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

NCT ID: NCT07294950

Last Updated: 2025-12-19

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 98 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-01-01
• Study Completion Date: 2029-05-31

Brief 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. 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.

Conditions

Obesity (Disorder); Weight Change; Blood Pressure Monitoring; Appetite Regulation

Keywords

Randomized controlled trial; Interventional

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Gradual dose reduction of semaglutide

Participants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16

Group Type: EXPERIMENTAL

Gradual dose reduction of semaglutide

Intervention Type: DRUG

Pparticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16

Cessation of semaglutide

Participants will discontinue treatment at once at week 16

Group Type: ACTIVE_COMPARATOR

Abrupt cessation of semaglutide

Intervention Type: DRUG

Cessation of semaglutide at 16-weeks

Interventions

Gradual dose reduction of semaglutide

Pparticipants will reduce semaglutide dosage by 25% every 4-weeks until complete treatment cessation at week 16

Intervention Type: DRUG

Abrupt cessation of semaglutide

Cessation of semaglutide at 16-weeks

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Heart and Stroke Foundation of Canada

OTHER

Sponsor Role: collaborator

Mount Sinai Hospital, Canada

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Leadership Sinai Centre for Diabetes

Toronto, Ontario, Canada

Countries

Canada

Central Contacts

Caroline K Kramer, MD PhD

Role: CONTACT

Phone: +1 4165864800 ext 7628

Email: caroline.kramer@sinaihealth.ca

Facility Contacts

Caroline K Kramer, MD PhD

Role: primary

Other Identifiers

REB#1360

Identifier Type: -

Identifier Source: org_study_id