Tirzepatide and the Weight-Regain Question: A Narrative Review of What Happens When Treatment Stops
DOI:
https://doi.org/10.5281/zenodo.22260596Keywords:
Tirzepatide, Weight regain, Randomised withdrawal, Obesity pharmacotherapy, Treatment continuationAbstract
The question of what happens when an incretin-based weight treatment is stopped has been answered directly by a randomised
withdrawal trial. After 36 weeks of open-label tirzepatide, during which mean weight fell by 20.9 per cent, 670 participants were
randomised either to continue or to switch to placebo for a further 52 weeks. Those who continued lost a further 5.5 per cent;
those switched to placebo gained 14.0 per cent, a difference of 19.4 percentage points. At week 88, 89.5 per cent of the continuing
group had maintained at least 80 per cent of their lead-in weight loss against 16.6 per cent of those withdrawn. Two qualifications
belong with those figures. The placebo group was still 9.9 per cent below its starting weight at the end, so withdrawal did not
simply undo the treatment; and regain was highly variable, with 54 of 308 withdrawn participants regaining less than a quarter of
what they had lost while 74 regained three quarters or more. This review sets out what the trial establishes and what it leaves
open.
References
Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, et al. "Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial". JAMA 331(2024):38-48.
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. "Tirzepatide once weekly for the treatment of obesity". N Engl J Med 387(2022):205-216.
Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, et al. "Effects of bariatric surgery on mortality in Swedish obese subjects". N Engl J Med 357(2007):741-752.
Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. "Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension". Diabetes Obes Metab 24(2022):1553-1564.
Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, 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 325(2021):1414-1425.
Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. "Long-term persistence of hormonal adaptations to weight loss". N Engl J Med 365(2011):1597-1604.
MacLean PS, Bergouignan A, Cornier MA, Jackman MR. "Biology s response to dieting: the impetus for weight regain". Am J Physiol Regul Integr Comp Physiol 301(2011):R581-R600.
Eli Lilly and Company. "A study of tirzepatide (LY3298176) in participants with obesity or overweight for the maintenance of weight loss (SURMOUNT-4)". ClinicalTrials.gov NCT04660643 (2023).
Quality of life investigators. "Tirzepatide associated with improved health-related quality of life in adults with obesity or overweight in SURMOUNT-4". Obes Sci Pract (2025).
Post hoc analysis investigators. "Cardiometabolic parameter change by weight regain on tirzepatide withdrawal in adults with obesity: a post hoc analysis of the SURMOUNT-4 trial". JAMA Intern Med (2026).
Oczypok EA, Anderson TS. "Weight regain after withdrawal of antiobesity medication". JAMA Intern Med (2026).
Rothwell PM. "External validity of randomised controlled trials: to whom do the results of this trial apply?". Lancet 365(2005):82-93.
Gasoyan H, Pfoh ER, Schulte R, Sullivan E, Le P, Rothberg MB. "Changes in weight and glycated hemoglobin by pharmacotherapy discontinuation status". JAMA Netw Open 8(2025):e2516231.
Gasoyan H, Rothberg MB. "Early- and later-stage persistence with anti-obesity medications: a retrospective cohort study". Obesity 32(2024):486-493.
Gudzune KA, Kushner RF. "Medications for obesity: a review". JAMA 332(2024):571-584.
Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, et al. "Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial". Lancet 402(2023):613-626.
Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. "Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial". Nat Med 29(2023):2909-2918.
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. "Once-weekly semaglutide in adults with overweight or obesity". N Engl J Med 384(2021):989-1002.
Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, et al. "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes". N Engl J Med 385(2021):503-515.
Nauck MA, Quast DR, Wefers J, Meier JJ. "GLP-1 receptor agonists in the treatment of type 2 diabetes: state-of-the-art". Mol Metab 46(2021):101102.
Muller TD, Bluher M, Tschop MH, DiMarchi RD. "Anti-obesity drug discovery: advances and challenges". Nat Rev Drug Discov 21(2022):201-223.
Ryan DH, Yockey SR. "Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over". Curr Obes Rep 6(2017):187-194.
Look AHEAD Research Group. "Eight-year weight losses with an intensive lifestyle intervention: the Look AHEAD study". Obesity 22(2014):5-13.
Hall KD, Kahan S. "Maintenance of lost weight and long-term management of obesity". Med Clin North Am 102(2018):183-197.
Greenway FL. "Physiological adaptations to weight loss and factors favouring weight regain". Int J Obes 39(2015):1188-1196.
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes". N Engl J Med 389(2023):2221-2232.
Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. "Tirzepatide for heart failure with preserved ejection fraction and obesity". N Engl J Med 390(2024):1394-1407.
Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, et al. "Tirzepatide for the treatment of obstructive sleep apnea and obesity". N Engl J Med 391(2024):1193-1205.
Jastreboff AM, le Roux CW, Stefanski A, Aronne LJ, Halpern B, Wharton S, et al. "Tirzepatide for obesity treatment and diabetes prevention". N Engl J Med 392(2025):958-971.
Wharton S, Astrup A, Endahl L, Lean MEJ, Satylganova A, Skovgaard D, et al. "Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data". Int J Obes 45(2021):923-933.
Hong Y, Lee JH, Kim W. "Adherence and persistence to anti-obesity medications: a systematic review". Obes Rev 24(2023):e13593.
Bray GA, Fruhbeck G, Ryan DH, Wilding JPH. "Management of obesity". Lancet 387(2016):1947-1956.
Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, et al. "Tirzepatide as compared with semaglutide for the treatment of obesity". N Engl J Med 393(2025):26-36.
Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, et al. "Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials". Lancet Diabetes Endocrinol 9(2021):653-662.
