Background
To quantify the extent of metabolic and cardiovascular rebound following the discontinuation of GLP-1 receptor agonist (GLP-1RA) therapy in adults with obesity, type 2 diabetes, or type 1 diabetes, and identify potential modifiers of these outcomes.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials including adults and adolescents treated with GLP-1RAs, followed by a post-discontinuation follow-up of at least 12 weeks. Databases searched included MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov, with no language restrictions, and published up to October 17, 2025. We assessed changes in anthropometric, glycemic, cardiovascular, and lipid parameters between the end of treatment and the post-cessation period. Random-effects models were used to calculate pooled mean differences. The risk of bias and certainty of evidence were evaluated using the Cochrane ROB 2.0 and GRADE frameworks. The study was registered with PROSPERO under CRD42025646185.
Findings
Eighteen RCTs (3771 participants) were included. Among individuals with obesity, discontinuation of GLP-1RA resulted in significant metabolic rebound, characterized by a body weight gain of 5.63 kg (95% CI: 3.52–7.73, I2 = 99.57%, moderate) and an increase in HbA1c of 0.25% (95% CI: 0.18–0.32, I2 = 98.45%, moderate). Waist circumference, BMI (Body Mass Index), SBP (Systolic Blood Pressure), and FPG (fasting plasma glucose) also showed significant deterioration. In the type 2 diabetes setting, weight gain was 2.03 kg (95% CI: 1.63–2.42, I2 = 42.28%, moderate), and HbA1c rose by 0.65% (95% CI: 0.22–1.08, I2 = 96.83%, moderate), while FPG remained stable (0.90 mmol/L; 95% CI: −0.36 to 2.17, I2 = 98.81%, moderate). Subgroup analyses revealed greater weight regain with longer follow-up (>26 weeks: 7.31 kg vs. 2.51 kg) and with semaglutide compared to liraglutide (8.21 kg vs. 4.29 kg). Semaglutide also led to greater increases in waist circumference (3.80 cm vs. 2.69 cm) and SBP (7.09 mmHg vs. 1.56 mmHg). Most outcomes showed no evidence of significant publication bias, with minor asymmetry detected for VLDL (very-low-density lipoprotein) levels in individuals with obesity and for weight change (kg) in patients with type 2 diabetes. The risk of bias assessment using the ROB 2.0 tool rated all included studies as having a low risk.
Interpretation
The magnitude and consistency of these effects underscore the physiological consequences of GLP-1RA discontinuation. As the clinical use of GLP-1RAs continues to grow in the management of obesity and diabetes, it is imperative that treatment guidelines address not only initiation and titration but also discontinuation and long-term maintenance strategies to sustain therapeutic gains.
Keywords
GLP-1 receptor agonist, Drug discontinuation, Weight regain, Metabolic outcomes, Cardiovascular risk, Meta-analysis
Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for the treatment of type 2 diabetes and obesity, offering substantial benefits in glycaemic control, weight reduction, and cardiovascular outcomes. By mimicking endogenous GLP-1, these agents stimulate insulin secretion, suppress glucagon release, delay gastric emptying, and reduce appetite. GLP-1RAs have demonstrated superior efficacy compared to conventional glucose- or weight-lowering agents, with some agents achieving body weight reductions of up to 20% after 1 year of treatment. Despite their therapeutic efficacy, real-world discontinuation rates remain high, 46.5% in people with diabetes and 64.8% in those without, primarily due to high cost, and gastrointestinal adverse effects, including nausea, vomiting, diarrhea, gastroparesis, and pancreatitis.
Emerging evidence suggests that treatment discontinuation may lead to rapid metabolic relapses; however, the long-term consequences of GLP-1RA cessation are poorly understood. For instance, the STEP-10 and SURMOUNT-4 trials reported substantial weight regain, deterioration of glycaemic control, and reversal of lipid and blood pressure improvements following treatment withdrawal. In STEP-10, over 40% of lost weight was regained within 28 weeks of stopping semaglutide, while in SURMOUNT-4, more than 50% of weight loss with tirzepatide rebounded over 52 weeks.
