GLP-1 receptor agonists (GLP-1RAs) such as semaglutide and tirzepatide have transformed obesity care and weight management, delivering unprecedented levels of weight loss in real-world practice. Several studies have demonstrated reversal of weight loss and other cardiometabolic benefits after patients discontinue GLP-1RAs. However, it is not clear whether this reversal is universal or if there are subsets of patients who are more likely to experience continued benefit after their therapeutic exposure. This question has recently been further complicated by the trend for patients to obtain GLP-1RA prescriptions  from other sources such as online providers or medical spas (source). Thus, at the intersection of the patient and clinician experience, it is important to better understand patient trajectories following the last GLP-1RA prescription by a primary care or specialist physician.  

Using large-scale longitudinal real-world data on the nSights platform, we analyzed weight trajectories before and after the last GLP-1RA prescription to directly address this question. Specifically, among patients who had at least three GLP-1RA prescriptions, we assessed the average percent change in weight in the year leading up to the date of their last prescription (defined as month 0) and in the six months following their last prescription (post-cessation). 

Separate analyses were performed for tirzepatide (Figure 1A) and semaglutide (Figure 1B), enabling a consistent comparison across agents. Patients were only included if they had a prescriptions for one of these medications but not another GLP-1RA, to limit potential confounding of treatment switching effects in the post-last prescription period.

Figure 1A

Figure 1B

What do the weight change trajectories show?

The distribution of average weight change after the last GLP-1RA prescription is approximately a normal distribution with a mean value of 0.29% (median value of 0), indicating that most patients do not experience significant weight gain following their last GLP-1RA prescription (Figure 2).


Figure 2

Patients were grouped retrospectively based on their post-cessation trajectories into two clinically intuitive categories:

> Patients with at least 5% increase in weight in the six months following their last GLP-1RA prescription.

> Patients without at least 5% increase in the weight following their last GLP-1RA prescription (i.e., patients with stable weight or weight loss following their last prescription). 

In both the tirzepatide- and semaglutide-treated cohorts, more than two-thirds of patients fell into the latter category, with either continued weight loss or stable weight after the last prescription. These findings provide important further context to previous reports that discontinuation of  GLP-1RAs typically leads to rapid weight regain.

There is indeed a distinct subset of patients who regain weight after their last GLP-1RA prescription. In these individuals, the average weight curves slope upward within months after the last prescription, reaching several percentage points of regain by the 4 to 6 month time frame. Importantly, this pattern is similar for both semaglutide and tirzepatide, suggesting shared underlying drivers rather than molecule-specific effects.

Potential for Durable Weight Retention After GLP-1 Therapy Discontinuation Despite Prolonged Drug Cessation:
Across both cohorts, discontinuation at day 0 after a full year of continuous therapy shows that, on average, most patients do not experience clinically meaningful weight regain over prolonged follow-up, despite assured non-prescription of GLP-1 therapy for at least the first 6 months post-cessation and continued monitoring out to 18 months. In the semaglutide cohort (N = 2,567; Figure 3B), the majority classified as stable weight or sustained weight loss (N = 1,720; ~67%) maintained a net mean weight reduction of approximately −1% to −2% through 18 months after stopping therapy, while the minority with weight regain (N = 847; ~33%) showed a gradual rebound peaking around +6% to +7% by months 8–12 and stabilizing thereafter. A similar but more pronounced separation is observed with tirzepatide (N = 1,615; Figure 3A), where a larger proportion remained weight stable or continued to lose weight (N = 1,170; ~72%), sustaining a mean reduction of approximately −3% to −4% at 18 months post-cessation, whereas the regain subgroup (N = 445; ~28%) demonstrated a higher mean rebound, reaching approximately +7% to +11% with greater variability over time. Importantly, mean trajectories in both drugs indicate that the dominant population signal favors durable weight retention rather than universal rebound, suggesting that one year of semaglutide or tirzepatide therapy can induce lasting metabolic or behavioral changes that persist well beyond treatment discontinuation for a 6-month period, even under conditions of prolonged GLP1RA absence.

Figure 3A

Figure 3B

Important caveats

There are several important caveats to consider when interpreting these real-world findings, some of which are outlined below. Further studies are merited to delineate the relative impact of each of these factors on the observed trends.

> The lack of GLP-1RA prescriptions may not uniformly translate to treatment cessation.
The prescriptions that were available for assessment in this analysis were placed within a network of tertiary clinical centers tied to academic medical centers in the United States through the nference nSights Analytics Platform. There are multiple possible paths that a patient may take with respect to their GLP-1RA therapy following the last documented prescription in these systems, including (1) discontinuation of therapy or (2) continuation of the same or another GLP-1RA, prescribed by another prescriber (including via online services, medical spas, etc). This uncertainty limits our ability to comment on weight patterns after true treatment cessation in this analysis, however it more accurately reflects the real-world trajectories that follow the cessation of prescriptions by primary care or specialist providers. Additional linkage and validation to confirm treatment status after the last prescriptions will enable stratified analyses in the future.

> There is likely variability in treatment adherence, even prior to the last prescription. 

