Inclusion Criteria:

• Postmenopausal women defined by for cessation of menses for at least one year without an alternative medical cause
• Age 46-60 years old.
• BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 in the presence of adiposity-associated diseases (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease).
• Presence of bothersome hot flashes (≥ 28 episodes per week and of sufficient severity to prompt patients to seek therapeutic interventions).
• Hot flashes must be present for >30 days prior to study entry.
• Ability to participate in all portions of the study, including willingness to self-inject drug
•  Provided informed consent to be part of the study.
• Willingness and capability to follow a hypocaloric diet, consisting of an energy deficit of approximately 500 kcal/day compared to baseline total energy expenditure, and composed of 30% from fat, 20% from protein, and 50% of carbohydrate. In addition to performing at least 150 min/week of physical activity.

Exclusion Criteria: 

• Current treatment with menopausal hormone therapy.
• Any current (past 4 weeks) or planned use of:
  • Estrogen-containing contraceptive methods or menopausal hormone therapy (oral, transdermal, high dose vaginal ring, injection, pellets). Low dose vaginal estrogen is acceptable.
  • Androgens.
  • Progestogens. 
• Current treatment for menopausal symptoms with cognitive behavioral therapy and/or hypnosis.
• Current use of fezolinetant.
• Menopause as a result of cancer treatments.
• Impaired renal function (GFR ≤ 30 ml/min/1.73 m²).
• Thyroid-stimulating hormone ≥7 with low free T4.
• 10-year ASCVD risk > 7.5%.
• Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignancy, or uncontrolled psychiatric disease.
• > 5% change in weight during the 3 months prior to screening and, or eight fluctuation of ≥20 pounds within the past 6 months (self-report).
• Other antiobesity medication used within the past 3 months.
• History of bariatric surgery. Prior or planned surgical treatment for obesity (excluding liposuction or abdominoplasty performed > 1 year before screening).
• Past or intended endoscopic and/or device-based therapy or removal within last six months.
•  Current or recent (within 3 months) use of medications that may cause weight gain, including tricyclic antidepressants, atypical antipsychotics, and mood stabilizers.
• Current or recent (within 3 months) use of chronic systemic glucocorticoid therapy for over 2 weeks within the past 3 months.
• Contraindications to GLP-1 receptor agonist therapy as per Tirzepatide (Zepbound ®) label.
• Currently enrolled in another clinical study involving an investigational product, or participated in one and received treatment (active or placebo) in the last 30 days.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/14/2025. Questions regarding updates should be directed to the study team contact.