Genetics May Determine How Well GLP-1 Weight Loss Drugs Like Ozempic Work

New research published in Genome Medicine suggests that the effectiveness of GLP-1 medications—such as Ozempic and Wegovy—may depend on a person’s genetic makeup. While these drugs have gained widespread popularity for weight loss and type 2 diabetes management, the study indicates they may not work equally for everyone.

Approximately 10% of people carry genetic variations linked to “GLP-1 resistance,” which may explain why some individuals experience limited benefits from these medications. Despite having higher-than-normal levels of the hormone glucagon-like peptide-1 (GLP-1), their bodies appear less responsive to its effects.

“This aligns with my clinical experience, where I frequently see a variable response to GLP-1 medications,” said Mir Ali, MD, a bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA. Ali was not involved in the study.

Why Some People May Not Respond to GLP-1 Drugs

The research focused on two genetic variants affecting the enzyme peptidyl-glycine alpha-amidating monooxygenase (PAM), which plays a role in activating hormones, including GLP-1. Certain PAM variants are more common in people with diabetes and may impair insulin release from the pancreas.

The study team investigated whether these variants also disrupt GLP-1 function. In addition to regulating blood sugar, GLP-1 stimulates insulin release after meals, slows stomach emptying, and reduces appetite. GLP-1 medications are designed to mimic these effects.

Key Findings on GLP-1 Resistance

When analyzing individuals with a specific PAM variant called p.S539W, researchers expected to find lower GLP-1 levels. Instead, they observed elevated GLP-1 levels. However, participants with this variant did not experience improved blood sugar reduction, even with higher GLP-1 levels. This suggests they required more GLP-1 to achieve the same biological effect, indicating GLP-1 resistance.

“These findings support the idea that some patients may have partial biologic resistance to incretin-based therapies.”

Robert Glatter, MD, attending physician in the Department of Emergency Medicine at Lenox Hill Hospital in New York City, and Assistant Professor of Emergency Medicine at Zucker School of Medicine at Hofstra/Northwell, explained. Glatter was not involved in the study.

He added, “Still, genetics explains only a portion of treatment heterogeneity, and routine pharmacogenomic screening is not yet ready for widespread clinical use.”

Alternative Strategies for Weight Loss and Diabetes Management

For individuals who do not respond well to GLP-1 medications, experts suggest considering alternative approaches. These may include:

• Combining different obesity pharmacotherapies for enhanced results
• Exploring lifestyle modifications, such as diet and exercise
• Considering other medications or interventions tailored to individual needs

The study highlights the importance of personalized medicine in weight loss and diabetes treatment, as genetic factors may influence drug efficacy.