These findings highlight the importance of understanding the long-term implications of GLP-1RA discontinuation and the need for high-quality evidence to inform clinical decision-making after therapy cessation. To date, no meta-analysis has systematically quantified the extent of metabolic and cardiovascular changes following the withdrawal of GLP-1RAs. Despite growing clinical use, few trials have evaluated the reversibility of treatment effects, and current guidelines provide no specific recommendations regarding dose tapering or structured maintenance approaches.
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify the metabolic and cardiovascular consequences of GLP-1RA discontinuation. The primary objective was to estimate the magnitude and consistency of rebound in anthropometric and glycemic outcomes following cessation at the end of the treatment phase. Additionally, we explored potential modifiers of rebound, including treatment duration, type of GLP-1RA, length of follow-up after cessation, and background pharmacologic therapy. These findings aim to inform evidence-based strategies for managing the transition off therapy and to clarify the downstream effects of discontinuation in the context of long-term care for obesity and diabetes.
Methods
Search strategy and selection criteria
A comprehensive search of MEDLINE (via PubMed), Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov was performed up to October 17, 2025 with search terms “glucagon-like peptide-1 receptor agonist”, “Exenatide”, “Liraglutide”, “Semaglutide”, “Tirzepatide”, “cessation” “discontinue”, “terminate”, “abort”, “treatment withdrawal”, “randomized controlled trial”, “without language restrictions.”. A full search strategy is detailed in Appendix S1 pp. 2. We excluded grey literature, including conference abstracts, dissertations, and non-peer-reviewed preprints, to minimize the risk of bias from incomplete or preliminary data. For any relevant grey literature identified, we attempted to locate corresponding full-length, peer-reviewed publications. Two authors independently screened titles, abstracts, and full texts of all retrieved articles for eligibility criteria. Discrepancies were resolved through discussion and consensus, with adjudication by a third reviewer when necessary.
We included randomized controlled trials (RCTs) that: (1) investigated the effects of GLP-1RA treatment (including dual GLP-1/GIP receptor agonists such as tirzepatide) in adult and adolescents with metabolically related baseline conditions such as obesity, type 1 diabetes, or type 2 diabetes; (2) reported outcomes at both the end of treatment phase (prior to cessation) and at one or more time points following cessation; (3) had ≥12 weeks of follow-up after cessation to ensure clinical relevance. Studies were excluded if they (1) lacked an explicit follow-up period; (2) did not report outcomes both before and after GLP-1RA cessation (3) focused on non-metabolic outcomes (e.g., neurological or psychiatric effects); only, (4) involved less than 12 weeks of GLP-1RA treatment; or (5) were pharmacodynamic studies with only short-term follow-up measured in days. Examples of studies excluded after full-text review are provided in Appendix S2 pp. 4). Of note, “discontinuation” was defined as the planned ending of GLP-1RA treatment at the end of the randomized trial's treatment phase, rather than premature termination due to adverse events or non-adherence in this study. Because treatment cessation was seldom the primary focus and rarely mentioned in titles or abstracts, the exclusion criterion “did not assess post-cessation outcomes” was applied during full-text screening, after confirming that studies met all other criteria. All full texts and Supplementary Materials were carefully reviewed for any post-cessation data.
Discussion
This meta-analysis reveals that discontinuation of GLP-1RAs is associated with significant rebound in body weight, waist circumference, glycemic control (HbA1c, fasting plasma glucose), SBP, and lipid profiles among patients with obesity. Within this subgroup, the extent of rebound varied by agent, with semaglutide being associated with a greater relapse rate than liraglutide. Rebound in weight and waist circumference followed a time-dependent pattern, with longer follow-up periods (>26 weeks) associated with greater deterioration. These findings are supported by the stability of placebo arms, which showed minimal changes in weight, glycaemia, and blood pressure. This reinforces the notion that the rebound observed after GLP-1RA withdrawal reflects a pharmacological discontinuation effect rather than lifestyle regression.
