23andMe study explains variable results with obesity drugs

Some people taking GLP-1 agonist-based weight-loss drugs have spectacular results, while others do less well and are affected badly by side effects – and a new study has started to explain why that is so.

An analysis carried out by the non-profit research arm of genetic testing company 23andMe on the genomes of almost 28,000 GLP-1 users has identified variations in two genes that are targeted by the drugs, such as Novo Nordisk's Wegovy (semaglutide) and Eli Lilly's Zepbound (tirzepatide), that can affect patient reactions to them.

Specifically, the researchers identified a missense variant in the GLP1R gene that seems to be associated with greater weight loss, along with multiple variants in the GIPR gene that appear to make patients more susceptible to side effects like nausea and vomiting when taking Zepbound, which also acts as a GIP agonist. They have published their findings in the journal Nature.

Hypothetically, the findings suggest that people who are eligible for weight-loss treatment using GLP-1-based therapies could be tested to see which therapy would deliver the best outcome for them, in efficacy and safety terms, as part of a precision medicine approach.

The 23andMe Research Institute said that some people lose less than 5% with GLP-1 drugs, while others can lose 20% or more, and the risk of gastrointestinal side effects with Zepbound ranges from 5% to 78%.

"The market is crowded with weight loss support and medications, but the approach to weight management is typically one of trial and error. This can lead people to leap into treatment with a high degree of uncertainty and unrealistic expectations about efficacy and possible side effects," said Dr Noura Abul-Husn, chief medical officer at the 23andMe Research Institute.

"We believe these reports are a step forwards in meeting an unmet need for a more informed and personalised approach to weight management."

One commentator on the findings, Dr Marie Spreckley of the University of Cambridge, said that "genetics is only one part of a much more complex picture."

The magnitude of the genetic effects is small in clinical terms, she contends, pointing out that in clinical trials typical weight loss with these medications is often in the range of around 10%-15%. That means that the difference in weight loss associated with the genetic variants – 0.76 kg additional loss per allele – is pretty modest.

"Importantly, non-genetic factors such as sex, drug type, dose, and duration appear to explain a substantially larger proportion of variability," added Spreckley. "The authors’ model suggests that most of the explained variance comes from these factors, with genetics adding only a modest incremental contribution."

That said, she said the study "is an important step towards understanding variability and the potential for future precision approaches."

Photo by Warren Umoh on Unsplash