Impact of Semaglutide Withdrawal on Cardiometabolic Profile and Physiology of Energy Balance: Recovery Effects After Semaglutide Termination (REST)

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.

Study Overview

• Status: Recruiting
• Conditions: Appetite Regulation; Weight Change; Obesity (Disorder); Blood Pressure Monitoring
• Intervention / Treatment: Drug: Gradual dose reduction of semaglutide; Drug: Abrupt cessation of semaglutide

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 Type: Interventional
• Enrollment (Estimated): 98
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Caroline K Kramer, MD PhD; Phone Number: +1 4165864800 ext 7628; Email: caroline.kramer@sinaihealth.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • Recruiting
      • Leadership Sinai Centre for Diabetes
      • Contact: Caroline K Kramer, MD PhD; Phone Number: +14165864800 ext 7628; Email: caroline.kramer@sinaihealth.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gradual dose reduction of semaglutide; Participants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16	Drug: Gradual dose reduction of semaglutide; Pparticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16
Active Comparator: Cessation of semaglutide; Participants will discontinue treatment at once at week 16	Drug: Abrupt cessation of semaglutide; Cessation of semaglutide at 16-weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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)	32 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in body mass index (BMI)	Changes in BMI [calculated as weight / height2 (in kg/m2)] between baseline visit 1 (semaglutide discontinuation) and 5 (16-weeks after complete semaglutide withdrawal) will be compared between the study groups	32 weeks
Changes in waist circumference	Changes in waist circumference between baseline visit 1 (semaglutide discontinuation) and 5 (16-weeks after complete semaglutide withdrawal) will be compared between the study groups	32 weeks

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: Heart and Stroke Foundation of Canada

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: December 15, 2025
• First Posted (Actual): December 19, 2025

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 9, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Interventional
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Body Weight Changes
• Other Study ID Numbers: REB#1360

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No