The rebound in weight and waist circumference following GLP-1RA cessation is both consistent and substantial, with a near-complete reversal of prior improvements within 52 weeks. This relapse is attributed to homeostatic responses to weight loss and the abrupt loss of the drug's effects. Weight loss triggers decreased leptin due to lower adipose composition and higher ghrelin levels, collectively enhancing appetite and promoting energy intake. GLP-1RAs counter these effects by acting centrally to suppress hunger, but this benefit vanishes upon withdrawal. These agents promote glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying, thereby attenuating postprandial glucose excursions. Therefore, the discontinuation of GLP-1RAs also impacts glycemic control.
Longer follow-up durations were significantly associated with greater rebounds in body weight and waist circumference, indicating a progressive, time-dependent relapse trajectory following GLP-1RA cessation. This pattern aligns with longitudinal findings from the STEP-1 extension and SURMOUNT-4 trials, where body weight increased steadily over 52 weeks of post-treatment follow-up. The gradual rather than abrupt rebound in body weight and waist circumference reflects the different time courses required to reverse its diverse biological effects. Some effects, such as delayed gastric emptying, reverse quickly through restored antral motility, and central anorexigenic signaling in the hypothalamus may downregulate soon after GLP-1R stimulation ends. In contrast, hormonal changes, including a rise in soluble leptin receptor and sustained free leptin levels, reverse more gradually, which is further followed by behavioral effects.
Previous meta-analyses have consistently demonstrated the phenomenon of weight regain following the discontinuation of GLP-1 receptor agonists or other anti-obesity medications. One study systematically quantified the rebound of body habitus after cessation of GLP-1 receptor agonist therapy, showing that approximately 50–60% of the lost weight was regained within one year. Similarly, Wu et al. delineated the short-term trajectory of body weight after withdrawal of various anti-obesity medications, identifying a marked weight regain that began as early as 8 weeks and plateaued after 20–26 weeks. Both studies established the pattern of post-treatment weight rebound, with a primary focus on anthropometric outcomes. The present meta-analysis extends these findings by quantifying the concurrent metabolic deterioration, including elevations in HbA1c, blood pressure, and lipid parameters, providing a more clinically comprehensive perspective on post-withdrawal physiology.
Among GLP-1RAs, discontinuation of semaglutide is associated with a more pronounced rebound in body weight and systolic blood pressure compared to liraglutide. This phenomenon may be attributed to several pharmacological and physiological factors. Long-acting agents, such as semaglutide, exert weaker effects on gastric motility inhibition but stronger central appetite suppression, which may heighten the risk of neural adaptation and subsequent relapse upon withdrawal. This risk appears most prominent with semaglutide, given its extended half-life of 1 week, compared to liraglutide (∼13 h). The sustained receptor activation seen with long-acting GLP-1RAs like semaglutide may induce counter-regulatory responses, including enhanced orexigenic signaling and sympathetic nervous system reactivation, which together promote weight regain upon cessation of therapy. Additionally, semaglutide's superior on-treatment efficacy may predispose patients to more substantial relapse upon discontinuation, as greater initial benefits are often followed by more pronounced rebound effects.
In patients with type 2 diabetes, discontinuation of GLP-1RAs was associated with significant rebound in body weight, systolic blood pressure, and glycemic control, as reflected by increased HbA1c levels. However, the magnitude of weight rebound appeared less pronounced compared to individuals with obesity. This may be partly due to less pronounced weight loss during treatment in the type 2 diabetes population, coupled with overlapping characteristics, as many type 2 diabetes patients also meet obesity criteria. Interestingly, FPG levels did not show a significant rebound. This may reflect the influence of concurrent glucose-lowering therapies, dietary regulation, or regular physical activity in trial participants, all of which can contribute to short-term glycemic stability. However, the observed rebound in HbA1c levels suggests a deterioration in long-term glycemic control, indicating that the withdrawal of GLP-1RA still impacts overall metabolic homeostasis despite stable FPG. These findings underscore the importance of recognizing that glucose-lowering therapies beyond GLP-1RAs can meaningfully contribute to glycemic control. Several observational studies have shown that using these agents either in combination with, or as follow-up to, GLP-1RA therapy helps mitigate rebound effects and sustain metabolic improvements, particularly when transitioning off GLP-1RAs. Although two included RCTs investigated GLP-1RA discontinuation in type 1 diabetes, these agents are not approved for this indication. Accordingly, findings from those trials should be interpreted as exploratory, and more data are needed if further application is considered.
