More than a quarter of people with type‑2 diabetes now take GLP‑1 receptor agonists, such as Ozempic. Recent research from Stanford Medicine and partners suggests that these drugs may not work for everyone because of their DNA.
What the Study Found
About 10% of people carry special genetic variants that cause what scientists call GLP‑1 resistance. These people make more of the hormone GLP‑1, which normally helps control blood sugar, but the hormone does not act as strongly in their bodies.
How the Researchers Looked
The team studied both humans and mice. In people, they gave a sugary drink and took blood every few minutes for four hours. They found that participants with a PAM gene variant (called p.S539W) had higher GLP‑1 levels, yet their blood sugar did not drop faster. In mice lacking the PAM gene, the same pattern appeared: high GLP‑1 but weaker blood‑sugar control.
Why PAM Matters
PAM (peptidyl‑glycine alpha‑amidating monooxygenase) is an enzyme that helps many hormones work better, including GLP‑1. When PAM does not work well, the hormone may be made but cannot signal properly, leading to resistance.
Impact on Diabetes Treatment
Data from three clinical trials with 1,119 diabetes patients showed that carriers of PAM variants improved their HbA1c (a blood‑sugar measure) less than non‑carriers. Only about 11‑19% of carriers hit the target level, compared with 25% of people without the variants. The variants did not change how patients responded to other drugs like metformin or sulfonylureas.
Weight‑Loss Question
Only two of the studies also measured weight loss, and they found no clear difference between carriers and non‑carriers. More research is needed to see if longer‑acting GLP‑1 drugs can overcome the resistance.
What Comes Next
Scientists think the resistance may involve many steps after the hormone binds to its receptor, similar to how insulin resistance works. Future medicines might be designed to make the body more sensitive to GLP‑1, or new drug versions could bypass the problem.
This work involved researchers from universities in the UK, Canada, Denmark, and the United States, and was funded by several public and private organizations.