Nobody knows if Ozempic or another GLP-1 will fail to work for them until they try it, be it for type 2 diabetes or intentional weight loss.
Researchers found that around 10% of people carry certain genetic variants that appear to make them less responsive to GLP-1, the hormone these drugs are designed to mimic.
A Genetic Clue to Treatment Success
The study focused on changes in a gene linked to an enzyme called PAM.
This enzyme helps activate several hormones in the body, including GLP-1.
Scientists discovered that people with these genetic variants actually had higher levels of GLP-1 circulating in their bloodstream.
Surprisingly, however, the hormone wasn’t producing stronger effects.
In other words, their bodies seemed to need more GLP-1 to achieve the same blood sugar control.
Researchers Call It GLP-1 Resistance
The finding points to a phenomenon known as GLP-1 resistance.
Researchers expected the opposite result. They thought the genetic variants would reduce GLP-1 activity by lowering hormone stability.
Instead, participants had elevated hormone levels but no extra benefit.
That unexpected discovery led scientists to spend years confirming the results through additional studies.
Researchers Can Learn from Mice
To verify what they were seeing, researchers examined mice lacking the PAM gene.
The animals showed many of the same patterns seen in people.
They had increased GLP-1 levels but weaker responses to the hormone.
The mice also experienced faster stomach emptying, another sign that GLP-1 activity was reduced despite higher hormone levels.
Humans in the Research
Researchers then looked at data from more than 1,100 people with diabetes who participated in clinical trials.
People carrying the PAM variants generally experienced smaller improvements in HbA1c, a key measure of long-term blood sugar control.
After six months of treatment, only about 11.5% of people with one variant reached target HbA1c levels, compared to about 25% of people without the variants.
Interestingly, the genetic differences appeared to affect only GLP-1-based medications.
Researchers found no meaningful impact on responses to other common diabetes treatments.
That suggests the reduced response is tied specifically to the GLP-1 pathway.
What About Weight Loss?
The study did not provide clear answers about weight loss results.
Only a small amount of weight-loss data was available, and researchers found no significant differences between people with and without the variants.
More studies will be needed before any conclusions can be made.