Recent evidence suggests that abrupt weight regain after discontinuation of GLP-1 receptor agonists may precipitate complications such as idiopathic intracranial hypertension. Dual GIP/GLP-1 receptor agonists have likewise shown potential benefits in IIH management, possibly through reduced CSF secretion and intracranial pressure. Meta-analyses confirm that GLP-1 and dual GIP/GLP-1 receptor agonists significantly lower major adverse cardiovascular events (MACE) and mortality during active therapy. However, the consequences of treatment withdrawal remain largely uncharacterized, underscoring the need for longitudinal studies on potential rebound risks. Given these results, systematic approaches are necessary for reducing the rebound effects that follow GLP-1RA discontinuation. Individualized long-term maintenance plans or extended therapy may be necessary for patients who experience significant weight loss while on GLP-1RA treatment, especially when using long-acting medications like semaglutide. Continued follow-up to monitor blood pressure, weight, and glycemia is recommended to facilitate early detection and timely intervention in the event of metabolic relapse. In patients with diabetes, continuing background glucose-lowering medications is particularly important to sustain glycemic control after discontinuation of GLP-1RA.
Some limitations should be noted. First, the analysis did not account for lifestyle factors, such as exercise or dietary interventions, despite their potential influence on outcomes. For example, the S-LiTE trial included a strict 8-week low-calorie diet prior to randomization, resulting in substantial initial weight loss (13.1 kg), which may have exaggerated rebound effects and limited generalizability to routine clinical settings. Second, our reliance on study-level data precluded exploration of individual-level modifiers such as age, sex, baseline BMI, or comorbidities, which may affect susceptibility to metabolic rebound. Third, the availability of rebound data was limited. Although our screening process identified hundreds of trials reporting efficacy outcomes during active treatment, only a small subset included follow-up data after discontinuation of GLP-1RA. There is a need for future trials to extend monitoring beyond the treatment phase, not only for safety surveillance but also to inform long-term strategies for managing obesity and diabetes. Specifically, studies should examine whether continued use of alternative glucose-lowering agents or implementation of structured lifestyle interventions can attenuate rebound effects.
Considerable heterogeneity was observed across multiple primary and subgroup outcomes, likely reflecting differences in study design, GLP-1RA agents, and treatment durations. However, such variability is common in meta-analyses involving diverse clinical settings, and the observed heterogeneity can be largely explained by subgroup variables, with plausible biological mechanisms. Significant differences in weight regain and metabolic rebound were observed based on the GLP-1RA agent used and follow-up duration, aligning with the biological properties of the drugs. In addition, leave-one-out sensitivity analyses did not reveal major discrepancies in the effect estimates, confirming the robustness of our findings. The outliers can be explained as follows: In Barnett 2007, no rebound in FPG and HbA1c occurred after GLP-1RA cessation because patients continued with insulin glargine, which stabilized glucose levels. In other cases, the rebound reflects the patients' high initial response returning to baseline. In SURMOUNT-4, the heart rate rebound after tirzepatide cessation is due to the loss of sinus node stimulation by the drug. In STEP-4, the rebound in HDL-C after cessation is attributed to the lipid-lowering effect of semaglutide.
In conclusion, our meta-analysis reveals that discontinuation of GLP-1 receptor agonists leads to consistent and clinically meaningful rebound effects across multiple cardiometabolic parameters, including body weight, waist circumference, glycemic control, and blood pressure. These findings underscore the importance of long-term treatment planning and structured transition strategies to mitigate relapse after therapy withdrawal. Given the increasing real-world use of GLP-1RAs for both diabetes and obesity, from a clinical standpoint, physicians should anticipate metabolic rebound after discontinuation and incorporate structured transition strategies such as gradual dose tapering, concurrent lifestyle modification, and regular metabolic monitoring post-cessation to minimize relapse. Future studies should also explore evidence-based tapering protocols, behavioral maintenance interventions, and post-discontinuation pharmacologic strategies to sustain the therapeutic benefits achieved during active treatment.