Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are two gut derived incretin hormones that play roles in glucose and insulin metabolism. GLP-1 Receptor Agonists (GLP-RA) are a class of medications that mimic the hormone glucagon-like peptide 1 (GLP-1), helping to regulate insulin release, glucose metabolism, and appetite. Dual GIP/GLP-1 receptor agonists, are medications that target both GIP and GLP-1 receptors. Either GLP-1 RA alone or the dual agonists are being used to assist with appetite regulation, satiety, improved insulin release, and weight management.
For a refresher on the GLP-1 and GIP hormones, check out on our blog on GLP-1 and GIP hormones: What do they do?
While many studies highlight the possible benefit of these medications, for some these medications may not help them achieve the desired outcome.
When GLP-RA and GIPs don’t work
As with most medications, the effects people experience differ. Some patients may not experience the same benefits as others on GLP-1 RA. The non-response rate to GLP-1 RA varies amongst studies. In one study, 13.8% of individuals did not achieve a clinically-relevant weight loss, greater than or equal to, 5% at 68 weeks.1 In another, 17.8% were labeled non-responders.2
Though, why don’t medications “work” for some people? Several factors may be at play:
- Individual response variability
Like any medication, GLP-RA and GIP medications don’t work the same way for every person. Some individuals may have a genetic predisposition or metabolic variation that causes them to respond differently to these medications. Studies have shown that females have a greater response to GLP-1 analogue therapy.2 This appears to be due to a lower average body mass, which results in higher drug concentrations in the body at any dose.2
- Underlying health conditions
In addition to sex, other health conditions can interfere with effectiveness of GLP-RA. Individuals with diabetes have been observed to have a less effective response than individuals without diabetes.3 The reasons for this are not fully understood, yet altered microbiome and genetic variations are proposed as possible contributors.
- Genetic variation
Similar to other underlying health conditions, genetic variations are thought to contribute to the varied response to these medications. Genetic variations in the incretin receptors may be a contributing factor as to why certain people do not respond to these therapies.4 As a refresher, GLP-1 and GIP are incretin hormones. If someone has a variation in the receptors of these hormones, it can affect how these medications may work.
- Side effects or tolerability issues
Many clients have side effects when starting GLP-1 RA medications, these include nausea, vomiting, constipation, and other gastrointestinal discomfort.5 For some, the side effects can interfere with their effectiveness – particularly when the side effects are severe enough for clients to stop taking the medication or miss doses. The discontinuation rate within 1 year is between 46.5% for individuals with type 2 diabetes and 64.8% for individuals without type 2 diabetes.6 Approximately two-third of weight lost is regained after discontinuation of these therapies and are associated with worsening cardiometabolic outcomes.7
- Not supporting GLP with lifestyle changes
Medication alone is not enough to achieve lasting improvements to blood glucose and metabolic heath outcomes. These medications work best when combined with lifestyle changes, including a balanced, nutrient-dense diet that includes adequate protein and fiber; physical activity that includes resistance training; and adequate hydration.
If these medications don’t work as anticipated, what should one do? Working with a registered dietitian who specializes in this area, who are Certified Eating Disorder Specialists (CEDS), Certified Diabetes Care and Education Specialists (CDCES), or have their PhD in this area of nutrition can help support you in meeting your goals.
Using a whole person approach to look at the big picture, several strategies can implemented.
- Reassess dietary habits
Consider working with a RD to review and optimize your dietary habits to improve outcomes and effectiveness of the medication. Creating a tailored plan to your unique physiology and needs can improve overall metabolic health and complement the effects of the medication. Optimizing your dietary habits to ensure you are getting adequate nutrition can help preserve your lean muscle mass and manage side effects of the medication.8
- Lifestyle changes are important for long term success on GLP-1 medications
A RD can help support the behavioral and lifestyle changes that are needed to optimize effectiveness of these medications. In addition to the nutrition support, it is important to take a whole person approach and consider physical activity, stress management, sleep hygiene, and emotional regulation as key components to overall health. Incorporating strategies to improve overall health is important to maximize effectiveness of these medications.
- Collaborating with other members of the team
We work closely with your doctors, endocrinologists, and other providers to monitor progress and adjust treatment plans. If medications aren’t working as expected, we can explore different therapeutic options.
While GLP-RA and GIPs may improve metabolic health, they are not a one-size-fits-all solution. When they do not work as expected, it’s important to assess the whole person through a patient-centered empowerment approach to make necessary adjustments to their plan. The team at LCWNS is made up of RDs with their CEDS, CDCES, and PhD credentials and can offer personalized nutrition advice, support behavior change, and ensure that you have the tools needed to succeed.
References
- Mosenzon O, Garvey WT, Hesse D, et al. Clinically-Relevant Weight Loss is Achieved Independently of Early Weight Loss Response to Once-Weekly Subcutaneous Semaglutide 2.4 MG (STEP 4). J Endocr Soc. 2021;5(Supplement_1):A7-A7. doi:10.1210/jendso/bvab048.013
- 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
- Jensterle M, Rizzo M, Haluzík M, Janež A. Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review. Adv Ther. 2022;39(6):2452-2467. doi:10.1007/s12325-022-02153-x
- Austin GO, Tomas A. Variation in responses to incretin therapy: Modifiable and non-modifiable factors. Front Mol Biosci. 2023;10:1170181. doi:10.3389/fmolb.2023.1170181
- Liu L, Chen J, Wang L, Chen C, Chen L. Association between different GLP-1 receptor agonists and gastrointestinal adverse reactions: A real-world disproportionality study based on FDA adverse event reporting system database. Front Endocrinol. 2022;13:1043789. doi:10.3389/fendo.2022.1043789
- Rodriguez PJ, Zhang V, Gratzl S, et al. Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity. JAMA Netw Open. 2025;8(1):e2457349. doi:10.1001/jamanetworkopen.2024.57349
- Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725
- Almandoz JP, Wadden TA, Tewksbury C, et al. Nutritional considerations with antiobesity medications. Obesity. 2024;32(9):1613-1631. doi:10.1002/oby.24067
