GLP-1 medications such as Ozempic and Wegovy have become widely used to manage type 2 diabetes and treat obesity, in part because many people experience substantial weight loss on them. New research published in Genome Medicine suggests, however, that GLP-1 drugs are not equally effective for everyone and that genetics may help explain some of the variation.
About 10% of people carry genetic variants linked to what researchers describe as “GLP-1 resistance.” The study focused on variants affecting the enzyme peptidyl-glycine alpha-amidating monooxygenase (PAM), which helps activate several hormones including GLP-1. One specific PAM variant, p.S539W, was associated with higher circulating GLP-1 levels but a reduced biological response: despite elevated hormone levels, affected individuals required more GLP-1 to achieve the same effect on blood sugar, indicating partial resistance.
Researchers emphasize the study examined GLP-1’s effects on blood sugar rather than weight loss, and it remains unclear whether these variants produce the same resistance at the higher GLP-1 doses typically used for obesity. Still, the findings point toward a role for genetics in treatment heterogeneity. As Robert Glatter, MD, noted, genetics explains only part of why responses differ, and routine pharmacogenomic screening is not yet ready for broad clinical use. Mir Ali, MD, observed that variable clinical responses to GLP-1 drugs align with these genetic findings.
Other factors that influence GLP-1 effectiveness include incomplete dosing, early discontinuation because of gastrointestinal side effects, insufficient treatment duration, and competing metabolic or lifestyle drivers such as severe insulin resistance, sleep disruption, sarcopenia, or other medications that cause weight gain. Addressing these issues—ensuring proper dosing and duration, managing side effects, and treating underlying conditions—often improves outcomes.
If GLP-1s are ineffective or responses are incomplete, alternatives and supplementary strategies include:
– Metabolic/bariatric surgery: Procedures such as sleeve gastrectomy and Roux-en-Y gastric bypass produce substantial, durable weight loss (average 25–35%) and improve metabolic health. Surgery also changes incretin signaling, increasing GLP-1 activity and insulin sensitivity in ways that can complement drug therapy. Experts argue surgery should be considered as a parallel treatment option rather than solely a last resort.
– Combination pharmacotherapy: Obesity involves multiple pathways—appetite, reward, gut-brain hormones, and energy expenditure—so combining agents that target different mechanisms is increasingly supported by evidence. Pairing incretin agents with drugs such as phentermine, topiramate, or bupropion-naltrexone, or using multi-receptor agents (for example, newer drugs that stimulate more than one receptor), can improve response when monotherapy is insufficient.
– Alternative medications: For some patients, drugs that act on multiple receptors or using different classes of weight-loss medications—either instead of or in combination with GLP-1s—may be effective.
– Lifestyle and behavioral strategies: Dietary changes remain foundational. Reducing refined carbohydrates and added sugars while emphasizing protein and vegetables supports weight loss; combining aerobic and resistance exercise helps burn calories and preserve muscle mass. Dietary patterns like the Mediterranean, DASH, or MIND diets, along with careful attention to hydration, protein intake, and caloric balance, are recommended for weight loss and cardiometabolic health.
The study’s findings contribute to a growing focus on precision medicine for obesity: clinicians are increasingly seeking to identify who benefits most from specific therapies and when to consider alternative pathways. For now, if a patient does not respond to GLP-1 therapy, clinicians should first optimize medication use and address contributing medical or lifestyle factors, then consider combination pharmacotherapy, alternative agents, or bariatric surgery as appropriate. Further research is needed to confirm how genetic variants affect weight-loss outcomes and to guide personalized treatment strategies.