To enrich for patients who were more likely to have had true therapy exposure, we required patients to have at least three GLP-1RA prescriptions in the participating health systems for inclusion in the study. However, it is possible that even these patients missed doses or stopped taking the medication before the last documented prescription. 

> Dosage and treatment duration matter.
We have not yet fully accounted for cumulative dose exposure, dose escalation patterns, or duration on therapy. These factors may strongly influence outcomes, both while patients are taking and after they discontinue these medications.

> Comorbidities must be examined.
Conditions such as type 2 diabetes, cardiovascular disease, depression, or endocrine disorders may meaningfully modify both weight loss and regain trajectories. It will also be valuable to explore whether there are certain pre-existing comorbidities that can help to predict which trajectory a patient will follow after their GLP-1RA prescriptions are discontinued.

> Lifestyle factors remain unmeasured.
Physical activity, dietary factors, and behavioral interventions could plausibly explain sustained weight loss in a subset of patients and must be incorporated into future analyses.

Why this matters

These findings have important implications and can help provide clarity to both patients and clinicians with respect to what happens in the real world after a primary care or specialist physician stops prescribing a GLP-1RA. 

> Clinical expectations may need recalibration. The prevalence of weight regain immediately following GLP-1RA discontinuation may be lower than what has been widely reported, including in patient-facing media. In this analysis of the real-world experience, most patients did not show weight gain after their last prescription in the health center, which may be related to multiple factors as outline above. 

> Biology may outlast pharmacology. Sustained weight loss in many individuals suggests longer-lasting changes in energy balance, appetite regulation, metabolic flexibility, or behavior.

> Post-treatment monitoring deserves more attention. Rather than assuming that weight regain is likely or inevitable, clinicians may be able to stratify patients by risk and tailor follow-up strategies accordingly. Implementation of systems to monitor patient outcomes (including but not limited to weight change) after prescription discontinuation could enable clinicians to proactively intervene (e.g., recommend to re-start therapy, provide referral to dietitian, prescribe exercise programs) in patients who appear to be on a higher risk trajectory.

Conclusions and Future Directions

This analysis provides new insights with respect to weight change outcomes following the discontinuation of GLP-1RA prescriptions by a primary care or specialist provider. The results highlight that while patients with an active GLP-1RA prescription tend to lose significant weight, weight regain is not universally observed after discontinuation of the prescription. In fact, the majority of patients showed stable weight or continued weight loss after their last documented GLP-1RA prescription in the participating health systems. 

This motivates future investigations to perform multimodal monitoring of patients after prescription and/or therapy cessation which integrate biology, behavior, comorbidities, and drug dosing information. Such investigations could have the potential to unlock features that can help to predict patients who are likely to show sustained benefit versus “rebound” of weight and other cardiometabolic parameters.

Understanding who maintains weight loss, and why, could reshape how GLP-1RAs are prescribed, discontinued, and complemented with lifestyle or maintenance strategies.

Bottom line

Weight loss after GLP-1RA therapy does not uniformly reverse after prescriptions are discontinued. In real-world data, a majority of patients maintain or continue their weight loss, while a smaller but important subset experiences weight regain. These findings illustrate the importance of a nuanced and biology-informed view of long-term weight regulation in the era of GLP-1 therapies.

Data source & selection

This study analyzed de-identified EHR data from a network of tertiary clinical centers tied to academic medical centers in the United States through the nference nSights Analytics Platform. nference, in collaboration with academic medical center (AMC) data partners provided the de-identified data for this study. nference has established a secure data environment, hosted by and within each of the AMCs, that house the AMC's de-identified patient data. The provisioning of and access to this data are governed by an expert determination that satisfies the HIPAA Privacy Rule requirements for the de-identification of protected health information. Each AMC’s de-identified data environment is specifically designed and operated to enable access to and analysis of de-identified data without the need for Institutional Review Board (IRB) oversight, approval, or an exemption confirmation. Given these measures, informed consent and IRB review were not required for this study.

Data Availability

This study involves the analysis of de-identified Electronic Health Record (EHR) data via the nference nSights Federated Clinical Analytics Platform (nSights). Data shown and reported in this manuscript were extracted from this environment using an established protocol for data extraction, aimed at preserving patient privacy. The data has been de-identified pursuant to an expert determination in accordance with the HIPAA Privacy Rule. Any data beyond what is reported in the manuscript, including but not limited to the raw EHR data, cannot be shared or released due to the parameters of the expert determination to maintain the data de-identification. Contact the corresponding author for additional details regarding nSights.

Conflict of Interest Statement

The authors are employees of nference, inc., which conducts research collaborations with various biopharmaceutical companies, including AstraZeneca, Eli Lilly and Company, and Novo Nordisk A/S, whose GLP-1 receptor agonist products (exenatide, dulaglutide, tirzepatide, liraglutide, and semaglutide formulations) are included in this study. None of these companies, nor any other nference collaborator, funded, supported, or had any role in the independent study design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit this work for publication. All analyses were conducted by the authors using de-identified electronic health record data. The authors declare no additional competing interests.