A genetic glitch may explain why a growing minority of patients do not benefit from GLP‑1 drugs such as Ozempic and Wegovy, researchers report. Scientists led by Anna Louise Gloyn at Stanford and collaborators including Mahesh Umapathysivam found that a variant in the PAM gene — known as p.S539W — reduces the body’s sensitivity to GLP‑1, the gut hormone that GLP‑1 analogues mimic, helping to blunt appetite and lower blood sugar.
The findings, published in Genome Medicine, combined a small metabolic study with a review of clinical trial data. In the laboratory arm, researchers compared 19 people carrying the p.S539W variant with 19 non‑carriers after a sugary drink challenge. Although carriers produced higher circulating levels of GLP‑1, their tissues responded less effectively: the team measured about an 18 percent reduction in GLP‑1 sensitivity among p.S539W carriers. In other words, the hormone was present but its downstream effects were blunted.
That mechanistic signal was echoed in a review of more than 1,100 participants from GLP‑1 clinical trials. Across those datasets, people with the common PAM genotype had stronger responses to GLP‑1 drugs than p.S539W carriers. The authors flag a stark example: only 11.5 percent of p.S539W carriers treated with GLP‑1 medication in the pooled analyses achieved the target blood sugar outcomes cited by the study, considerably lower than among non‑carriers. The research team interprets the pattern as evidence that the PAM variant interferes with peptide hormone activation or processing, reducing the biological effectiveness of both natural GLP‑1 and its pharmaceutical mimics.
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“Clinically we see variable responses to GLP‑1 medications, and this helps explain why some people seem effectively ‘resistant’ despite correct use,” said Dr. Gloyn, associate chair for Basic Science Research at Stanford. Mahesh Umapathysivam, the study’s lead author and an endocrinologist at the University of Adelaide, cautioned that genetic screening is not yet ready for routine clinical use: “We are not yet at the point of applying this in the clinic,” he said, though he added that identifying more variants could eventually yield tests to guide prescribing.
The discovery has practical implications for patients who do not lose weight or fail to improve glycaemic control on GLP‑1 therapy. Endocrinologists and pharmacologists cited in the study note that other diabetes treatments retain efficacy in PAM variant carriers. Jamie Alan, a pharmacology professor, highlighted alternatives such as metformin, DPP‑4 inhibitors and SGLT‑2 inhibitors; the study found p.S539W carriers responded to these medications similarly to non‑carriers. Dual‑agonist drugs that engage multiple receptors — for example tirzepatide (marketed as Mounjaro) — may also offer benefit because they do not rely solely on GLP‑1 signalling.
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For now, the authors and independent clinicians recommend the pragmatic approach most patients already follow: try a GLP‑1 therapy under medical supervision and assess response over weeks to months. When benefit fails to materialise, clinicians can switch or combine therapies and emphasize lifestyle measures. Longer term, the researchers say, mapping genetic contributors to drug response could help personalise obesity and diabetes treatment, reducing trial‑and‑error prescribing and sparing patients months of ineffective therapy.
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