Why Ozempic does not work equally well for everyone

A new study published in the journal Genome Medicine found that around 10% of people carry variants of the PAM gene that appear to make their bodies less sensitive to GLP-1, a hormone involved in regulating blood sugar. The discovery could help explain why some patients see smaller improvements in blood glucose levels despite taking widely used diabetes drugs that mimic the hormone.

Researchers from Stanford Medicine and international partner institutions analyzed data collected over a decade, combining studies in humans and mice with evidence from clinical trials involving more than 1,100 people with type 2 diabetes.

The team focused on two PAM gene variants that reduce the activity of an enzyme responsible for activating several hormones, including GLP-1. Surprisingly, people carrying these variants produced higher levels of GLP-1 than non-carriers, but the hormone appeared to have a weaker effect on blood sugar control.

To investigate, researchers recruited volunteers without diabetes and monitored their blood sugar and hormone levels after consuming a glucose-rich drink. Although carriers of the genetic variants had increased GLP-1 levels, they did not show stronger biological responses, suggesting that their bodies required more of the hormone to achieve the same effect.

Experiments in genetically modified mice produced similar results. Animals lacking the PAM gene also had elevated GLP-1 levels but showed signs that the hormone was less effective. One key finding was that food moved through their stomachs more quickly, even after treatment with GLP-1-based drugs that would normally slow digestion and help regulate blood sugar.

The researchers then examined whether the genetic differences affected responses to diabetes treatment. In a meta-analysis of three clinical studies involving 1,119 participants, carriers of PAM variants generally experienced smaller reductions in HbA1c, a measure of long-term blood sugar control, after six months of treatment with GLP-1 receptor agonists.

Among participants without the variants, about 25% achieved recommended HbA1c targets. By comparison, only 11.5% of carriers of one PAM variant and 18.5% of carriers of another reached those goals, according to the study. The variants did not appear to influence responses to other commonly prescribed diabetes medications such as metformin, sulfonylureas or DPP-4 inhibitors.

Researchers stressed that the findings relate primarily to blood sugar control and do not yet provide clear answers about weight loss outcomes. While GLP-1 drugs such as Ozempic and Wegovy are also widely used to treat obesity, the available data were too limited to determine whether the same genetic factors affect weight loss.

Earlier, Qazinform News Agency reported that a new experimental diabetes drug outperformed Ozempic in early trial results.