If you aren't losing weight with GLP-1 drugs, this may be one reason why - WaPo

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Some people experience profound weight loss; others barely see the scale budge. Some tolerate the drugs, but others experience nausea and vomiting so unpleasant that they stop taking them. In clinical trials, around 10 to 15 percent of the people who take the drugs are considered “non-responders” because they did not lose at least 5 percent of their body weight. A new study published Wednesday in the journal Nature finds that part of the reason people’s responses to the drugs vary so widely may be in their DNA.

Researchers at the nonprofit 23andMe Research Institute pinpointed two versions of genes that help predict whether people will lose a few extra pounds on the drugs or will be more prone to nausea and vomiting. Genetics are only one piece of how people respond to GLP-1s, but when coupled with other factors, such as age, sex and other medical conditions, the researchers created a model to predict the potential weight loss benefit and risk of side effects.

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In the new study, scientists scoured the genome of 15,000 people who have taken the drugs. DNA is a 3-billion-long string of letters, and each person carries distinct variations in the spelling. The team examined the code, looking for changes that were shared among people who reported losing more weight or experiencing side effects such as nausea and vomiting.

That approach flagged variants of two genes — GLP1R and GIPR — both of which are directly targeted by the drugs that mimic the effects of our natural gut hormones. The semaglutide drugs, such as Ozempic and Wegovy, target the GLP-1 pathway, which is involved in insulin secretion, appetite and stomach emptying. The tirzepatide drugs, such as Mounjaro and Zepbound, target the GLP-1 pathway along with a second one, the GIP pathway.

The study showed that some people carry a specific version of the GLP1R gene that creates a protein in which one of the amino acid building blocks is different. People with this variant were more likely to lose weight on GLP-1s. The overall effect was relatively modest. People carry two copies of every gene, one from each parent. Those who had one copy of the GLP1R gene variant lost a little more than 1.5 pounds more than people with the regular version. With two copies of the variant, they lost more than three additional pounds.

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