This multi-site clinical trial will generate data on the efficacy of tirzepatide for smoking cessation and associated outcomes (e.g., post-cessation weight gain) in treatment-seeking people who smoke (PWS) with overweight or obesity. A sample of 300 treatment-seeking people who smoke with body mass index of 25 kg/m2 or greater will be recruited from four geographic sites (University of Southern California, Yale University, University of Chicago, and University of Colorado Anschutz Medical Campus) to participate in a parallel-arm, dose-escalating, placebo-controlled trial. Participants will attend weekly clinic visits to receive subcutaneous tirzepatide or placebo over 16 weeks (Visit Weeks 1-16), followed by follow-up visits at Week 17 and Week 27. Medication will be prescribed according to the standard dose titration schedule for the first 16 weeks of treatment (initial dose: 2.5mg/week; final dose: 10mg/week). All participants will also receive nicotine patches.

Inclusion Criteria:

1. Age 21-65 years
2. Body mass index ≥ 25kg/m2 at the baseline screening
3. Reporting ≥10 cigarettes per day, on average, for the past 6 months and > 2 year duration of smoking
4. Interest in making a long-term cessation attempt within the next 30-60 days
5. Willingness to receive study medication and standard-of-care smoking cessation supports (nicotine replacement therapy and a smoking cessation app)
6. Ability to adhere to weekly visits and study procedures over the study period (i.e., no plans to move or travel for extended periods)
7. Exhaled CO of >5ppm at baseline
8. Use of an acceptable birth control method for female participants*
9. Ability to read and communicate in English

Exclusion Criteria:

1. BMI < 25 kg/m2 at screening
2. History of diabetes, diabetes-attributable medical conditions, or HbA1c ≥6.5% at baseline
3. Recent (past 90 days) active suicidal ideation or lifetime history of suicide attempt
4. Current treatment for psychotic disorders or mood disorders with psychotic features (e.g., schizophrenia, schizoaffective disorder, depression with psychotic features), current treatment for bipolar disorder (with or without psychotic features), or current secondary psychosis due to substance use or another medical condition
5. Meeting DSM-5 criteria for a current (past 12 months) substance use disorder other than tobacco use disorder, mild or moderate cannabis use disorder, or mild or moderate alcohol use disorder.
6. Recent (past 30 day) self-report of illicit drug use (excluding cannabis) or non-prescribed opioids; or positive urine screen for illicit drugs. A positive screen for opioids will be allowed if the participant is prescribed an opioid replacement therapy medication and can provide documentation.
7. Past 30-day initiation of psychiatric medications (e.g., SSRIs) or changes to medication dose
8. Treatment with tirzepatide or another GLP-1RA medication in the prior 6 months
9. Current (past month) treatment with other weight loss, diabetes, or smoking cessation medications (varenicline or bupropion; excluding nicotine replacement products)
10. Severe GI disease (e.g., gastroparesis, ulcerative colitis).
11. History of gastric bypass surgery or other surgeries of the stomach
12. Any health condition or treatment/medication that would preclude the use of tirzepatide or NRT, in the opinion of the study physician, including severe cardiovascular disease
13. History of chronic pancreatitis or acute pancreatitis in the last 6 months
14. Currently nursing, pregnant, or anticipating pregnancy
15. History of diabetic retinopathy, proliferative retinopathy, or maculopathy
16. Elevated serum lipase, amylase, bilirubin, or ALP, ALT, or AST (>5x upper limit of normal range)
17. History of malignant neoplasms in the last 5 years, except non-melanoma skin cancer
18. Inability to attend weekly clinic visits as scheduled (i.e., based on travel or work schedule)
19. Currently enrolled in another clinical study involving an investigational product
20. Currently living in the same household as someone taking a GLP-1 medication, or living with a current or former participant in the present trial
21. Planned surgical procedures requiring anesthesia during the planned study medication period
22. Personal or family history of medullary thyroid cancer
23. Personal or family history of multiple endocrine neoplasia syndrome type 2 (MEN 2)
24. Treatment with other weight loss (e.g., phentermine), or FDA-approved, non-NRT smoking cessation therapies (varenicline, bupropion) or FDA-approved AUD medications (naltrexone, acamprosate, disulfiram) or off-label AUD medications (e.g., topiramate) in the past 90 days
25. Any health condition or treatment/medication that would preclude use of tirzepatide or NRT, in the opinion of the site physicians including thyroid enlargement.

The protocol and SAP will be made available at or before the completion of the study. Requests for IPD will be reviewed following publication of primary study results.

Data will be made available to researchers whose proposed purpose for accessing the data has been approved, and provided a data sharing agreement is in place.