This study will compare the effect of orforglipron and phentermine on weight maintenance.
Inclusion Criteria:
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:
16. 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).
18. Any condition (e.g., drug or alcohol abuse, diagnosed eating disorder, other psychiatric disorder) that in the investigator's opinion may preclude protocol compliance
dwexler@mgh.harvard.edu617-726-8767
Phentermine
Orforglipron
skanbour@mgh.harvard.edu617-726-8767
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