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

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.

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