Model Finds Weight Regain After Stopping Semaglutide or Tirzepatide

A Bayesian hierarchical longitudinal meta-analysis published in Endocrinology, Diabetes, & Metabolism found that patients who discontinue semaglutide or tirzepatide regain weight quickly, losing half of their treatment-associated weight loss back within an estimated 7.5 months.¹

The researchers reconstructed timepoint-level aggregate data from 6 randomized trials comprising 10 intervention arms and 1776 participants to model the regain trajectory beyond what the original studies observed directly. Under a constant linear regain rate, the model projected a return to baseline weight by approximately 15 months post-discontinuation, though the authors cautioned that estimate extends beyond the trials' observed follow-up and represents a model-based extrapolation rather than an observed outcome.¹

Modeling the Regain Trajectory

The 6 trials included in the analysis—SURMOUNT-4 (NCT04660643), the SURMOUNT-1 extension (NCT04184622), STEP 10 (NCT05040971), the SURPASS-1 (NCT03954834) follow-up, STEP 4 (NCT03548987), and the STEP 1 (NCT03548935) extension—were drawn entirely from a prior systematic review and meta-analysis published in BMJ that covered 37 studies and 63 intervention arms across all weight-management medications.¹

Observed postdiscontinuation follow-up in the reanalyzed subset ranged from 4 to 52 weeks. The Bayesian model estimated an overall weight loss of 15.35 kg (95% credible interval [CrI], 11.18-19.60) at the time of discontinuation, followed by a monthly regain slope of 1.04 kg/month (95% CrI, 0.80-1.29).¹

Translated into clinical milestones, the model estimated that 50% of initial weight loss would be regained by 7.5 months (95% CrI, 5.05-10.57) and that patients would return to their baseline weight by 15.0 months (95% CrI, 10.10-21.13). Within the observed follow-up window, the modeled average weight change remained below baseline at 6 months (-9.12 kg), 9 months (-6.01 kg), and 12 months (-2.90 kg), corresponding to roughly 41.4%, 62.1%, and 82.8% of the initial weight loss regained, respectively. The posterior probability that patients had regained at least half of their initial weight loss was 12.5% at 6 months, 86.7% at 9 months, and 99.5% at 12 months.¹

Semaglutide vs Tirzepatide: No Clear Difference

Unadjusted regain slopes were numerically faster for tirzepatide (1.10 kg/month; 95% CrI, 0.79-1.43) than for semaglutide (0.89 kg/month; 95% CrI, 0.56-1.23), translating into a projected time to 50% regain of 7.24 months versus 8.65 months, respectively.¹

After adjustment in a Bayesian meta-regression, however, the researchers found no clear independent drug-specific difference. Tirzepatide's estimated effect on the regain slope was -0.04 kg/month relative to semaglutide (95% CrI, -0.46 to 0.44), with only a 40.2% posterior probability that tirzepatide was associated with faster regain.¹

Greater initial weight loss showed the strongest directional association with faster absolute regain—each additional 5 kg lost was linked to a 0.20 kg/month faster regain slope (95% CrI, -0.10 to 0.44), with a 92.1% posterior probability of a positive association—though the credible interval crossed zero, and the authors described the finding as hypothesis-generating rather than confirmed.¹

Behavioral or lifestyle support after discontinuation was directionally associated with slower regain (-0.19 kg/month; 95% CrI, -0.57 to 0.17), but that estimate was similarly imprecise. The authors noted their meta-regression included only 10 intervention arms and should be considered exploratory.¹

Real-World Data Show a Softer Landing

A separate retrospective cohort study from Cleveland Clinic, examining 7938 adult patients in Ohio and Florida who discontinued semaglutide or tirzepatide after 3 to 12 months of treatment, found smaller regain than the trial-based projections.²

Among patients originally treated for obesity, who lost an average of 8.4% of body weight before stopping, the cohort regained an average of just 0.5% of body weight 1 year after discontinuation. Approximately 45% maintained their weight loss or continued losing weight. Patients originally treated for type 2 diabetes, who had lost an average of 4.4% of body weight before stopping, showed an additional 1.3% average loss 1 year after discontinuation, with 56% maintaining or continuing to lose weight.²

Researchers pointed to treatment-switching patterns as a likely explanation. Among the cohort, 27% switched to an alternative obesity medication, 20% restarted their original medication, 14% pursued lifestyle modification with a healthcare professional, and fewer than 1% underwent bariatric surgery.²

"Our real-world data show that many patients who stop semaglutide or tirzepatide restart the medication or transition to another obesity treatment, which may explain why they regain less weight than patients in randomized trials," Hamlet Gasoyan, DS, PhD, MPH, a researcher at Cleveland Clinic's Center for Value-Based Care Research, said in an article.²

"Many patients do not give up on their obesity treatment journey, even if they need to stop their initial medication," Gasoyan said.² "In our future work, we will examine the comparative effectiveness of alternative treatment options for obesity in patients who discontinue semaglutide or tirzepatide to help patients and their clinicians make informed decisions."

Why Patients Discontinue

Discontinuation itself is common. A separate analysis of 125,474 US adults with overweight or obesity published in JAMA Network Open found that within 1 year, 64.8% of patients without type 2 diabetes and 46.5% of patients with type 2 diabetes had discontinued their glucagon-like peptide-1 (GLP-1) receptor agonist. By 2 years, those figures rose to 84.4% and 64.1%, respectively.³

Adverse effects and cost were the most frequently cited reasons for stopping, and moderate to severe gastrointestinal adverse events were associated with a higher hazard of discontinuation in both groups. Among the 41,792 patients in that study who discontinued, 47.3% of those with type 2 diabetes and 36.3% of those without reinitiated treatment within a year—and each 1% of weight regained after stopping was associated with a 2.3% increase in the hazard of reinitiation among patients with type 2 diabetes and a 2.8% increase among those without.³

For pharmacists, the pattern across all 3 analyses suggests weight regain after stopping a GLP-1 receptor agonist or dual GIP/GLP-1 agonist is common and can begin within months, but it is not automatic or uniform. Pharmacists are often the first point of contact when a patient's prior authorization lapses, a prescription goes unfilled due to cost, or a patient asks whether to restart therapy after a gap—each a moment to discuss realistic expectations for regain, the value of continued lifestyle support, and the range of alternative or maintenance options available before weight trends reverse significantly.

REFERENCES

1. Kow CS, Thiruchelvam K, Ramachandram DS, Zaihan AF. Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate-Data Bayesian Longitudinal Meta-Analysis. Endocrinol Diabetes Metab. 2026;9(5):e70325. doi:10.1002/edm2.70325

2. Cleveland Clinic Newsroom. What happens when patients stop taking GLP-1 drugs? New Cleveland Clinic study reveals real-world insights. March 12, 2026. Accessed September 1, 2026. https://newsroom.clevelandclinic.org/2026/03/12/what-happens-when-patients-stop-taking-glp-1-drugs-new-cleveland-clinic-study-reveals-real-world-insights

3. 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. Published 2025 Jan 2. doi:10.1001/jamanetworkopen.2024.57349