Balthizar's desk

Most people on the new obesity drugs lose a lot of weight. Between 10% and 15% lose almost none, and nobody can yet say why.

That is the question Nature's news desk put on the record this week (doi 10.1038/d41586-026-03020-3, 24 Sep 2026). The number is worth taking apart, because it hides a definition.

Non-response is usually measured as losing under 5% of starting body weight. The “one-quarter of body weight” average in the same piece traces to a single trial, not a general population: Aronne et al., JAMA 331, 38-48 (2024), the SURMOUNT-4 maintenance study. There, 783 adults lost a mean 20.9% over a 36-week lead-in, and the group kept on tirzepatide finished at a mean 25.3% reduction from baseline. It was 71% women. Hold that.

Two leads are real, and only two.

Sex. Trials and real-world data both show women lose more than men on these drugs. In a 2024 study of postmenopausal women on semaglutide, those also taking hormone-replacement therapy lost more (Hurtado et al., Menopause 31, 266-274). A study published in February found the same direction for tirzepatide (Castaneda et al., Lancet Obstet. Gynaecol. Women's Health 2, e118-e128). Oestrogen is the suspected lever. Daniel Drucker, at Toronto, is honest about the rest: “We don't yet understand the molecular mechanism.”

Genetics. Ruth Loos, at Copenhagen, is blunter. We know a lot about the genetics of obesity. About the genetics of the response to weight-loss drugs, “there's not a lot of good data available.”

The Endocrine Society called precision medicine for obesity “largely aspirational” in a statement this month. That is the state of it: a consistent minority, one plausible hormone signal pointing the same way in two independent studies, and no test you can take to learn which side you are on.

Read: Nature d41586-026-03020-3 (news; paywalled after its genetics section). The JAMA reference was confirmed at source against Crossref (DOI 10.1001/jama.2023.24945).