Blog Viewer

November Blog - What happens when we stop GLP-1 receptor agonists?

By Courtney Cameron posted 9 days ago

  

What happens when we stop GLP-1 receptor agonists?

Author: Shelley Jeon, PharmD Candidate 2025, Northeastern University School of Pharmacy

Reviewer: Courtney Cameron, PharmD, BCACP

What data are available on weight regain after stopping GLP-1 receptor agonists?

Data from randomized controlled trials suggest that withdrawing either glucagon-like peptide-1 (GLP-1) receptor agonists or dual gastric inhibitory polypeptide (GIP)/GLP-1 receptor agonists leads to a substantial regain of lost weight.

The STEP (Semaglutide Treatment Effect in People with obesity) 1 trial was a randomized, placebo-controlled trial that evaluated the efficacy of once-weekly subcutaneous (SC) semaglutide 2.4 mg plus lifestyle interventions in adults with obesity without diabetes (n = 1961).1 This trial demonstrated clinically meaningful reductions in body weight after 68 weeks of treatment. An extension analysis of the original STEP-1 trial (n = 327) aimed to observe weight gain and cardiometabolic effects after withdrawal of both SC semaglutide and lifestyle interventions following 68 weeks of therapy. Though mean weight loss was 17.3% with SC semaglutide from week 0 to week 68, it was found that following therapy discontinuation, participants had regained 11.6% of lost weight by week 120. In other words, participants regained two-thirds of their prior weight loss after withdrawal of SC semaglutide 2.4mg weekly.


The SURMOUNT-4 randomized clinical trial assessed the effect of tirzepatide discontinuation on the maintenance of weight reduction in adults with obesity and a weight-related complication, excluding diabetes.2 In this study, following 36 weeks of therapy with once weekly SC tirzepatide (10 or 15 mg), participants (n = 670) were randomized to continue tirzepatide or switch to placebo for an additional 52 weeks. It was found that the mean percent change in weight from week 36 to week 88 was -5.5% with tirzepatide vs. 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%); P < 0.001). In short, withdrawing tirzepatide led to substantial regain of lost weight and continued pharmacotherapy was necessary to maintain initial weight reduction.


What physiological factors promote weight regain after weight loss?

An ongoing area of research is focused on understanding the physiological mechanisms behind this weight regain commonly observed after weight loss. Several peripheral and central mechanisms are believed to be involved, including altered gut hormone secretion, decrease in energy expenditure following weight loss, and psychological processes associated with the food reward system.3,4 For instance, following diet-induced weight loss, there is an observed increase in ghrelin and GIP and decrease in leptin, peptide YY (PYY), cholecystokinin (CCK), amylin, insulin, and GLP-1 from baseline.5 Overall, these mechanisms support the concept that body weight and fat mass are regulated by a number of physiological mechanisms beyond voluntary food intake and physical exercise.3 This represents an important shift in our understanding of obesity—away from viewing it as a result of personal lifestyle choices and recognizing it as a complex, chronic disease influenced by genetic, environmental, and metabolic factors.

How can we avoid weight regain after stopping GLP-1 receptor agonists?

The weight regain observed after the discontinuation of currently approved GLP-1 and GIP/GLP-1 receptor agonists represents an unmet need for anti-obesity regimens with sustained efficacy.

A recent randomized clinical trial from Denmark evaluated weight loss maintenance after one of four 52-week regimens (placebo, once daily liraglutide 3.0 mg alone, supervised exercise alone, or liraglutide plus supervised exercise) in 109 adults with obesity without serious chronic illnesses, including diabetes. One year after stopping all treatment, 63% of participants who received combination liraglutide plus supervised exercise were able to maintain ≥5% weight loss and 45% maintained ≥10% weight loss.6 Of individuals who received liraglutide only, 33% maintained ≥5% weight loss and 16% maintained ≥10% weight loss. The results of this relatively small study suggest that exercise may be an important component to minimize weight regain after GLP-1 receptor agonist discontinuation.7

Lastly, investigational agents hold promise for new anti-obesity therapies that may sustain weight loss or minimize weight regain. GIP/GLP-1/glucagon (GCG) triple agonists represent a particularly exciting new drug class that is being studied in patients with obesity. Three triple agonists are currently in clinical trials: retatrutide (Eli Lilly), HM15211 (Hanmi Pharmaceutical), and SAR441255 (Sanofi).8 Data from a phase 2 trial of 338 adults with obesity without diabetes suggests substantial weight loss benefit with retatrutide, with 26% of participants having a body weight reduction of ≥30% with the highest dose of retatrutide (12 mg SC once weekly).9 Clinical data on weight regain following withdrawal of triple agonists is not yet available. However, it is postulated from preclinical data that incorporating GCG receptor agonism may reduce food intake and increase resting energy expenditure, potentially enhancing efficacy.9,10

Summary

●        A large body of high-quality evidence suggests that in patients with obesity without diabetes, GLP-1 and GIP/GLP-1 receptor agonists are associated with significant regain of lost weight after therapy discontinuation.

●        A number of complex physiological mechanisms have been suggested to promote weight regain after weight loss, including hormonal changes, changes in resting energy expenditure, and neuronal factors affecting hunger and reward.

●        Ongoing research and investigational therapies, such as GIP/GLP-1/glucagon triple agonists, may inform future strategies for sustainable weight loss after discontinuation of weight loss pharmacotherapy.

References

  1. 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
  2. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38-48. doi:10.1001/jama.2023.24945
  3. Busetto L, Bettini S, Makaronidis J, Roberts CA, Halford JCG, Batterham RL. Mechanisms of weight regain. Eur J Intern Med. 2021;93:3-7. doi:10.1016/j.ejim.2021.01.002
  4. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. doi:10.1056/NEJMoa1105816
  5. Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond). 2015;39(8):1188-1196. doi:10.1038/ijo.2015.59
  6. Jensen SBK, Blond MB, Sandsdal RM, et al. Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. EClinicalMedicine. 2024;69:102475. Published 2024 Feb 19. doi:10.1016/j.eclinm.2024.102475
  7. Manne-Goehler J, Teufel F, Venter WDF. GLP-1 Receptor Agonists and the Path to Sustainable Obesity Care. JAMA Intern Med. Published online October 14, 2024. doi:10.1001/jamainternmed.2024.3579
  8. Novikoff A, Müller TD. The molecular pharmacology of glucagon agonists in diabetes and obesity. Peptides. 2023;165:171003. doi:10.1016/j.peptides.2023.171003
  9. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
  10. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK, Pirro V, Wainscott DB, Willard FS, Abernathy M, Morford L, Du Y, Benson C, Gimeno RE, Haupt A, Milicevic Z. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022 Sep 6;34(9):1234-1247.e9. doi: 10.1016/j.cmet.2022.07.013. Epub 2022 Aug 18. PMID: 35985340.
0 comments
11 views

Permalink