Switching to Oral Weight Management Pharmacotherapy to Prevent Weight Regain After GLP-1 Therapy Discontinuation

Inclusion criteria

• Age 18-80 years at screening
• History of BMI ≥30 kg/m²
• Current or recent (within 8 weeks) treatment with injectable semaglutide, tirzepatide, or similar GLP-1 based medication
• Achieved ≥10% body weight loss since initiation of injectable semaglutide, tirzepatide or similar GLP-1 based medication
• Willing to participate in the study after reviewing study infographic and confirming understanding of randomization and study procedures
• Ability to understand and the willingness to sign a written informed consent document
• Residence in Massachusetts

Exclusion criteria

• Current type 2 diabetes mellitus
• Recent or planned surgical obesity treatment (bariatric surgery >1 year prior to GLP-1 initiation allowed)
• Pregnancy, intent to become pregnant, or current breastfeeding (participants of childbearing potential must have a negative pregnancy test at baseline)
• History of pancreatitis
• History of transplanted organ (corneal transplants permitted) or awaiting organ transplant
• Obesity induced by endocrinologic disorders (e.g., Cushing syndrome) or diagnosed monogenic/syndromic obesity (e.g., MC4R deficiency, Prader-Willi syndrome)
• History of significant active or unstable major depressive disorder or other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder, serious mood or anxiety disorder) within the past 2 years
• Any history of a suicide attempt
• Systemic glucocorticoid therapy >2 weeks within the prior 3 months, or anticipated need within the next 12 months
• Use of medications known to cause significant weight gain (e.g., olanzapine, lithium) within the last 3 months.
• Quit using nicotine-containing products less than 6 months prior to baseline visit or intention to quit use in the next year
• Current use strong CYP3A4 inducer medications (which may include: phenytoin, carbamazepine, phenobarbital, primidone, lumacaftor, midostaurin, and pentobarbital).
• Use of prescription or over-the-counter weight loss medications within the last 3 months, other than semaglutide, tirzepatide, or other injectable GLP-1 medication
• Chronic kidney disease stage 3b or lower (eGFR <45 mL/min/1.73m²)
• Acute hepatitis or liver failure/cirrhosis
• Known contraindications to phentermine:

• History of coronary artery, cerebrovascular or peripheral arterial disease including myocardial infarction, unstable angina, revascularization, stroke/TIA, carotid intervention, claudication
• Poorly-controlled blood pressure (>149/94) or elevated heart rate (>110 bpm)
• History of cardiac arrhythmia
• History of valvular heart disease
• Congestive heart failure (any history or current)
• Active / currently-treated hyperthyroidism (thyroid function screening required if pulse>100)
• History of glaucoma or been told by an ophthalmologist that you are at high risk for glaucoma
• Heavy alcohol use within the last 6 months (men: more than 4 drinks on any day or more than 14 drinks per week; women: more than 3 drinks on any day or more than 7 drinks per week)
• History of substance use disorder or active use of illicit substances within the last 12 months. Tetrahydrocannabinol (THC)-containing products will not be considered an illicit substance. (e.g., uncontrolled hypertension, active/unstable cardiovascular disease, arrhythmia, hyperthyroidism [thyroid function screening required if pulse>100], glaucoma, history of substance use disorder

• Use of any stimulant medications. 17. Known contraindication to orforglipron (e.g., personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2).

• Any condition (e.g., drug or alcohol abuse, diagnosed eating disorder, other psychiatric disorder) that in the investigator's opinion may preclude protocol compliance