This study will evaluate the effect of semaglutide on eating behavior, appetite (hunger/fullness), and food liking in the long-term, as compared to placebo. All participants will receive lifestyle modification (diet and exercise) counseling, and will be prescribed the FDA-approved weight loss medication, semaglutide, or placebo (an inactive saline solution) for 72 weeks.

This trial consists of a single 72-week treatment period during which two studies will be conducted. Study 1 (i.e., long-term treatment trial; weeks 0-60) is a 60-week, single center, double-blinded, randomized controlled, parallel group design trial, and Study 2 (i.e., re-randomized medication withdrawal trial; weeks 60-72) is a separate, 12-week, double-blind, re-randomized medication withdrawal trial.

The long-term treatment trial (Study 1) will randomly assign (in a 3:2 semaglutide:placebo ratio) 120 subjects with a body mass index (BMI) ≥30 kg/m2, or ≥27 kg/m2 with ≥1 obesity-related co-morbidities, to 60 weeks of: 1) placebo with moderate intensity lifestyle intervention (as used in STEP 1); or 2) semaglutide 2.4 mg with the same lifestyle intervention. All subjects will receive 60 weeks of trial product, which will be up-titrated over 16 weeks in those assigned to semaglutide 2.4 mg. They will complete assessments of energy intake, appetite, food reward, mood, symptoms of disordered eating, and anthropomorphic measurements at baseline (week 0) and weeks 20, 40, and 60.

The primary aim in the initial long-term treatment trial will be to compare the long-term effect of semaglutide 2.4 mg vs placebo on ad libitum energy intake during a lunch meal at weeks 20, 40, and 60. Confirmatory secondary aims will test the effect of semaglutide 2.4 mg at weeks 20, 40 and 60 on subjective appetite ratings (both measured during a standardized breakfast in the lab and as experienced more globally over the past week), explicit food reward, as measured with the Power of Food Scale (24), and implicit food reward, as measured with the Leeds Food Preference Task (25, 26). Measures of food cravings, mood, eating disorder symptoms, and self-report measures of eating behavior will be considered supportive secondary endpoints and will provide additional evidence of the medication's safety and efficacy.

Following the completion of Study 1 at week 60, all subjects who complete a week 60 assessment and remain on drug will be enrolled in Study 2. Semaglutide-treated subjects will be re-randomized (in a 1:4 semaglutide:placebo ratio) to receive semaglutide 2.4 mg or placebo for 12 weeks. All subjects originally assigned to placebo will continue with that medication for an additional 12 weeks. Both researchers and subjects will remain blinded to subjects' original and re-randomized (or continued) treatment assignments. The goal of this re-randomized medication withdrawal period will be to compare the 80% of subjects originally assigned to semaglutide 2.4 mg who receive placebo at week 60 (semaglutide-to-placebo group) to the subjects originally randomized to placebo (continuous-placebo group) on all primary and secondary outcome measures at week 72 (after controlling for Study 1 baseline/week 0 values). All subjects will terminate trial product at cumulative week 72 and will return to clinic for a final safety visit at week 76.

Outcome assessments including ad libitum energy intake, subjective measures of appetite, food reward, eating behavior, mood, and eating disorder symptoms will occur at weeks 0, 20, 40, and 60 of Study 1 and at week 12 (72 weeks from original randomization) of the re-randomized treatment period. Measurements of body weight, waist circumference, blood pressure, pulse, and global, past-week appetite and food cravings (COEQ) also will be collected every 4 weeks throughout both treatment studies.

Inclusion Criteria:

1. Men and women who report a desire to lose weight

2. Aged 18-70 years

3. Body mass index [BMI] ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with an obesity-related comorbidity (e.g., treated or untreated hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)

4. Eligible female patients will be:

   • non-pregnant, evidenced by a negative urine pregnancy test
   • non-lactating
   • surgically sterile or postmenopausal, or they will agree to continue to use an accepted method of birth control during the study

5. Subjects must

   • Plan to remain in the Philadelphia area for the next 1.5 years.
   • Ability to provide informed consent before any trial-related activities.

Exclusion Criteria:

1. A diagnosis of type I or II diabetes
2. Hemoglobin A1c (HbA1c) > 6.5%
3. Uncontrolled hypertension (blood pressure ≥ 160/100 mm Hg)
4. Clinically significant hepatic (i.e., liver fibrosis, cirrhosis or confirmed NASH) or renal disease
5. Uncontrolled thyroid disease
6. Experienced a cardiovascular event (e.g., stroke, myocardial infarction) in the last 6 months, congestive heart failure, or heart block greater than first degree
7. A history of acute pancreatitis in the last 6 months
8. Any history of chronic pancreatitis
9. A history of malignancy (other than non-melanoma skin cancer) within the last 5 years
10. A personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2
11. A self-reported change in body weight >5kg (11 lbs) within 90 days before screening
12. Used within the last 6 months medications known to produce weight loss/gain (e.g., medications approved for weight loss, oral steroids, antipsychotic medications) or any GLP-1 receptor agonist.
13. Known or suspected allergy or hypersensitivity to trial medication(s), excipients, or related products
14. The receipt of any investigational drug within 6 months prior to this trial
15. Applicants with current severe major depressive disorder (BDI-II score ≥ 29 or Patient Health Questionnaire-9 [PHQ-9] score > 15) or severe anxiety disorder
16. Applicants with current, active suicidal ideation, and/or a suicide attempt within the past year (such individuals will be referred for psychiatric treatment if they have not previously received it).
17. Any severity of psychotic or bipolar disorder
18. Bulimia nervosa diagnosis within the past 5 years
19. Self-reported alcohol or substance abuse within the past 6 months, including at-risk drinking (current consumption of ≥ 14 alcoholic drinks per week)
20. History of (or plans to receive in the next 1.5 years) bariatric surgery or a weight loss device. (However, the following will be allowed: liposuction or abdominoplasty > 1 year before screening, laparoscopic banding if removed > 1 year before screening, intragastric balloon or aspire assist if removed > 1 year before screening.)
21. Inability to walk 5 blocks or more (comfortably) or engage in another form of aerobic activity.
22. Women who are nursing, pregnant, or planning to become pregnant in the next 1.5 years or are not using adequate contraceptive measures
23. Previous participation in this trial (e.g., randomized but failed to participate)
24. Changes to any chronic medication (type or dosage) within the past 3 months.
25. Food allergy or dietary preference that would prevent the individual from consuming the standard breakfast or ad libitum lunch.

Double-blind