Study design

We propose an open-label, parallel-arm, randomized controlled trial designed to evaluate the impact of semaglutide discontinuation strategies on weight and cardiometabolic outcomes. The total study duration will be 32 weeks, including a 16-week treatment discontinuation phase followed by a post-discontinuation follow-up period (Figs 1 and 2).

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Fig 1. Participant timeline: Schedule of enrollment, interventions, and assessments.

https://doi.org/10.1371/journal.pone.0354237.g001

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Fig 2. Schematic of study design: randomized controlled trial to evaluate the impact of semaglutide withdrawal (gradual dose reduction versus immediate treatment cessation) on weight changes and cardiometabolic outcomes.

https://doi.org/10.1371/journal.pone.0354237.g002

Participants

Men and women aged 18–75 years with obesity, or overweight with adiposity-related complications, will be eligible for inclusion. Participants will be required to be receiving weekly subcutaneous semaglutide at a minimum dose of 1 mg, to have achieved at least 10% weight reduction from pre-treatment body weight, and to have demonstrated stable weight over the preceding 12 weeks. Individuals with preexisting cardiovascular disease, type 2 diabetes, pregnancy, prior bariatric surgery, eating disorders, or significant renal, hepatic, or malignant disease will not be considered eligible (Table 1).

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Table 1. Inclusion and exclusion criteria.

https://doi.org/10.1371/journal.pone.0354237.t001

Randomization and interventions

Participants will be randomized in a 1:1 ratio using a random number generator to one of two semaglutide discontinuation strategies: (i) immediate cessation, in which participants will continue their current dose for 16 weeks followed by complete discontinuation, or (ii) gradual dose reduction, in which the semaglutide dosage will be reduced by 25% every 4 weeks until complete discontinuation at week 16. All participants will receive standard lifestyle recommendations, including physical activity, portion control, and self-monitoring of weight.

Follow-up and assessments

Participants will undergo study visits at baseline, 16 weeks, and 32 weeks, with interim phone assessments. Measurements will include anthropometry, fasting biochemical analyses, questionnaires assessing eating behavior, and 24-hour ambulatory blood pressure monitoring. Specifically, biochemistry will include fasting glucose, hemoglobin A1c, lipid profile, C-reactive protein, complete blood count, electrolytes, creatinine and liver enzymes. Control of Eating and appetite questionnaires will be completed to evaluate eating pattern. Nutritional intake will be assessed by a validated automated 24-hour self-administered dietary tool to be completed on-line during the in-person study visits (https://asa24.nih.gov/demo/) [18]. Once the participant completed the food record the data which is de-identified, the information will be downloaded by the research coordinator and kept at Sinai server. 24-h ambulatory BP monitoring (ABPM) will be obtained by oscillometry (Spacelabs Healthcare device with calibration certification), with a 30- min interval in the daytime and 60-min interval in the nighttime period. ABPM will be performed on an ordinary workday, and participants will be advised to maintain their usual daily activities. This monitoring enables the recording of the means of 24-h, daytime, and nighttime systolic and diastolic BP as well as systolic and diastolic BP loads, pulse pressure, and the overnight dipping pattern. It also enables the diagnosis of hypertension, white coat hypertension, and masked hypertension. A standardized meal test will enable assessment of the post-prandial response of hormones involved in appetite regulation (including ghrelin that is a secondary outcome). After a minimum of 8-hour overnight fast, participants will be provided with a standard breakfast (commercially available shake) containing ~500–600 kcal, with approximately 51% of the energy from carbohydrate, 33% from fat, and 16% from protein. Blood samples will be collected at fasting and at 30, 60, 90, 120, and 150 minutes after the meal. Frozen samples will be obtained for the future assessment of satiety hormones, emerging cardio-metabolic risk factors, biomarkers, proteomics and metabolomics relevant to the current research question. These samples will be de-identified and kept at a -80C freezer at Lunenfeld Taunenbaum Research Institute under the Principal Investigator laboratory. In case of a later consent withdrawal, samples will be disposed according to the standards of our institution. Visual analogue scales will be used to evaluate appetite and desire to eat at each timepoint [19].

