Tirzepatide

GLP-1 and GIP are gut hormones released after a meal. Both help the pancreas release insulin when blood sugar is high, and both act on appetite. Tirzepatide is a single molecule that switches on both receptors, which is why it is called a dual agonist [2].

It is injected once a week. Zepbound starts at 2.5 mg for 4 weeks and goes up in 2.5 mg steps, at least 4 weeks apart, to a maintenance dose of 5, 10 or 15 mg; 15 mg is the maximum [2]. In the SURMOUNT-1 trial, adults with obesity or overweight lost on average 15.0%, 19.5% and 20.9% of their body weight over 72 weeks on 5, 10 and 15 mg, against 3.1% with placebo [3]. Nausea, diarrhea, vomiting and constipation are the most common side effects [2], and the slow start is there to keep them manageable.

GIPR carries the instructions for the GIP receptor. At rs1800437 the usual form, G, codes for glutamic acid at position 354 of the receptor (Glu354); the other form, C, codes for glutamine (Gln354). Laboratory studies describe Gln354 as a partial loss-of-function variant: the receptor holds on to its hormone longer, is pulled inside the cell faster and becomes desensitized, so GIP signaling is weaker over time [4].

In the 2026 genome-wide study by the 23andMe research team, survey participants who took tirzepatide and carried the Gln354 form reported moderate or severe vomiting more often. Each C allele was associated with about 1.8 times the odds of vomiting (P = 5.1 × 10^-9), nausea showed the same pattern, and the direction was repeated in a smaller group of Latino participants. In people taking semaglutide, which does not act on the GIP receptor, the variant made no difference. It also made no difference to how much weight people lost [1].

These are the observed rates among survey participants, from the study's Supplementary Table 14; they are not adjusted for dose or time on treatment [1]. Two things stand out. With tirzepatide, the rates rise with each copy of Gln354. And on average, people with zero or one copy reported less vomiting and nausea on tirzepatide than people on semaglutide did, while people with two copies reported about the same on either drug (the difference was not statistically significant).

Why would a weaker GIP receptor mean more vomiting? The authors suggest that the GIP side of tirzepatide normally softens the nausea caused by its GLP-1 side, and that a less responsive GIP receptor gives less of that protection [1]. Animal studies support the idea that GIP receptor activity has anti-nausea effects [5].

Allele frequencies are from the gnomAD database as reported in the study [1]; the last column is calculated from them.

The same study found that the T allele of rs10305420 in GLP1R (Pro7Leu) was associated with slightly more weight loss, about 0.76 kg per copy across both drugs, and with more nausea and vomiting. The weight effect looked larger with tirzepatide (an extra 0.95% of body mass index per copy) than with semaglutide (0.51%), although the estimates overlapped. Between 40% and 7% of gene copies carry T, depending on ancestry, so this variant is common; the semaglutide page explains it in full [1].

The effect on weight is small. Age, sex, diabetes, dose and time on treatment explained about a quarter of the differences in weight loss in the study, and adding genetics barely changed that [1].

Gene2Rx wrote this guideline itself; no guideline body has published pharmacogenetic guidance for tirzepatide. Because both genes affect the same side effects, the report reads them together. It places you in one of nine combinations and gives an estimated chance of moderate or severe vomiting on tirzepatide, which Gene2Rx calculated from the study's published side-effect model (Supplementary Table 21) and calibrated to the observed rates above [1].

The report pairs each estimate with advice written for the prescriber:

• GIPR G/G (Normal Function): standard dosing and dose increases. With one or two GLP1R T alleles, expect somewhat more weight loss and a modestly higher chance of nausea, and slow the dose increases if early stomach symptoms appear.
• GIPR C/G or C/C (Decreased or Poor Function): standard dosing, but consider a slower dose-escalation schedule and be prepared for nausea and vomiting. If symptoms cannot be managed, semaglutide is an option because the GIPR variant does not affect it.
• Two GLP1R T alleles with two GIPR C alleles, the highest-risk combination: the report suggests considering semaglutide, or starting tirzepatide at the lowest dose with a much slower schedule and close follow-up.

