Data from clinical trials of GLP-1 agonists indicate that patients typically regain weight after discontinuing these medications, reinforcing the understanding of obesity as a chronic condition requiring ongoing management.
Weight Regain Evident in Clinical Trials
Several clinical trials have demonstrated weight regain following the cessation of GLP-1 drugs. The STEP 1 trial extension, involving weekly semaglutide 2.4 mg (Wegovy) alongside lifestyle interventions, revealed that participants regained approximately two-thirds of their lost weight within a year after discontinuing the drug. Specifically, in the initial phase of the trial, participants on semaglutide experienced a mean weight loss of 14.9% compared to 2.4% with placebo over 68 weeks. However, during the extension phase, those who stopped semaglutide regained 11.6 percentage points of weight, while the placebo group regained only 1.9 percentage points, resulting in net weight losses of 5.6% and 0.1%, respectively, at 120 weeks.
John Wilding, DM, of Aintree University Hospital, noted that the findings align with expectations for treatments of long-term conditions, such as high cholesterol or blood pressure, where medication cessation typically leads to a reversal of benefits.
The STEP 4 trial further examined semaglutide withdrawal in adults with overweight or obesity but without diabetes. Participants who initially experienced a mean weight loss of 10.6% after 20 weeks on semaglutide were randomized to either continue the maintenance dose or switch to placebo, while maintaining lifestyle interventions. Those who remained on semaglutide continued to lose weight, averaging an additional 7.9%, whereas those switched to placebo regained an average of 6.9% of their lost weight.
The SURMOUNT-4 trial investigated tirzepatide (Zepbound), a combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist. After 36 weeks on tirzepatide, patients achieved a mean weight loss of 20.9%. Upon randomization to either continue tirzepatide or switch to placebo, those continuing treatment experienced further weight loss, while those on placebo regained weight, resulting in mean weight losses of 25.3% and 9.9%, respectively, at 88 weeks.
Robert Kushner, MD, of Northwestern University Feinberg School of Medicine, highlighted the significance of these trials, emphasizing that participants were blindly randomized to either continue or discontinue the medication. He noted that those who stopped the medication, despite feeling optimistic and participating in regular counseling, still regained weight, underscoring the biological underpinnings of obesity and the importance of medication.
Challenges of Long-Term GLP-1 Agonist Use
Experts acknowledge challenges associated with long-term GLP-1 agonist use, including logistical considerations such as medication access during travel and prescription refills when moving. Tolerability can also be an issue, with gastrointestinal side effects commonly reported. Switching between GLP-1 drugs may improve tolerability for some patients. Careful titration is crucial to prevent rapid weight loss, which can lead to side effects, muscle mass loss, or gallstones. Additionally, discontinuing GLP-1 agonists can have mental health implications, as the drugs affect brain mechanisms that regulate weight.
Nate Wood, MD, of Yale School of Medicine, noted the potential mental health toll when stopping GLP-1 drugs, stating that the return of cravings can be "tragic and hard for patients to deal with."
Strategies for Weight Loss Maintenance
Currently, limited data exist on strategies to mitigate weight regain after stopping GLP-1 drugs. Clinicians are encouraged to individualize patient care, considering dose tapering, intermittent therapy, alternative medications, or significant lifestyle changes. Kushner advises against abruptly stopping medication, based on evidence from extension trials like STEP 4 and SURMOUNT-4. He suggests that managing patients who want to stop GLP-1 drugs falls under the "art of medicine," given the lack of definitive data. Further research, including randomized controlled trials and case studies, is needed to guide clinical decisions.
Kushner advises patients who have successfully lost weight on GLP-1 drugs to maintain regular contact with their doctors, emphasizing that obesity is not a condition that can be considered "cured."
