Genetics May Help Explain Why GLP-1 Weight-Loss Drugs Work Better for Some People Than Others

Key Takeaways: 

• Researchers have identified two genetic variants that may help explain why people respond differently to GLP-1 weight-loss medications such as Wegovy and Mounjaro.
  
• One genetic variant was linked to slightly greater weight loss, while another appeared to increase the likelihood of nausea and vomiting in people taking tirzepatide.
  
• Experts say the findings are important for understanding treatment variability, but non-genetic factors such as sex, medication type, dosage and treatment duration still appear to play a much larger role.
  
  
  

Genetic differences may help explain variable responses to GLP-1 weight-loss drugs

Scientists have uncovered new evidence suggesting that genetics may partly explain why GLP-1 weight-loss medications produce very different results from one person to another.

The research, published in Nature, examined how specific genetic differences may influence both weight-loss outcomes and the risk of side-effects in people taking glucagon-like peptide-1 receptor agonists, commonly known as GLP-1 drugs.

The findings could eventually contribute to more personalised approaches to obesity treatment, where therapies are selected based on an individual’s biological profile. However, researchers and independent experts stressed that the genetic effects identified in the study were relatively modest and are not yet strong enough to guide routine clinical decisions.

GLP-1 medicines and their growing role in obesity care

GLP-1 receptor agonists, including semaglutide, sold under the brand name Wegovy, and tirzepatide, marketed as Mounjaro, mimic naturally occurring gut hormones involved in regulating appetite, digestion and insulin release.

These medicines have transformed obesity treatment in recent years and are now used by millions of people globally. By helping reduce appetite and slow gastric emptying, they can support significant weight loss in many individuals.

However, clinical experience and research have consistently shown substantial variation in treatment response. Some people lose large amounts of weight, while others experience more limited benefits. Similarly, side-effects such as nausea and vomiting can vary considerably between individuals.

Until now, the biological reasons behind these differences have remained poorly understood.

Large genetic analysis involving nearly 28,000 people

To investigate the issue, researchers from 23andMe and a nonprofit medical research institute analysed data from 27,885 people taking GLP-1 medications.

The study focused on variations in genes linked to gut hormone pathways that regulate appetite and digestion.

Researchers identified one GLP1 receptor variant, known as rs10305420, that was associated with slightly greater weight loss among people carrying the variant compared with those who did not carry it.

A second genetic variant, rs1800437, was linked to a greater likelihood of nausea and vomiting in people taking tirzepatide. However, this variant was not associated with the amount of weight lost.

The findings suggest that inherited genetic differences may contribute to how people respond to GLP-1 therapies, both in terms of effectiveness and tolerability.

Genetics appears to play only a modest role

Despite the findings, researchers emphasised that the overall contribution of genetics appeared relatively small.

Marie Spreckley, an obesity expert at the University of Cambridge who was not involved in the study, said the research offered biologically plausible evidence that genetic variation may influence treatment outcomes.

“However, the magnitude of these genetic effects is small in clinical terms,” she said. “Importantly, non-genetic factors such as sex, drug type, dose and duration appear to explain a substantially larger proportion of variability. The authors’ model suggests that most of the explained variance comes from these factors, with genetics adding only a modest incremental contribution.

“In terms of how this fits with the wider evidence, it reinforces that while there is substantial variability in response to GLP1 therapies, genetics is only one part of a much more complex picture. Behavioural, clinical and treatment-related factors remain the dominant drivers of outcomes.

“Overall, this is an important step toward understanding variability and the potential for future precision approaches, but the effects are modest and the evidence is not yet sufficient to support using genetic information to guide treatment decisions in routine clinical practice.”

Toward more personalised obesity treatment

The findings contribute to a growing body of research exploring precision medicine approaches in obesity care.

As scientists continue to investigate why individuals respond differently to treatments, future obesity management may increasingly incorporate biological, behavioural and clinical information to tailor therapies more effectively.

However, experts caution that current evidence does not support the use of genetic testing to determine which GLP-1 medication a person should receive.

Instead, the study primarily advances understanding of the complex biological factors that may influence treatment response, while reinforcing that genetics represents only one piece of a much larger puzzle involving lifestyle, clinical characteristics and medication-related factors.