Why Some Patients Do Not Respond to GLP-1 Therapies

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Ozempic, Wegovy; Novo Nordisk) have transformed obesity and type 2 diabetes management. These therapies promote significant weight loss, improve glycemic control, and provide cardiovascular and metabolic benefits.¹

However, despite their success, not all patients respond equally. Emerging evidence suggests that some individuals develop nutritional deficiencies during treatment, whereas others experience biologically driven GLP-1 resistance that limits therapeutic response.^1-5

The Hidden Nutritional Impact of GLP-1 Therapy

GLP-1 therapies reduce appetite and slow gastric emptying, which can unintentionally lower overall nutrient intake. As long-term use increases, concerns surrounding micronutrient deficiencies are gaining attention.

A large observational study involving approximately 460,000 adults prescribed GLP-1 therapies found that nearly 1 in 5 patients developed at least 1 nutrient deficiency within a year of treatment initiation.¹ Another study reported that 13.6% of GLP-1 users developed vitamin D deficiency, whereas nearly 60% consumed inadequate amounts of iron or calcium.¹ Additional deficiencies involving magnesium, potassium, and vitamins A, C, D, and E have also been reported.^1,2

These micronutrients, although required in small amounts, are essential for immune function, cardiovascular health, neuromuscular activity, and energy metabolism. Persistent deficiencies may contribute to fatigue, weakness, anemia, and reduced treatment tolerance. Despite these risks, nutritional monitoring is not consistently incorporated into routine GLP-1 therapy management. Table 1^1-4 highlights real-world evidence on these nutritional deficiencies.

Understanding the GLP-1 “Nonresponder”

Another growing concern is the phenomenon of the GLP-1 nonresponder. Clinicians have long observed that some patients experience minimal weight loss despite adherence to medication and lifestyle changes. Historically, poor outcomes were often attributed to nonadherence; however, emerging evidence suggests biology may play a major role.^2,3 Research now indicates that approximately 10% to 14% of patients may have genetically driven GLP-1 resistance.²

Evidence of this variability has also been observed in major obesity trials. The phase 3 STEP 1 (NCT03548935) clinical trial, a landmark study evaluating semaglutide for chronic weight management, found that approximately 13.6% of participants failed to achieve even a 5% reduction in total body weight.³ In real-world settings, nonresponse rates may reach 20% to 25% when additional clinical variables are considered.⁴ Importantly, increasing medication doses does not consistently overcome this resistance, suggesting the barrier is biological rather than behavioral.

The Genetic Basis of GLP-1 Resistance

Recent studies conducted by researchers affiliated with Stanford Medicine identified variants within the GLP1R gene, which encodes the GLP-1 receptor targeted by semaglutide and related therapies.^2,3 Specific polymorphisms, including variants associated with the rs6923761 locus, may alter receptor structure and impair signaling.³ As a result, GLP-1 medications may bind less effectively, reducing insulin secretion, delaying satiety signaling, and limiting overall metabolic response.

Researchers also found that therapeutic response may vary based on sex-specific genetic expression, with some male patients demonstrating poorer outcomes compared with females carrying similar variants.³ These findings support the growing role of precision medicine in obesity and diabetes treatment.

Recognition of GLP-1 resistance is changing how clinicians approach obesity management. Rather than assuming treatment failure reflects poor adherence, clinicians are increasingly encouraged to evaluate biological and metabolic factors contributing to reduced response.

Early Identification of Poor Responders

Patients who fail to achieve meaningful weight reduction within the first few months of therapy may require reassessment rather than indefinite dose escalation.⁴ Clinicians should also evaluate additional factors that may limit treatment efficacy, including type 2 diabetes, concurrent medications, hormonal abnormalities, poor nutritional intake, gastrointestinal conditions, and sedentary lifestyle factors. Early identification of poor responders may reduce unnecessary health care costs, adverse effects, and prolonged ineffective treatment.

Beyond Single-Pathway Therapy

For patients with suspected GLP-1 receptor resistance, single-pathway therapy may be insufficient. This has increased interest in multi-receptor agonists such as tirzepatide (Mounjaro; Eli Lilly) and investigational agents such as retatrutide (Eli Lilly).² These therapies target multiple metabolic pathways and may help bypass isolated GLP-1 resistance mechanisms.

Clinical Limitations and Safety Considerations

Although GLP-1 receptor agonists are generally effective, adverse effects remain common. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea may further contribute to reduced nutritional intake. Additional complications may include gastroparesis, gallbladder disease, and injection-site reactions.⁵

Cost and medication accessibility also remain major concerns. Patients who fail to respond may face unnecessary financial burden and prolonged exposure to adverse effects while delaying alternative treatments such as bariatric surgery.⁵ These challenges highlight the importance of individualized treatment planning and early therapeutic response assessment in patients receiving GLP-1 therapy.

Conclusion

GLP-1 receptor agonists have significantly advanced obesity and diabetes management, but therapeutic response is not universal. Nutritional deficiencies, genetic receptor variants, and biologically driven GLP-1 resistance may explain why some patients experience limited benefit despite adherence to therapy.

As GLP-1-based therapies continue to evolve, integrating genomic insights, nutritional monitoring, and personalized treatment strategies may help optimize patient outcomes and advance the future of precision metabolic medicine.

REFERENCES

1. Su QJ, Ashenhurst JR, Xu W, et al. Genetic predictors of GLP1 receptor agonist weight loss and side effects. Nature. 2026;653(8115):770-775. doi:10.1038/s41586-026-10330-z

2. Bai N. One in 10 people may have resistance to GLP-1 diabetes drugs. Stanford Medicine. April 10, 2026. Accessed June 2, 2026. https://med.stanford.edu/news/all-news/2026/04/glp-1-diabetes.html

3. Phan A, Carette C, Narjoz C, et al. A GLP1R gene variant and sex influence the response to semaglutide treatment in patients with severe obesity. Obesity (Silver Spring). 2025;33(7):1237-1242. doi:10.1002/oby.24300

4. Squire P, Naude J, Zentner A, Bittman J, Khan N. Factors associated with weight loss response to GLP-1 analogues for obesity treatment: a retrospective cohort analysis. BMJ Open. 2025;15(1):e089477. doi:10.1136/bmjopen-2024-089477

5. Klein MP, Akturk HK, Snell-Bergeon JK, Shah VN. Reduced efficacy of glucagon-like peptide-1 receptor agonists therapy in people with type 1 diabetes and genetic forms of obesity. J Diabetes Sci Technol. 2024;19(2):297-303. doi:10.1177/19322968241245680