This pilot randomized trial will assess the impact of 12 weeks of semaglutide administration (vs placebo) on changes in: (i) tobacco use and related factors (nicotine craving, withdrawal, motivation to quit, etc.) and (ii) biological biomarkers of health (e.g., epigenetics, glucose variability via continuous glucose monitoring [CGM], etc.) in adult smokers with obesity (n = 40). We will integrate molecular biology procedures (e.g., epigenetics) to maximize internal validity with real-world smartphone-based ecological momentary assessment (EMA) surveys to maximize external validity

Inclusion criteria :

1. Aged 18-65;
2. report daily use of >2 cigarettes per day (CPD), as this is a sufficient threshold for detecting tobacco use disorder, per MPI Oliver's published work57;
3. meet criteria for obesity (BMI ≥30 kg/m2); and
4. no immediate desire to quit tobacco use (using criteria form the clinical practice guidelines for treating tobacco dependence)

Exclusion criteria:

1. Severe psychiatric disturbance precluding successful completion of the study, defined as

   a. Ever schizophrenia, schizoaffective disorder, or bipolar disorder (assessed at the screener and again at baseline); b. Psychiatric hospitalization in the past year (assessed at the screener and again at baseline); c. Suicidal ideation in the past month or any past year suicide attempt (assessed at baseline) i. Suicidal ideation determined by the Ask Suicide Screening Questions (ASQ) Question 1-3 ii. Any suicide attempts in the past year (ASQ 4) iii. Suicidal intent and plan (ASQ 5) iv. PHQ-9 score of 20 or higher, indicating severe depression or PHQ-9 score of 15 or higher if participant also indicates worsening of symptoms in the past 3 months.

   v. Worsening symptoms of depression or anxiety in the past 3-months (as determined by Medical History Questionnaire).

2. personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome, and personal history of pancreatitis, type I or type II diabetes, diabetic retinopathy, or gastroparesis;

3. current use of nicotine replacement therapy or other quit smoking medication;

4. history of bariatric surgery;

5. Current or past 6-month use of a GLP-1 agonist or any other weight-lowering/anti-obesity or glucose-lowering medications. These include (but are not limited to: sulfonylurea, insulin, metformin, thiazolidinediones (TZD), dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or GLP-1 analogs.

6. Clinical labs out of range/unacceptable:

   1. creatinine ≥ 2 mg/dL, eGFR ≤ 60 mL/min/1.73 m2,
   2. triglycerides> 500 mg/dl,
   3. ALP > 4x the upper normal limit,
   4. abnormal blood lipase levels,
   5. other substantially abnormal clinical lab values as determined by the Study Practitioner
   6. A1C 6.5% or higher
   7. Glucose >126 mL fasting or >200mg/dL random
   8. Alanine aminotransferase (ALT) >3x upper normal limit

7. History of significant gastrointestinal disorder, including inflammatory bowel disease or gastrointestinal malignancy (celiac disease is accepted if in remission), diverticular disease, severe gastroparesis, diagnosis of mega-rectum or colon, congenital anorectal malformation, or clinically significant rectocele, intestinal or colonic obstruction, or suspected intestinal obstruction, intestinal resection (with an exception for appendectomy, cholecystectomy and inguinal hernia repair), pancreatitis, active biliary disease

8. Any other reason or clinical condition that the investigators judge would interfere with study participation and/or be unsafe for a possible subject.

9. Known or suspected allergy to semaglutide, any of the product components, or any other GLP-1 analogue.

This is a small-scale feasibility study with very limited resources to manage data sharing and support efforts by other investigators.

Participants and investigators are blind to the intervention condition