New research suggests that about 10 percent of people may carry certain genetic variants that reduce the effectiveness of GLP-1 treatments, like Ozempic and Wegovy, for managing type 2 diabetes.
These treatments mimic the glucagon-like peptide-1 (GLP-1) hormone, helping regulate blood sugar by increasing insulin production and slowing digestion. However, how these drugs impact individuals with type 2 diabetes can vary widely. Researchers aimed to understand if genetics might influence this variability.
The study focused on an enzyme known as PAM (peptidyl-glycine alpha-amidating monooxygenase) and the corresponding gene responsible for it. Approximately one in ten people has variants in the PAM gene, which can hinder hormone activation, including that of GLP-1. These variants appear to be more prevalent among those with diabetes.
“In diabetes clinics, I’ve observed a huge range of responses to GLP-1 medications, making it tough to predict outcomes,” explains Mahesh Umapathysivam, an endocrinologist from Adelaide University. “This research is a first step toward using genetic profiles to improve treatment decisions.”
In their analysis, the researchers compared 19 individuals with the PAM variant p.S539W to a matched group of 19 controls, specifically looking at how their bodies reacted to sugary drinks.
Interestingly, those with the gene variant had high levels of GLP-1 present in their bodies. However, the presence of the p.S539W variant seemed to cause GLP-1 resistance, preventing the hormone from functioning effectively.
“Despite higher levels of GLP-1 in individuals with the PAM variant, we didn’t see a corresponding increase in biological activity,” comments Anna Gloyn, an endocrinologist from Stanford University. “They weren’t able to lower their blood sugar levels any faster. It took more GLP-1 for the same effect, indicating resistance.”
This unexpected result led researchers to conduct further tests on mice with a deactivated PAM gene. The absence of the PAM enzyme also resulted in GLP-1 resistance in the mice, which failed to regulate blood sugar levels, even with elevated GLP-1 levels.
The team continued by analyzing clinical trials with 1,119 participants to assess whether specific PAM variations resulted in poorer responses to GLP-1 drugs.
Once again, the findings suggested that individuals with traditional PAM gene variants had a more favorable reaction to GLP-1 treatments compared to those without these variants. Interestingly, this connection wasn’t observed with other diabetes medications tested.
This area presents numerous opportunities for further exploration. Understanding the mechanisms behind the ineffective response to GLP-1 treatments is still a priority. Researchers may also investigate how PAM gene variations relate to GLP-1 drugs used for weight loss, which generally involve higher dosages.
There’s potential for genetic tests to assist in determining the efficacy of GLP-1 treatments for individuals with type 2 diabetes—possibly saving time and resources on ineffective medications.
In the future, there could be ways to modify GLP-1 drugs to bypass the impacts of these PAM gene variations, although this is still in its early stages.
“It’s common for pharmaceutical companies to gather genetic data from participants,” Gloyn points out. “For newer GLP-1 treatments, it would be valuable to explore if there are genetic variants, such as those in PAM, that might explain poor responses.” She adds, “Perhaps we could develop medications that enhance sensitivity to GLP-1s or explore longer-acting formulations that might avoid resistance issues.”
The study has been published in Genome Medicine.
