GLP-1 drugs fail to help some people lose weight — scientists are on a quest for answers

Most people taking the popular GLP-1 drugs shed substantial amounts of weight — an average of one-quarter of their body weight according to one study¹. So why do 10–15% of people using the drugs lose minimal weight or none at all?

“There is tremendous heterogeneity” in the response to these medications, says Daniel Drucker, an endocrinologist at the University of Toronto in Canada, whose work aided in the development of GLP-1 drugs. “And we really don’t understand that.”

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Solving this mystery might lead to new medications for people who do not benefit from today’s versions of such drugs, and could make it possible to match individuals to treatments that are most likely to work for them. Those tantalizing possibilities have made people’s individualized responses to GLP-1s a key line of enquiry for obesity scientists. The Endocrine Society, a leading medical and research organization in Washington DC, has already called for it to be a priority for the field, with scientists looking into various explanations, including biological sex, genetics and behavioural factors.

For now, research to identify the differences between those who do or don’t respond to the drugs is in its early days, and precision medicine for obesity remains “largely aspirational”, according to a scientific statement published by the Endocrine Society earlier this month. But researchers are starting to dig into these questions with energy.

Oestrogen effect

One factor that has already been the subject of study is the link between biological sex and response to GLP-1 drugs. Clinical trials² and real-world data³ consistently show that women tend to lose more weight than do men on the medications, which mimic a natural hormone called glucagon-like peptide 1 and are prescribed for obesity and type 2 diabetes.

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In a 2024 study⁴ of postmenopausal women who were taking the GLP-1 drug semaglutide, those who also received hormone-replacement therapy lost more weight than those who did not have the hormone therapy. A study⁵ published in February found similar results for women who took tirzepatide, a drug that mimics both GLP-1 and another hormone called gastric inhibitory polypeptide.

This suggests that oestrogen, a female sex hormone that is given as part of hormone-replacement therapy, might enhance the effects of the obesity drugs, says Drucker. “We don’t yet understand the molecular mechanism. But I have confidence we’ll be able to make headway there,” he adds. Animal studies⁶ have already shown that oestrogen reduces food intake and acts on similar brain regions as GLP-1. Research has also highlighted that combining GLP-1 and oestrogen has a synergistic effect on weight loss.

Genetic influence

Scientists are only just beginning to understand how genes might affect people’s response to obesity drugs, says Ruth Loos, a genetic epidemiologist at the University of Copenhagen. “We know a lot about the genetics of obesity,” she says, “but when it comes to the genetic contribution to the response to weight-loss drugs … there’s not a lot of good data available.”

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