Are the Weight Loss Effects of Tirzepatide and Semaglutide Temporary?

Introduction

Obesity is a multifactorial chronic disease caused by poor lifestyle habits, family history, concurrent medical conditions, or medications.¹ Obesity can lead to different cardiovascular diseases such as hypertension, heart failure, coronary artery disease, and dyslipidemia. Treatment for obesity includes a wide range of options, both pharmacological and nonpharmacological. Some nonpharmacological options include a diet high in protein and fiber, caloric deficit, and increasing exercise.² Pharmacological treatments include phentermine (Lomaira; KVK Tech), orlistat (Xenical; Roche), and naltrexone/bupropion (Contrave; Currax Pharmaceuticals). Newer medications, such as glucagon-like peptide-1 (GLP-1) agonists and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, have shown efficacy in body weight reduction.^3-5 Although these medications have demonstrated efficacy in reducing body weight, there is less evidence evaluating weight regain after stopping GLP-1 or GLP-1/GIP agonists.

Background

The GLP-1 receptor is an incretin hormone located in the pancreas, brain, and gastrointestinal tract.³ GLP-1 agonists and GLP-1/GIP agonists imitate GLP-1 by decreasing fasting and postprandial blood glucose and regulating appetite and gastric motility. GLP-1 agonists aid in weight loss by reducing food cravings and hunger and increasing satiety.⁴ Certain GLP-1 agonists and GLP-1/GIP agonists are approved by the FDA for type 2 diabetes as well as weight management.^4,5 The GLP-1 agonists approved for weight loss are liraglutide (Saxenda; Novo Nordisk) and semaglutide (Wegovy; Novo Nordisk). Tirzepatide (Zepbound; Eli Lilly and Co), which is also approved by the FDA for weight management, imitates both GLP-1 and GIP hormones.⁵ GLP-1/GIP agonists have demonstrated the ability to significantly reduce body weight by up to 15% or more in patients.⁵

Some adverse effects (AEs) of these medications include diarrhea, vomiting, nausea, headache, dizziness, and injection site erythema.⁴ These medications are contraindicated in patients who are pregnant, hypersensitive to any ingredient in the medication, have pancreatitis, or have a family/personal history of multiple endocrine neoplasia 2 or medullary thyroid cancer.⁴

Mechanism of Weight Regain After GLP-1 or GLP-1/GIP Agonist Discontinuation

GLP-1 and GLP-1/GIP agonists help increase satiety and mediate appetite by slowing gastric motility, which leads to weight reduction. Upon discontinuation of a GLP-1 agonist, some proposed pathways that can lead to weight regain include hormonal imbalances, dysregulation of the central nervous system, disruption of beta cell function in the production of insulin, and alterations in intestinal flora.⁶ Weight gain primarily occurs in a caloric surplus when the calories burned are less than the calorie intake. The hypothalamus plays a crucial role in regulating one’s appetite by receiving signals from ghrelin and leptin. Ghrelin is a hormone that increases appetite, and the leptin hormone suppresses appetite. After discontinuing a GLP-1 or GLP-1/GIP agonist, leptin decreases, reducing satiety, which can increase appetite and result in weight regain.⁶

Summary of Evidence

Several studies have shown that chronic management of obesity is recommended even after weight loss to maintain body weight long term. In the phase 3 STEP 4 trial (NCT03548987) conducted by Rubino et al, 803 participants were followed for 48 weeks after completing 20 weeks of once-weekly subcutaneous semaglutide. The participants were then randomly assigned to 2 groups: 1 group continued semaglutide 2.4 mg once weekly (n = 535), and the other group received a placebo (n = 268).⁷ At week 68, the group that continued semaglutide experienced a weight loss of about 7.9% and the placebo group experienced a weight gain of 6.9%.⁷

The phase 3 SURMOUNT-4 trial (NCT04660643) conducted by Aronne et al included 670 participants with either overweight or obesity without diabetes who were followed for 52 weeks after completing 36 weeks of a maximum-tolerated tirzepatide lead-in regimen. At week 36, participants had a mean weight loss of approximately 20.9%.⁸ Participants were then randomly assigned to 2 groups: 1 group continued once-weekly tirzepatide (n = 335), and the other group received placebo (n = 335). At week 88, the tirzepatide group lost an additional average of 5.5% in body weight, and the placebo group gained an average of 14% in body weight.⁸

