Obesity (Disorder)Phase 3RESTNCT07294950
Impact of Semaglutide Withdrawal on Cardiometabolic Profile and Physiology of Energy Balance: Recovery Effects After Semaglutide Termination
A Phase 3 study testing Gradual dose reduction of semaglutide and Abrupt cessation of semaglutide in people with Obesity (Disorder) and Weight Change, run by Mount Sinai Hospital, Canada at 1 site in Canada.
Trial summary
Semaglutide is a medication from the class of drugs called glucagon-like peptide-1 agonists that promote weight loss. There is little clinical data on the best strategy to achieve weight maintenance following weight reduction induced by semaglutide. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Obesity (Disorder), Weight Change, Blood Pressure Monitoring
- What is being tested?
- Gradual dose reduction of semaglutide and Abrupt cessation of semaglutide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 98 participants
- Where
- 1 siteCanada
- Study dates
- 1 Feb 2026to May 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women with previously diagnosed BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 and adiposity-related complications (such as osteoarthritis, nonalcoholic liver disease, sleep apnea, and hypertension) without preexisting cardiovascular disease or type 2 diabetes.
- Age 18 - 75 years inclusive
- Ongoing weight-loss treatment consisting of weekly subcutaneous semaglutide at minimum dose of 1 mg/weekly with documented weight reduction of at least 10% of pre-treatment body weight
- Stable weight over past 12 weeks (less than 5% change in body weight) (self-reported)
- Ability to read and understand English
Who cannot join
- Previously diagnosed cardiovascular disease defined as previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease.
- Currently pregnant or lactating
- Previously diagnosed type 2 diabetes
- Use of any other pharmacological treatment for weight-loss
- Previous surgical treatment for weight loss such as gastric bypass or gastric band
- Any history of eating disorder
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- Renal dysfunction as evidenced by estimated glomerular filtration rate < 25 ml/min by CKD-EPI Creatinine Equation
- New York Heart Association class II-IV heart failure
- Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, or previous liver transplant) or transaminases >2.5X the upper limit of normal
- Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy within the previous 5 years (with the exception of basal cell skin cancer)
- Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2
- Any other factor likely to limit adherence to the study, in the opinion of the investigators
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Leadership Sinai Centre for Diabetes
Toronto, Ontario, M5T 3L9
Caroline K Kramer, MD PhD, +14165864800 ext 7628, caroline.kramer@sinaihealth.ca
About this study
Official title: Impact of Semaglutide Withdrawal on Cardiometabolic Profile and Physiology of Energy Balance: a Randomized Controlled Trial Comparing Gradual Dose Reduction With Immediate Treatment Cessation.
Semaglutide is a medication from the class of drugs called glucagon-like peptide-1 agonists that promote weight loss. There is little clinical data on the best strategy to achieve weight maintenance following weight reduction induced by semaglutide. For people who need to discontinue treatment, it is unknown whether the weight regain, its accompanied health benefits could be ameliorated with a gradual reduction in semaglutide. The investigators will study if a gradual reduction of semaglutide is associated with different heart risk profile and hormones involved in energy regulation as compared to immediate treatment cessation.
Read the detailed description
It is known that semaglutide induces a supra-physiologic agonism of GLP-1 receptors on central nervous system receptors associated with hedonic eating which likely promotes a homeostatic response (i.e. adaptation) related to appetite control. This concept raises the question of whether a gradual de-escalation of GLP-1RA could ameliorate the tendency for weight regain/cardiometabolic deterioration and compensatory changes in energy balance regulation following cessation of treatment.Thus, the investigators propose an open-label, parallel-arm, randomized controlled trial to determine whether a gradual dose reduction in semaglutide prior to complete discontinuation is associated with differential changes in weight and cardiometabolic profile (blood pressure homeostasis and energy balance regulatory hormones) as compared to immediate treatment cessation in individuals living with obesity without pre-existing cardiovascular disease who are receiving semaglutide for weight management.
- Being tested
- Gradual dose reduction of semaglutide, Abrupt cessation of semaglutide
- Keywords
- Randomized controlled trial, Interventional
- Medical subject headings
- Obesity, Body Weight Changes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gradual dose reduction of semaglutideDrug
Pparticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16
Abrupt cessation of semaglutideDrug
Cessation of semaglutide at 16-weeks
| Study group | Role | What they receive |
|---|---|---|
| Gradual dose reduction of semaglutide | Experimental | Participants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16 Receives: Drug: Gradual dose reduction of semaglutide |
| Cessation of semaglutide | Active comparator | Participants will discontinue treatment at once at week 16 Receives: Drug: Abrupt cessation of semaglutide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in changes in body weight between each study group
Differences in body weight change (%) between baseline visit 1 (semaglutide discontinuation) and 5 (16-weeks after complete semaglutide withdrawal) will be compared between the study groups
Measured: 32 weeks
Secondary outcomes (2)
Differences in 24-h systolic BP levels between each study group
Systolic BP will be assessed as the difference in 24-h ambulatory systolic BP between the study groups at visit 5 (16-weeks after complete semaglutide withdrawal)
Measured: 32 weeks
Differences in fasting ghrelin between each study group
Differences in fasting ghrelin between the study groups will be assessed at week 5 (16-weeks after complete semaglutide withdrawal)
Measured: 32 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2025
- Study start1 Feb 2026
- Primary completionSep 2028 (estimated)
- Study completionMay 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Obesity (Disorder)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 98 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mount Sinai Hospital, Canada
- Sponsor type
- University, hospital or other
- Collaborators
- Heart and Stroke Foundation of Canada
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07294950
- Sponsor's protocol ID
- REB#1360
- Acronym
- REST
- Status last verified
- Oct 2025
- First submitted
- 17 Nov 2025
- Last updated
- 11 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Yevusiak T, Weisman A, Retnakaran R, Wharton S, Drucker DJ, Kramer CK. Impact of semaglutide withdrawal on cardiometabolic profile and physiology of energy balance: Recovery effects after semaglutide termination - The REST trial study protocol. PLoS One. 2026 Jul 27;21(7):e0354237. doi: 10.1371/journal.pone.0354237. eCollection 2026.
