This could be why your weight-loss medication isn’t delivering results

The skyrocketing popularity of GLP-1 receptor agonists has transformed the weight-loss industry, but not all shots are created equal in terms of how they work.

A study published in Nature investigated how genes affect the success of modern weight-loss drugs — specifically, GLP-1s like semaglutide and tirzepatide.

In analyzing genetic data and self-reported weight loss from over 27,000 users, researchers pinpointed a specific variation in the GLP-1 receptor gene (GLP1R) that acts as a “booster” for the drug’s effectiveness.

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Individuals carrying one copy of this variant lost an average of 1.6 pounds more than those without it, according to the findings.

This suggests that genetic testing could eventually help doctors steer sensitive patients toward medications they are more likely to tolerate.

“We believe these reports are a step forward in meeting an unmet need for a more informed and personalized approach to weight management,” said study co-author Noura Abul-Husn, chief medical officer at the 23andMe Research Institute in California, in a press release.

While this genetic “boost” is measurable, it remains relatively modest when compared to the total average weight loss of 24 pounds observed across the study population, the researchers noted.

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Beyond genetics, other factors such as age, sex and specific medications remain much stronger predictors of success.

For instance, the study found that women generally saw a higher body mass index (BMI) reduction (12.2%) compared to men (10.0%).

The study may also reveal why certain patients experience stomach issues. Scientists identified a different genetic variant that was linked to increased reports of nausea and vomiting.

The presence of this side effect did not impact the drug’s effectiveness, however. Patients with variants in the GLP1R and GIPR genes lost just as much weight as those without it; they simply felt more sick during the process, the study found.

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“GLP-1 treatment decisions are complex, and having access to clinical expertise to help contextualize your genetic results alongside your full health picture is exactly the kind of guidance this report is designed to support,” said Abul-Husn.

Dr. Peter Balazs, MD, a hormone and weight-loss specialist serving the New York and New Jersey area, was not involved in the study but reiterated the role of the genetic variants in treatment response and side effects.

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“Notably, there appears to be a drug-specific effect: The GIPR variant associated with these side effects is observed with tirzepatide, but not with semaglutide,” he told Fox News Digital.

Balazs said he was surprised by the extremely wide nausea risk range (5%–78%). “Additionally, the drug-specific genetic dissociation was unexpected,” he added.

Study limitations

The data relied on participants reporting their own weight, which could be subject to bias.

“The data is self-reported and not medically verified, which may affect its reliability firstly,” Balazs told Fox News Digital. “It also does not account for key treatment variables, such as titration, discontinuation or dosing schedules.”

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The 23andMe participant pool may not reflect a diverse, real-world population, he added.

“The study also lacks data on important clinical endpoints, such as diabetes progression, and severe adverse effects, such as gastroparesis or pancreatitis,” Balazs pointed out. “Many of its findings also have not been supported by more clinically and statistically robust studies.”

For example, a sub-study comparing these reports to objective iPhone health data suggested that participants might over-report their progress. While users reported an 11.8% loss, electronic data in that subset showed a 5.8% loss.

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As an observational study rather than a controlled clinical trial, it could not definitively prove that the genetic variants caused the difference in weight loss, only that they are associated with it, the researchers noted.

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“I think this article is interesting, raising the possibility of genetic factors, and the use of genetic testing incorporated into further decision-making when picking weight-loss medications,” Balazs said. “However, I would be careful to draw conclusions solely based on this study.”