GLP-1 Discontinuation Results in Significant Weight Regain, With Michael Weintraub, MD

Within a year of discontinuing GLP-1 therapy, ≥50% of patients with overweight/obesity or type 2 diabetes mellitus (T2DM) regained weight, with patients who initially lost the most weight regaining the most, according to a recent study.1

Previous trials have established that patients must continue GLP-1 therapy for the medication’s effects to be sustained. However, ongoing use has been shown to decrease significantly after 1 year in patients with T2DM. This has been associated with inequities in access and adherence to effective treatments, which exacerbate disparities in patients with obesity or overweight.2

This descriptive retrospective cohort study of US adults was conducted by Michael Weintraub, MD, assistant professor of medicine in the division of endocrinology at NYU Langone Health, and colleagues, and included patients who filed GLP-1 prescriptions and subsequently discontinued usage between 2010 and 2024. Patients with and without T2DM were combined with GLP-1 prescriptions for all indications.1

A total of 17,935 patients were enrolled, with ≥90 days of claims enrollment before and ≥365 days of claims enrollment after the first GLP-1 prescription fill, a recorded weight value within 90 days before and including first fill, recorded weight values within 60 days before/after and ≤1 year after GLP-1 discontinuation, and ≥5% weight loss at discontinuation.1

At the time of discontinuation, Weintraub and colleagues saw a mean weight loss of 10.1% (standard deviation [SD], 4.8%; 10.9 kg, SD, 5.9 kg). During the monitored year post-discontinuation, based onthe latest weight measurements, 58.4% of patients regained any amount of weight, 34.4% maintained their weight or continued to lose ≤10% of their weight at discontinuation, and 7.2% continued to lose an additional ≥10% of their discontinuation weight.1

The proportion of patients with weight regain increased with greater weight loss between the first prescription fill and discontinuation: 56.1% regained weight among those with 5-<10% initial weight loss, 61.5% among those with 10-<15% initial weight loss, 62.3% among those with 15-<20% weight loss, and 63.8% among those with ≥20% initial weight loss. Relative and absolute weight gain were also substantially higher among patients with more initial weight loss.1

To address these new data, the editorial team at HCPLive spoke with Weintraub in the following Q&A:

HCPLive: The study required ≥5% weight loss at discontinuation. What was the rationale for that threshold, and how might the findings differ if all discontinuers were included?

Weintraub: Weight loss of ≥5% is what is considered a clinically meaningful response. Conditions such as hypertension, hyperlipidemia, and prediabetes all improve with weight loss of ≥5%. This is a common threshold that we consider a medication is effective at attaining weight loss. In fact, 5% is what the US Food and Drug Administration (FDA) requires for a drug to be considered an obesity treatment.

HCPLive: One of the more striking findings is that patients who lost the most weight were the most likely to regain it. How do you interpret that gradient biologically, behaviorally, or both?

Weintraub: This is likely a biological response – a return to the state prior to the GLP-1 medicine being initiated. These medications act on the appetite centers of the brain to decrease our food intake. A common theory on how this operates is the “body weight set point” theory – our brain has a predetermined body weight set point. If we lose weight intentionally, our brain doesn’t know this weight loss was intentional, and it fights for us to regain the weight to return to this body weight set point. I believe that GLP-1 medications essentially lower that body weight set point, and we lose weight until we reach this new body weight set point – this is why our weight loss plateaus. The way anyone responds to any individual medication is different – the degree to which this body weight set point changes is different for each person, hence why some patients lose a lot of weight and others may lose none at all. However, once someone stops the medication, I believe their body weight set point returns to what it was prior, in most scenarios.

HCPLive: Given that GLP-1 discontinuation often leads to weight regain, how should clinicians counsel patients at therapy initiation about expectations for long-term treatment?

Weintraub: In my clinic, I remind patients that obesity is a chronic disease that will require chronic treatment, which could change over time. It could be one medication now, a lower dose along with increased lifestyle modifications, or even bariatric surgery in the future. The important thing to recognize and communicate is that, without some combination of long-term intervention, patients will experience weight recurrence.

HCPLive: Your findings highlight an unmet need for persistence strategies. What types of interventions do you think hold the most promise for improving long-term adherence?

Weintraub: There is no one-size-fits-all approach – everyone is different, so a tailored approach to each person is needed. This is why it is critical for a patient to receive regular guidance and care by a team of experienced medical providers – a physician, a dietician, et cetera. In 1 patient, a medication that has fewer gastrointestinal side effects may be more tolerable in the long term. In another patient, a medication with a less frequent administration may be better for long-term success. Each person is different, and a personalized treatment plan is needed.

HCPLive: Do you believe that the newer, more potent incretin combinations, such as GLP-1/GIP agonists, will show similar patterns of regain upon discontinuation, or do you hypothesize differences?

Weintraub: I believe the GLP-1/GIP agonist tirzepatide behaves the same as GLP-1 agonists, both in clinical trials and in our real-world analysis. Regarding whether other novel incretin-based medications will behave the same way, I eagerly await future study results.

References

1. Chang E, Almandoz J, Weintraub M, et al. Weight Change After GLP-1 Discontinuation in US Patients Living With Overweight/Obesity or Diabetes. Oral Abstracts. Obesity. 2025;33(S2):6-70. doi:10.1002/oby.70102

2. 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