| Trial results
A new study found that adults who carry a rare, damaging change in the gene for the GLP-1 receptor lost much less weight on semaglutide (Ozempic, Wegovy) than similar adults without it: 2.4% of body weight versus 8.8%. On tirzepatide (Mounjaro, Zepbound), carriers lost 13.3% versus 15.2%. These changes turned up in 33 of the 13,725 adults studied, about 0.2% or roughly 1 in 400 to 500, so the groups were very small. This was a look back at medical records. It is not a clinical test, and no one should change a medicine because of it.
What the researchers did
The paper appeared in Nature Metabolism on November 11, 2026. It comes from Helix, a genetics company, working with 13 health systems in North America. Helix had sequenced the protein-coding part of the DNA of 351,818 people who agreed to link their results to their health records.
From that group, the researchers picked 13,725 adults with a body mass index of 25 or higher who had started semaglutide or tirzepatide injections in routine care and had weight records covering at least six months of treatment. They looked for rare changes in GLP1R, the gene that holds the instructions for the GLP-1 receptor. That receptor is the docking point both medicines attach to. Computer scores or lab experiments suggested that these changes could weaken it.
In all, 33 of the 13,725 people carried one. Each carrier was compared with up to 10 people who did not, matched on the drug, the dose, sex, diabetes status, earlier use of GLP-1 medicines, starting body mass index, how long they were followed and genetic similarity group. Weight loss was measured as each person's lowest recorded weight between 6 and 12 months after starting, compared with their starting weight.
What it found
| Medicine | People with a rare GLP1R change | Their average weight loss | Matched people without one |
|---|---|---|---|
| Either medicine | 33 | 8.2% | 12.5% (274 people) |
| Semaglutide | 17 | 2.4% | 8.8% (149 people) |
| Tirzepatide | 19 | 13.3% | 15.2% (154 people) |
Average percent of starting body weight lost, 6 to 12 months after starting. The two medicine rows add up to more than 33, most likely because some people took both medicines at different times and count in each row. Source: Levy and colleagues, Nature Metabolism, 2026.
Nearly all the semaglutide carriers lost less than the people matched to them (15 of 17). With tirzepatide, 11 of 19 did. The semaglutide gap was large enough that chance is an unlikely explanation (P = 0.0007). The tirzepatide gap was small enough that chance could explain it (P = 0.23). The paper's test of whether the two medicines really differ gave P = 0.009.
A P value estimates how often a gap this big would appear by chance alone. Smaller numbers make chance a less likely explanation.
Why tirzepatide might respond differently
Semaglutide acts only on the GLP-1 receptor. Tirzepatide acts on that receptor and on a second one, the GIP receptor. The authors suggest the second route could partly make up for a weak GLP-1 receptor. They call the idea speculative and say experiments are needed to test it. This study did not.
The researchers also checked rare changes in the gene for the GIP receptor (63 carriers). Those carriers lost a little less overall, 10.3% versus 12.1%, but that did not hold for the most clearly damaging changes and did not differ by medicine.
What this does not mean
- It is not a clinical test, and the study was not designed to guide anyone's treatment. No one should start, stop or switch a medicine because of this finding. Questions about how a medicine is working belong with your prescriber.
- It does not show that semaglutide fails in general. Only about 0.2% of the people in the study carried one of these changes, so they are unlikely to explain most cases of weak response.
- It does not show that tirzepatide is unaffected. Carriers on tirzepatide also lost a little less on average (13.3% versus 15.2%), and 19 people is too few to rule out a real gap. Among carriers of the most clearly damaging changes, tirzepatide weight loss was about two-thirds of what their matched peers lost, which the authors call a trend in a small subgroup. The paper counts 11 such carriers across both medicines.
- It does not prove the gene change caused the difference. The study compared records from routine care. It was not a trial.
- It is not advice about which medicine suits carriers. The authors suggest people with these changes might be better suited to tirzepatide or to drugs that do not rely on the GLP-1 receptor. No trial has tested that.
How far the finding can be trusted
The semaglutide result pointed the same way in the checks the authors ran, but each check involved very few people.
- Small groups: 33 carriers in all, 17 on semaglutide and 19 on tirzepatide. The authors say this limits what can be said about any single gene change.
- Records, not a trial: medicines taken and weights recorded in routine care are imperfect, and the authors say hidden differences between carriers and non-carriers remain possible even after matching.
- Mostly one ancestry group: about 11,300 of the 13,725 people (roughly 8 in 10) were genetically similar to European reference populations, and the authors say carriers were predominantly in that group. They call for more carriers from other ancestries.
- Two other datasets, tiny numbers: in the All of Us research program, 8 semaglutide carriers lost 2.6% versus 5.7% in their matches, a gap that did not reach statistical significance (P = 0.12). In a separate group from the same health systems, 7 semaglutide carriers lost 4.1% versus 7.5%, and 11 tirzepatide carriers showed no shortfall.
- A weaker test in one analysis: when the analysis was limited to people of European genetic similarity, the semaglutide gap held (P = 0.005) and tirzepatide showed none, but the formal test of a difference between the two medicines was weaker (P = 0.085).
- How "damaging" was judged: part of it relied on computer predictions. The most common change, p.Arg421Trp, was in 15 of the 33 carriers and scored only "possibly damaging" by computer, but earlier lab studies found it weakens the receptor's signal. The authors say mislabeled changes would more likely blur a real effect than create one.
Helix runs the research network behind the data. Eight of the 21 authors are Helix employees, and the authors report no specific funding. The other authors declare no competing interests. See how to read study numbers.
A different kind of gene study from April
In April, researchers at 23andMe published a study in Nature of 27,885 people who had used GLP-1 medicines. It relied on self-reported weight loss and linked a common change in GLP1R to somewhat more weight loss, about 0.76 kg more per copy of the change. It also linked variation in GLP1R and GIPR to nausea and vomiting, with the GIPR link seen only in people taking tirzepatide. A change that many people carry is a different question from a rare change carried by about 0.2%. The new paper found the same direction for the common change in its own data and says its findings extend and complement the April study.
Where this fits on the Atlas
The Atlas guide to switching between Wegovy, Zepbound and Mounjaro covers a different kind of evidence: a chart review of people who moved to tirzepatide after a poor response to semaglutide. That review did not look at genes, so it cannot say whether any of those people carried a rare change. For background, see the semaglutide and tirzepatide pages and how long GLP-1 medicines take to work.
This page is general information, not medical advice.
Sources: Levy ME and colleagues. Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide. Nature Metabolism, published November 11, 2026 Peer-reviewed paper, observational real-world study, company-affiliated authors. Su QJ and colleagues. Genetic predictors of GLP1 receptor agonist weight loss and side effects. Nature, volume 653, published April 8, 2026 Peer-reviewed paper, self-reported outcomes, company-affiliated authors.