If you lost less weight on semaglutide than you expected and keep seeing talk of genes, you are asking the right question. A study published in Nature Metabolism on November 11, 2026 links rare, damaging changes in the GLP1R gene to smaller weight loss on semaglutide, while carriers taking tirzepatide had a near-normal response. The study used real-world health records for 13,725 treated adults, and 33 of them carried a rare GLP1R variant.
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What is the GLP1R gene?
GLP1R is the name of the glucagon-like peptide-1 receptor gene. Semaglutide is a GLP1R agonist, meaning it acts on that receptor, and a 2025 study indexed by PubMed describes it that way. The 2026 study looked at rare variants in this gene. Tirzepatide is different: according to the Nature Metabolism paper, it acts on both GLP-1 and GIP receptors. For background on gene-based risk research, see the NHLBI’s gene forecast study page.
Why would a gene affect semaglutide but not tirzepatide?
The authors hypothesize that tirzepatide, because it acts on both the GLP-1 and GIP receptors, may keep working when GLP-1 receptor function is reduced. That is their hypothesis, and it is the reason they give for the difference between the two drugs.
What did the Nature Metabolism study find?
The Nature Metabolism Brief Communication, published online November 11, 2026, combined exome sequencing with electronic health records in the Helix Research Network. The paper describes this as real-world data from 13 North American health systems. Adults aged 18 or older with a baseline BMI of at least 25, who started treatment, were included, and carriers were matched to non-carriers.
Quick facts, dated 2026-11-11
| Item | Detail |
|---|---|
| Study | \”Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide\” (Nature Metabolism, Brief Communication) |
| Published online | November 11, 2026 |
| Data source | Real-world data from the Helix Research Network, 13 North American health systems |
| Treated adults | 13,725 adults aged 18 or older with a baseline BMI of at least 25 |
| GLP1R carriers | 33 people with a rare GLP1R variant |
| Primary matched analysis | 17 semaglutide-treated and 19 tirzepatide-treated GLP1R carriers |
| Funding | \”The authors received no specific funding for this work.\” |
| Author affiliations | Eight authors work for Helix, a genomics company |
The numbers
These are mean weight loss figures from the paper’s primary analysis, with the response ratio as the paper reports it. A ratio of 0.27 means carriers lost about 27% as much weight as non-carriers in that group.
| Measure | Semaglutide | Tirzepatide |
|---|---|---|
| Mean weight loss, GLP1R carriers | 2.4% | 13.3% |
| Mean weight loss, non-carriers | 8.8% | 15.2% |
| Response ratio, carriers vs non-carriers | 0.27 | 0.88 |
| P value | 0.0007 | 0.23 |
| Response ratio at higher doses | 0.41 (1.7 mg or more, P=0.044) | 0.84 (10 mg or more, P=0.18) |
| Carriers in primary analysis | 17 | 19 |
Across both drugs, GLP1R carriers lost a mean 8.2% of weight against 12.5% for non-carriers (response ratio 0.65, 95% CI 0.46 to 0.85, P=0.0007). The carrier-by-drug interaction for GLP1R was beta -4.4 percentage points (95% CI -7.7 to -1.1, P=0.009). For the most damaging variants only, the tirzepatide ratio was 0.67 (P=0.015), so the paper reports that some reduction remained.
The Helix replication group had 7 semaglutide carriers, who lost 4.1% against 7.5% (ratio 0.54, P=0.004), and 11 tirzepatide carriers (ratio 1.19, P=0.43). In the All of Us cohort, 8 semaglutide carriers lost 2.6% against 5.7% (ratio 0.46, P=0.12, not statistically significant).
Carriers of rare variants in GIPR, the second tirzepatide target, also had normal weight loss responses, at 10.3% against 12.1% overall (ratio 0.85).
Who carries these variants?
The paper puts rare damaging GLP1R variants at roughly 0.1 to 0.4% of people, and rare damaging GIPR variants at about 1%. Among the treated adults, 11,347 were in the European genetic similarity group, and the carrier group was mostly of European genetic similarity. One variant, rs146868158 (p.Arg421Trp), was carried by 15 people and had a semaglutide ratio of 0.38 against a tirzepatide ratio of 1.13.
Common mix-ups to avoid
- A different Nature paper. Su and colleagues’ Nature paper reported a common GLP1R variant, p.Pro7Leu, linked to about 0.76 kg extra weight loss per copy of the effect allele (P=2.9 x 10-10), in over 27,885 survey respondents as of August 2025. The Nature Metabolism paper cites it as earlier work on common variants. Its numbers are not the numbers in this study.
- A different variant and study. A 2025 Obesity journal study looked at variant rs6923761 in 112 patients on semaglutide 2.4 mg weekly. It found that variant and sex both predicted weight loss.
- Tirzepatide is not unchanged across the board. Overall, tirzepatide did not show the same gap, but for the most damaging variants the paper reports a remaining reduction (ratio 0.67, P=0.015).
Who ran the study and who paid for it?
The authors received no specific funding for this work. Eight of them are employees of Helix, a genomics company that sells such data services, and the rest declare no competing interests.
How much weight should you put on this study?
The paper itself lists these limits: the number of carriers is small, especially in drug-specific groups; it is an observational real-world study rather than a randomized trial, so it shows association, not proof of cause; the adherence and weight records are imperfect and residual confounding is possible despite matching; carriers were mostly of European genetic similarity; non-coding and structural variants were not covered; variant classification relies on prediction tools that can be less reliable for membrane proteins such as GPCRs; and the study compares different people on each drug rather than the same people on both. For another example of gene-linked research, see the NIAMS page on microbiomes in people with RAG deficiency.
If semaglutide is not giving you the result you want, see mounjaro alternatives for weight loss. For more on weight-loss research, see Weight Loss and Metabolic Health.
Key dates
- March 2023 to July 2024: enrollment period for the 2025 Obesity journal study on rs6923761.
- 2026: Su and colleagues’ Nature paper on the common GLP1R variant p.Pro7Leu.
- November 11, 2026: the Nature Metabolism Brief Communication published online.
Questions to bring to your prescriber
Questions about your own medicine belong with your prescriber or a pharmacist, who can see your full record. Consider asking:
- How does my weight change on my current dose compare with what you would expect at this point?
- Has my weight been recorded at regular visits, so we can see the trend?
- What other options should we discuss if my results stay below my goal?
By the Clinical Research Explained Editorial Team