PubMed 42507673
Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Semaglutide Withdrawal on Cardiometabolic Profile and Physiology of Energy Balance: a Randomized Controlled Trial Comparing Gradual Dose Reduction With Immediate Treatment Cessation.
- ClinicalTrials.gov ID
- NCT07294950
- Acronym / sponsor ID
- REST / REB#1360
- Keywords
- Randomized controlled trial, Interventional
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 98 participants (estimated)
- Lead sponsor
- Mount Sinai Hospital, CanadaUniversity, hospital or other
- Collaborators
- Heart and Stroke Foundation of Canada
- Study start
- 1 Feb 2026 (actual)
- Primary completion
- Sep 2028 (estimated)
- Study completion
- May 2029 (estimated)
- First posted
- 19 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Semaglutide is a medication from the class of drugs called glucagon-like peptide-1 agonists that promote weight loss. There is little clinical data on the best strategy to achieve weight maintenance following weight reduction induced by semaglutide. For people who need to discontinue treatment, it is unknown whether the weight regain, its accompanied health benefits could be ameliorated with a gradual reduction in semaglutide. The investigators will study if a gradual reduction of semaglutide is associated with different heart risk profile and hormones involved in energy regulation as compared to immediate treatment cessation.
Detailed description
It is known that semaglutide induces a supra-physiologic agonism of GLP-1 receptors on central nervous system receptors associated with hedonic eating which likely promotes a homeostatic response (i.e. adaptation) related to appetite control. This concept raises the question of whether a gradual de-escalation of GLP-1RA could ameliorate the tendency for weight regain/cardiometabolic deterioration and compensatory changes in energy balance regulation following cessation of treatment.Thus, the investigators propose an open-label, parallel-arm, randomized controlled trial to determine whether a gradual dose reduction in semaglutide prior to complete discontinuation is associated with differential changes in weight and cardiometabolic profile (blood pressure homeostasis and energy balance regulatory hormones) as compared to immediate treatment cessation in individuals living with obesity without pre-existing cardiovascular disease who are receiving semaglutide for weight management.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Gradual dose reduction of semaglutide | Experimental | Drug: Gradual dose reduction of semaglutideParticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16 |
| Cessation of semaglutide | Active comparator | Drug: Abrupt cessation of semaglutideParticipants will discontinue treatment at once at week 16 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Men and women with previously diagnosed BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 and adiposity-related complications (such as osteoarthritis, nonalcoholic liver disease, sleep apnea, and hypertension) without preexisting cardiovascular disease or type 2 diabetes.
- Age 18 - 75 years inclusive
- Ongoing weight-loss treatment consisting of weekly subcutaneous semaglutide at minimum dose of 1 mg/weekly with documented weight reduction of at least 10% of pre-treatment body weight
- Stable weight over past 12 weeks (less than 5% change in body weight) (self-reported)
- Ability to read and understand English
Key exclusion criteria (12 listed)
- Previously diagnosed cardiovascular disease defined as previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease.
- Currently pregnant or lactating
- Previously diagnosed type 2 diabetes
- Use of any other pharmacological treatment for weight-loss
- Previous surgical treatment for weight loss such as gastric bypass or gastric band
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gradual dose reduction of semaglutidePparticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16 | Drug | Gradual dose reduction of semaglutide |
| Abrupt cessation of semaglutideCessation of semaglutide at 16-weeks | Drug | Cessation of semaglutide |
Primary outcome
Differences in changes in body weight between each study group
Time frame: 32 weeks
Differences in body weight change (%) between baseline visit 1 (semaglutide discontinuation) and 5 (16-weeks after complete semaglutide withdrawal) will be compared between the study groups
2 secondary outcomes
Differences in 24-h systolic BP levels between each study group
Time frame: 32 weeks
Differences in fasting ghrelin between each study group
Time frame: 32 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2026.
- Derived from this study: PubMed 42507673Yevusiak T, Weisman A, Retnakaran R, Wharton S, Drucker DJ, Kramer CK. Impact of semaglutide withdrawal on cardiometabolic profile and physiology of energy balance: Recovery effects after semaglutide termination - The REST trial study protocol. PLoS One. 2026 Jul 27;21(7):e0354237. doi: 10.1371/journal.pone.0354237. eCollection 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Gradual dose reduction of semaglutide and Abrupt cessation of semaglutide in people with Obesity (Disorder) and Weight Change, run by Mount Sinai Hospital, Canada at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Caroline K Kramer, MD PhD (+1 4165864800 ext 7628, caroline.kramer@sinaihealth.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in changes in body weight between each study group (time frame: 32 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07294950, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2026.