Outcomes

The primary outcome will be the difference in percentage change in body weight between baseline (treatment discontinuation) and 16 weeks after complete semaglutide withdrawal. Secondary outcomes will include differences in 24-hour systolic blood pressure and fasting ghrelin levels at 16 weeks after discontinuation. Additional outcomes will include other anthropometric measures, energy balance hormones, and blood pressure regulation parameters (Table 2).

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Table 2. Primary and secondary outcomes.

https://doi.org/10.1371/journal.pone.0354237.t002

Sample size and statistical analysis

A total sample size of 98 participants is estimated to provide 80% power to detect a 3% difference in weight change between groups, accounting for a 10% loss to follow-up. Comparisons between groups will be performed using Student’s t test. Longitudinal changes in body weight will be evaluated using generalized estimating equation models to assess treatment effects, time effects, and treatment-by-time interactions. Statistical analyses will be conducted after completion of all study visits, with no interim analysis planned.

Setting and recruitment

This trial will take place at a single academic center, Mount Sinai Hospital (MSH) in Toronto, Canada. It has received institutional research ethics and board approval (#REB 1360) and all participants will provide informed consent form. We will conduct recruitment by contacting eligible participants at MSH, recruiting through nearby community physicians’ offices, and advertising with social media. Initial contact with interested participants will be made by one of the patient’s healthcare providers. Following the first interaction, the individuals will then be contacted by our research coordinator to determine eligibility. Potential participants will be emailed a consent form and provided with as much time as needed to review and decide on whether or not they wish to participate. This study has just started recruitment on 01/March/2026 and has estimated completion date of recruitment and follow up (data collection) of 31/July/2028 with completion of data analysis and reporting of results expected for 2030.

Knowledge dissemination

We will work with patient partners to ensure that the research results are communicated in a manner that is easily accessible to the patients’ community. For researchers, we plan to make presentations at the American Diabetes Association (ADA) and Diabetes Canada annual meetings as well as publish scientific papers. Patients will be informed about our findings at the end of the study through a newsletter sent out to all participants. Lastly, the general public will be informed of our findings through forms of media such as newspaper coverage, online articles, and television outlets.

No datasets were generated or analyzed during the current study protocol. Data will be made available upon study completion.

Future perspective

This randomized controlled trial is designed to evaluate whether a gradual dose reduction of semaglutide prior to discontinuation is associated with improved weight maintenance and cardiometabolic outcomes compared to immediate cessation. Based on existing evidence, it is anticipated that participants undergoing immediate treatment cessation will experience significant weight regain, consistent with previous trials demonstrating that a substantial proportion of lost weight is regained following withdrawal of pharmacological therapy [11,12]. In contrast, gradual dose reduction may attenuate this effect by allowing physiological adaptation in energy balance regulation.

It is expected that differences in body weight change between the study groups will emerge within 12–16 weeks following treatment discontinuation, a period during which the steepest rebound in weight has previously been observed. In addition to weight outcomes, gradual dose reduction is hypothesized to result in more favorable cardiometabolic profiles, including lower 24-hour systolic blood pressure and improved regulation of appetite-related hormones such as ghrelin. These effects may reflect a reduced compensatory response in appetite stimulation and energy conservation that typically follows rapid weight loss or abrupt cessation of therapy [17,20–22].

The findings of this study will address an important gap in the literature, as previous trials have primarily focused on continued treatment versus abrupt discontinuation, without evaluating alternative discontinuation strategies. Importantly, the high real-world rates of treatment discontinuation highlight the clinical relevance of identifying strategies that preserve therapeutic benefits after stopping medication [22]. This study has important implications for clinical practice and future research. If gradual dose reduction is shown to mitigate weight regain and cardiometabolic deterioration, it may represent a pragmatic and lower-cost approach to long-term obesity management. This would be particularly relevant for individuals facing financial barriers or limited access to long-term pharmacotherapy. Additionally, these findings could inform the design of larger trials aimed at optimizing treatment duration and discontinuation strategies for incretin-based therapies.