About 1 in 7 people taking GLP-1 weight-loss drugs such as semaglutide and tirzepatide lose little to no weight at all, even as most people on the same medications shed close to a quarter of their body weight. That gap has sat largely unexplained through years of blockbuster sales and clinical trials, and the endocrinologists who prescribe the drugs say they still cannot say with confidence why a meaningful slice of patients simply do not respond.
Some of the gap traces to biological sex. Some traces to hormone status after menopause. The rest sits in a genetic layer researchers have barely begun to map.
A 10 to 15 Percent Non-Response Rate
Across the semaglutide and tirzepatide trials examined by a Nature news feature, roughly 10 to 15 percent of users lose minimal weight or none at all on the standard dosing schedule, a proportion that lines up with the “1 in 7” figure now attached to the drugs. Daniel Drucker, an endocrinologist at the University of Toronto whose early research on the gut hormone GLP-1 helped make Ozempic and Wegovy possible, said there is “tremendous heterogeneity in the response to these medications” that has not been scientifically pinned down.
That heterogeneity shows up even among patients matched for starting weight, age and dose. Some lose more than 20 percent of body weight within a year; others plateau within weeks. Drucker’s own work, cited among the studies now being used to explain the split, has made him one of the field’s most closely watched voices on why the mechanism remains unresolved despite the drugs’ commercial success.
Women Losing More Weight Than Men on the Same Dose
One of the clearest patterns to emerge is sex-based: women tend to lose more weight than men on the same GLP-1 or dual-hormone medication, across multiple trial populations rather than one cohort.
Confirmation came from a second drug class. A study published in February 2026 on tirzepatide, which mimics both GLP-1 and a second gut hormone called gastric inhibitory polypeptide, showed comparable variability in outcomes by sex, according to Nature’s review of the trial data. Researchers have floated several explanations for the split, from differences in body composition and fat distribution to how estrogen interacts with the same appetite-regulating brain circuits the drugs target. That the same pattern appears on a chemically different drug argues against a single-molecule quirk and toward something more fundamental in how male and female metabolism handles the entire class of medications.
Hormone Therapy Changes the Outcome for Postmenopausal Women
The sharpest evidence for a hormonal driver comes from postmenopausal women specifically. A 2024 study in the journal Menopause, covered in detail by the OBG Project, tracked 106 postmenopausal women on semaglutide and found that the 16 who were also on hormone-replacement therapy lost 16 percent of total body weight at 12 months, against 12 percent for the 90 women not on hormone therapy — a gap present as early as the three-month mark and statistically significant at every checkpoint measured.
A follow-up study extended the same question to tirzepatide. Mayo Clinic researcher Maria D. Hurtado Andrade, senior author on both the 2024 semaglutide work and a newer retrospective cohort study in The Lancet Obstetrics, Gynaecology, & Women’s Health, found that 40 postmenopausal women on hormone therapy lost 19.2 percent of body weight on tirzepatide, compared with 14.0 percent among 80 women without it — a difference Mayo Clinic’s own release quantified as roughly 35 percent more total weight lost.
Hurtado Andrade, describing the finding in Mayo Clinic’s news release, said “women who used menopausal hormone therapy lost about 35% more weight than women taking tirzepatide alone,” while cautioning that the retrospective design cannot prove hormone therapy caused the extra loss rather than simply correlating with it. Animal studies cited in the Nature review suggest a possible route: estrogen appears to reduce food intake through some of the same brain regions GLP-1 drugs act on, raising the possibility of a synergistic effect rather than two separate mechanisms working in parallel.
A Genetic Explanation Still Largely Missing
Sex and hormone status do not account for the entire gap. Ruth Loos, a genetic epidemiologist at the University of Copenhagen, told Nature that despite decades of work mapping the genetics of obesity itself, “there’s not a lot of good data available” on the genetic contribution to drug response specifically.
Drucker was more optimistic about eventually closing that gap than about explaining it today. Researchers, he said, have not yet worked out the molecular mechanism behind the variation in outcomes, though he expressed confidence that ongoing work will make headway on the question in the coming years. Until a genetic or hormonal test exists, doctors prescribing semaglutide or tirzepatide have no way to predict, before the first dose goes in, which patients will land in the 10 to 15 percent who see little change on the scale — and which will lose a quarter of their body weight within a year, the outcome the drugs are now famous for delivering.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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