Scientists May Now Know Why GLP-1s Don't Work For 10% of People

Key Points:

• New research indicates that genetic variants in the PAM gene, carried by about 10% of people, may reduce the effectiveness of GLP-1-based treatments like Ozempic and Wegovy for type 2 diabetes by causing GLP-1 resistance.
• The study found that individuals with the PAM variant p.S539W had higher circulating GLP-1 levels but showed no increased biological activity, meaning they required more GLP-1 to achieve the same blood sugar regulation effect.
• Mouse models lacking the PAM enzyme also exhibited GLP-1 resistance, supporting the connection between PAM gene variants and reduced response to GLP-1 drugs.
• Analysis of clinical trial data involving 1,119 participants confirmed that those with standard PAM gene variants responded better to GLP-1 medications than carriers of the variants, a pattern not observed with other diabetes drugs.
• These findings suggest potential for genetic testing to predict individual responses to GLP-1 treatments and highlight the need for further research into modifying GLP-1 drugs or developing new medications to overcome PAM-related resistance.