The Rebound Effect—Weight Regain after Tirzepatide Discontinuation

Introduction and Objective: Tirzepatide (TZP) is a highly effective antiobesity medication, but discontinuation leads to significant weight regain (WR). While trials report up to two-thirds of lost weight is regained within a year, no studies have examined factors associated with this WR. This study aims to determine the incidence, proportion, and predictors of WR after TZP discontinuation in a real-world setting. Methods: This retrospective cohort study included patients who used TZP for ≥12 months for weight loss. We excluded those with active malignancy, concomitant use of other antiobesity medications, and prior bariatric surgery. Endpoints: incidence, percentage, and predictors of WR post-TZP discontinuation. We present categorical data as percentages and continuous data as medians [interquartile range]. We used Wilcoxon tests to compare changes in weight post-TZP discontinuation. We used univariate and multiple regression analyses to identify predictors of WR considering total body weight loss (TBWL) before TZP discontinuation and baseline age, sex, race, and BMI. Results: We included 68 patients: 55 [46-66] years; 69% females; 96% White; weight 109 [99-125] kg. After 14 [13-16] months on TZP, TBWL% was 13 [8-22] (p<0.001). Post-TZP discontinuation, over a median time of 5 [3-8] months, only 28% of patients maintained ≥90% of the TBWL, while 72% regained >10% of the TBWL, 47% regained >20% of the TBWL, 38% regained >30% of the TBWL, and 24% regained >50% of the TBWL. Three, 6, and 9 months post-TZP discontinuation, patients regained 11% [7-29] (n=55, p=0.01), 20% [8-43] (n=35, p=0.01), and 45% [24-56] (n=14, p=0.002), of the TBWL, respectively. Greater TBWL before TZP discontinuation was the only predictor of WR; parameter estimate 2.2, 95% CI [0.3-4.1], p=0.02. Conclusion: WR is highly prevalent post-TZP discontinuation. TBWL before TZP discontinuation strongly predicts WR. These findings highlight the need for interventions to sustain weight loss and mitigate recidivism if TZP is discontinued. Disclosure: D. Bechenati: None. R. Castaneda: None. R. Rivera: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. T. Rajjo: None. M.D. Hurtado Andrade: Advisory Panel; Novo Nordisk. Research Support; Phenomix, National Institutes of Health. Funding: National Institute of Health (K12-AR084222)