New studies from 23andMe suggest genetic variation may modestly influence GLP-1 weight-loss response and side effects.
New research from 23and ME sheds a light on why GLP-1 weight-loss drugs work differently across patients, with two studies suggesting that genetic variation and cardiovascular mechanisms independent of weight loss may both play significant roles in determining individual outcomes.
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A study of nearly 28,000 23andMe users who reported taking GLP-1 weight-loss medications, published in Nature, found that a mutation in GLP1R, the gene encoding the protein targeted by GLP-1 drugs, was modestly but significantly associated with greater weight loss.1
Participants carrying one copy of the variant lost an average of 1.7 pounds more over a median of eight months of treatment compared to non-carriers, while those carrying two copies lost approximately 3.3 pounds more.
The study also identified genetic links to side effects. Mutations in both GLP1R and GIPR, a gene related to insulin secretion and energy production, were associated with nausea and vomiting.1 The GIPR association was specific to
Researchers acknowledged the genetic effect on weight loss was relatively small but said the findings lay the foundation for precision medicine approaches to obesity treatment by providing direct evidence that variation in drug-target genes contributes to differences in how patients respond.
A second study suggests the cardiovascular benefits of GLP-1 drugs may operate through mechanisms independent of weight reduction, a finding with potentially significant implications for how physicians manage patients on these medications.2
Researchers analyzed data from 47,199 patients with cardiovascular disease who received semaglutide for up to two years. As expected, higher doses were associated with greater weight loss.
Two years after stopping treatment, patients who had received higher doses had lower risks of death from any cause, as well as reduced risks of heart attack, stroke, cardiovascular-related death, heart failure, and heart valve problems.1 However, those cardiovascular benefits were not correlated with how much weight patients had lost.
Analysis of tissue samples found that GLP-1 receptor proteins were most numerous in the pancreas, consistent with the drugs' known benefits in diabetes, but the heart had the second-highest concentration. Study leader Venky Soundararajan of data analytics firm nference said the findings raise the hypothesis that GLP-1 drugs may be acting directly on the heart, though he characterized it as a hypothesis requiring further experimental investigation.1
If confirmed, the finding could eventually allow physicians to optimize GLP-1 dosing strategies with cardiovascular outcomes in mind, distinct from weight management goals.
Together, the two studies point toward a more nuanced understanding of how GLP-1 drugs work, and who benefits most. As these medications become among the most widely prescribed in the world, the ability to tailor treatment based on genetic profile or to target specific clinical outcomes such as cardiovascular risk reduction could transform prescribing practices well beyond their current primary use in obesity and diabetes management
