Study sheds light on why some people benefit more from weight-loss drugs than others

Weight-loss drugs (agonists) such as Ozempic, Mounjaro, and Zepbound have transformed weight management and obesity care.

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However, they are not as effective for all patients; some lose less than 5% of their body weight, whilst others lose more than 20%.

Genetics may play a key role in why these weight-loss GLP-1 receptor agonist drugs work better for some people than others, including in the variation of side effects, researchers from the non-profit 23andMe Research Institute have found.

"The market is crowded with weight loss support and medications, but the approach to weight management is typically one of trial and error," said Noura Abul-Husn, chief medical officer at the 23andMe Research Institute.

"This can lead people to leap into treatment with a high degree of uncertainty and unrealistic expectations about efficacy and possible side effects."

GLP-1 receptor agonists are a class of drug that makes people feel full for longer by mimicking the effects of the GLP-1 hormone, which the body produces naturally and helps regulate appetite and blood sugar.

The study, published in the journal Nature, analysed genetic markers and patient experiences using GLP-1 drugs. It then identified a set of genetic variants that could help to explain why responses to obesity drugs vary between patients.

The researchers analysed data from almost 28,000 participants who had used some of the most common weight-loss drugs at least once. Participants reported taking GLP1 medications for a median of 8.3 months.

They found that a missense variant in GLP1R was linked to higher efficacy of GLP-1 medications. People carrying one copy of the GLP-1 receptor variant rs10305420 lost, on average, 0.76 kilograms more over a median of eight months of treatment than people who had no copies.

A separate variant in the Gastric Inhibitory Polypeptide Receptor (GIPR) was associated with nausea and vomiting in people taking tirzepatide (like Mounjaro or Zepbound), but did not impact how much weight they lost.

Not all about genetics

The authors of the study consider the findings to open the door to personalised treatment, but warn that the genetic effect sizes were modest and more research is needed.

According to Marie Spreckley, research programme manager at the University of Cambridge, who did not participate in the study, the results provide biologically plausible evidence that genetic variations contribute to the variability in responses.

"However, the magnitude of these genetic effects is small in clinical terms," she said. "In clinical trials, typical weight loss with these medications is often in the range of around 10-15%, so a difference of less than 1kg per allele is modest."

Spreckley added that other factors, such as sex, drug type, dose, and duration, appear to explain a substantially larger proportion of variability.

"From my perspective, this points towards a highly promising future," said Cristóbal Morales, head of the metabolic health, diabetes and obesity unit at Vithas Hospital in Seville and a member of the Spanish Society for the Study of Obesity (SEEDO).

Morales added that the ability to anticipate treatment response through pharmacogenomics — the study of how someone's genetic makeup affects their response to medications — represents a major milestone.

This enables a more precise approach not only in selecting therapies but also in optimising their use by distinguishing responders from non-responders and identifying those at higher risk of side effects.