The phase 3 STEP 1 trial (NCT03548935) conducted by Wilding et al followed participants for 68 weeks of once-weekly subcutaneous semaglutide or placebo. Upon completion of the study, there was an average weight loss of about 17.3% in the semaglutide group and 2% in the placebo group.⁹ The STEP 1 trial extension, conducted by Wilding et al, followed patients after the STEP 1 trial until week 120. At week 120, 52 weeks after semaglutide discontinuation, the original semaglutide group regained 11.6% and the original placebo group regained 1.9% of total weight loss.⁹

In a study conducted by Bartelt et al, researchers analyzed 20,274 patients over 1 year who completed semaglutide and lost at least 5 pounds. At month 3 after the discontinuation of semaglutide, 29% either lost additional weight or doubled their initial weight loss, 39% maintained their initial weight loss, and 32% had some weight regain or complete weight regain.¹⁰ At month 12 after stopping semaglutide, 36% of patients either lost additional weight or doubled their initial weight loss, 20% maintained their initial weight loss, and 44% had some weight regain or complete weight regain.¹⁰

Researchers also analyzed 17,733 patients over 1 year who completed liraglutide and lost at least 5 pounds. At month 3 after stopping liraglutide, 28% either lost additional weight or doubled their initial weight loss, 33% maintained their initial weight loss, and 32% had some weight regain or complete weight regain.¹⁰ At month 12, 35% of patients either lost additional weight or doubled their initial weight loss, 21% maintained their initial weight loss, and 45% had some weight regain or complete weight regain.¹⁰

These studies demonstrate that both weight loss and weight regain are seen with GLP-1 agonists; however, participants who received placebo also had some weight loss and weight regain, although to a lesser extent. This could show that there could be other factors contributing to weight regain after GLP-1 agonist discontinuation, such as environment, diet, exercise, or other lifestyle choices.

Clinical Implications

These findings suggest that obesity should be treated as a chronic condition, even after weight loss goals have been achieved. To treat obesity long term, health care professionals and pharmacists can consider lifestyle modifications to combat the decreased satiety and increased hunger that come with GLP-1 agonist discontinuation. If weight control is not possible with nonpharmacological options, keeping the patient on the lowest dose of a GLP-1 or GLP-1/GIP agonist can be an option as maintenance therapy to support weight control. This could not only improve patient outcomes but also minimize psychological distress that can occur due to weight regain.

Importantly, GLP-1 and GLP-1/GIP agonists are associated with several AEs. Health care professionals should weigh the benefits and risks of using a GLP-1 agonist indefinitely, especially in patients without comorbid conditions requiring GLP-1 agonists, such as type 2 diabetes. Pharmacists should counsel patients starting GLP-1 or GLP-1/GIP agonists on potential weight gain after medication discontinuation and how to best maintain weight by incorporating permanent lifestyle changes, such as healthy eating habits and daily physical activity, in conjunction with the medication. Offering additional support, such as referrals to registered dietitians or personal trainers, can also help patients feel more in control of their health.

Although multiple studies have shown the efficacy of GLP-1 and GLP-1/GIP agonists in facilitating weight loss, there have been some studies evaluating weight regain after discontinuing GLP-1 or GLP-1/GIP agonist therapy, and potential reasons for weight regain. Unfortunately, there are very few data on the safety and efficacy of using GLP-1 and GLP-1/GIP agonists indefinitely to maintain weight loss after goal weight is reached in patients who are strictly on these medications for weight management.

Conclusion

GLP-1 and GLP-1/GIP agonists have helped millions of people combat obesity and improve their quality of life; however, gaps remain in the literature on how to maintain weight loss after medication discontinuation, as well as the long-term effects of these medications in patients using them only for weight management. Multiple studies have demonstrated that weight regain after discontinuation of GLP-1 or GLP-1/GIP agonists is a significant risk, highlighting the need for further studies to address their long-term use for weight management and continued patient counseling on how to maintain weight loss utilizing nonpharmacotherapy options. Ultimately, patients and health care providers should work together to create individualized treatment plans, weighing the risks and benefits of GLP-1 and GLP-1/GIP agonist discontinuation or long-term use.

REFERENCES

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7. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.3224

8. 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

9. 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

10. Bartelt K, Mast C, Deckert J, et al. Many patients maintain weight loss a year after stopping semaglutide and liraglutide. Epic Research. January 23, 2024. Accessed July 5, 2025. https://epicresearch.org/articles/many-patients-maintain-weight-loss-a-year-after-stopping-semaglutide-and-liraglutide