The observed rates above put the semaglutide option in context: for most people with a GIPR variant, tirzepatide remained the drug with less reported vomiting, so the result is mainly a reason to go slowly with tirzepatide rather than a reason to avoid it. If only one of the two genes has a result, the report shows the single-gene guidance instead.

The GIPR finding is unusual among drug-response signals, and that is the main reason for the guideline. The variant sits in one of tirzepatide's two targets. It changes how that receptor works in laboratory studies. Its association with vomiting reached genome-wide significance, pointed the same way in a second ancestry group and appeared only in people taking the drug that acts on the receptor, which is the pattern a real drug-gene effect should show. A formal test of the GIPR-by-drug interaction in the study's side-effect model was strongly significant (P = 1.7 × 10^-6) [1].

Side effects are also where genetics added the most in the study. A model without genetics separated people who would and would not have moderate or severe vomiting with an accuracy (AUC) of 0.66; adding the variants raised it to 0.68. For weight loss the gain was close to nothing [1]. So the guideline is built around side effects and the dose schedule, the lever prescribers already use to manage them, and it does not try to say how much weight anyone will lose.

If your report shows a GIPR variant, tell your prescriber before starting or before the next dose increase. The schedule already allows at least 4 weeks between steps [2], and a slower climb is the main tool for nausea. Do not skip, delay or change doses on your own.

A higher estimate is still a minority outcome: even in the highest-risk combination, most people in the model's estimate do not have moderate or severe vomiting. A low estimate does not rule it out, since nausea is common with every drug in this class.

If you are deciding between tirzepatide and semaglutide with your prescriber, the GIPR result is one input among several, including cost, coverage, how much weight loss is needed and your medical history. The which GLP-1 is right for me guide and the GLP-1 genetics overview go through the choice. The labels also note practical interactions: tirzepatide slows stomach emptying, which can affect some tablets taken by mouth (including hormonal contraceptives taken by mouth), and it can cause low blood sugar with insulin or a sulfonylurea [2].

These are associations measured across thousands of people, mainly women of European ancestry who reported their own side effects and weight in a survey. Self-reported weight loss ran well ahead of medical records in the people who shared both [1]. The risk estimates in the report are Gene2Rx's calculation from the published model, not numbers the study reported for each combination.

Gene2Rx reads both positions from your DNA data, measured directly or inferred by imputation from nearby markers. Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. Side effects also depend on dose, the speed of dose increases, meal size and other medicines, none of which a genotype can capture.

I have a GIPR variant. Should I avoid tirzepatide?

Not on that basis alone. People with one copy reported less vomiting on tirzepatide than people on semaglutide in the study. The result is mainly a reason to increase the dose slowly and to keep semaglutide in mind if side effects cannot be managed.

Does the GIPR variant change how much weight I will lose?

No. In the study it was not associated with weight loss on either drug [1]. The GLP1R variant is the one linked to weight, and its effect is about a kilogram per copy.

What about retatrutide?

Retatrutide also acts on the GIP receptor, so the GIPR finding may apply to it, but there is no genetic data from people taking it yet. See the retatrutide page.

1. Su QJ, Ashenhurst JR, Xu W et al. Genetic predictors of GLP1 receptor agonist weight loss and side effects. Nature 653:770-775 (2026). The study behind the guideline, including Supplementary Tables 14 (side effects by GIPR genotype), 21 (side-effect models) and 22 (model performance).
2. Zepbound (tirzepatide) injection: prescribing information. DailyMed. Uses, dose escalation, side effects and interactions.
3. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med (2022). Average weight loss at each dose.
4. Gabe MBN et al. Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. Basic Clin Pharmacol Toxicol (2020). Laboratory evidence that Gln354 weakens GIP signaling over time.
5. Borner T et al. The antiemetic actions of GIP receptor agonism. Am J Physiol Endocrinol Metab (2024). Animal evidence that GIP receptor activity reduces nausea and vomiting.