLP-1 drugs, possibly because they have a different fat distribution compared to men, or because their smaller average size could mean higher exposure to the drug.
And while GLP-1 drugs were first approved as a diabetes treatment to improve blood sugar levels, they’re less likely to produce significant weight loss in people with type 2 diabetes. Researchers have suggested genetics, altered microbiomes, and other medications that promote weight gain as possible reasons for this. “A lot depends on a person’s physiology and biology. We can’t expect that a drug will be a one-size-fits-all for everyone,” says Amy Rothberg, an endocrinologist at the University of Michigan.
GLP-1 drugs lead to weight loss by slowing the movement of food in the stomach and by interacting with receptors in the brain to promote a feeling of fullness. Some people taking them report less “food noise”—they no longer have cravings or think about food all the time. As a result, they eat less. Patients start on a low dose that’s gradually increased each week. Schmidt says some people may not respond to the lower doses but do eventually see weight loss as the medication is ramped up.
Without lifestyle changes, these medications are likely to be less effective for weight loss. Novo Nordisk, which makes Ozempic and Wegovy, and Eli Lilly, which makes Mounjaro and Zepbound, stress that the drugs are meant to be used alongside a healthy diet and exercise. In trials of semaglutide and tirzepatide, the medications were paired with a reduced-calorie diet and increased physical activity. Clinical trials are often the best-case scenario when it comes to a drug’s efficacy because they involve careful tracking of participants and many follow-up visits with providers. In real life, patients may not follow their weight-loss plan as diligently or see their doctor as regularly.
And while these drugs help curb appetite, they don’t magically eliminate all temptations. After all, there is a major social component to eating food. “We may eat because it looks good, tastes good, we’re in the company of others, or because it’s available,” Rothberg says. A person who has those environmental pushes or stimuli competing with the drug won’t lose as much weight as the person who doesn’t have to deal with those factors, she argues.
Differences in metabolism, or how people break down food and convert it into energy, could also be at play. A person’s age and hormone function, as well as the amount of physical activity they get, can have an effect on metabolism.
Researchers are also looking into whether genetic factors may explain some of the variability in response. In 2022, Pearson and his colleagues published a paper that identified a gene called ARRB1 that seems to be involved in glucose control. When they looked at genetic data from more than 4,500 adults, they found that people with certain variants in this gene have lower blood sugar levels while taking GLP-1 drugs.