A Study of Weight Loss Intervention With Tirzepatide and Progestin Intrauterine Device to Treat Endometrial Hyperplasia and Grade 1 Endometrial Cancer

Inclusion Criteria:

* Women who have a pathologic diagnosis of AH/EIN or grade 1 endometrioid endometrial cancer confirmed on dilation and curettage (D\&C) and desire non-surgical management, who are overweight (body mass index \[BMI\] ≥ 27 kg/m\^2) with a weight-related comorbidity (hypertension, type 2 diabetes, or high cholesterol) or obese (BMI ≥ 30 kg/m\^2) with or without weight-related comorbidities
* Prior progesterone treatment for conditions other than AH/EIN or endometrial cancer is allowed, but a 28-day washout period is required before levonorgestrel IUD placement. If archival tissue is available from prior to any progesterone treatment but after the diagnosis of AH/EIN/EC, the washout period is not needed
* Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently available on the use of tirzepatide in participants \< 18 years of age, children and adolescents \< 18 years of age are excluded from this study but will be eligible for future pediatric trials, if applicable
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For participants with a history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
* Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
* Ability to comply with EMB every 3 months
* Women currently using oral hypoglycemic agents (e.g., metformin) are eligible for the study
* Ability to understand and the willingness to sign a written informed consent document in English or Spanish

Exclusion Criteria:

* Women with grade 2-3 endometrioid, or women with serous, clear cell, mucinous, squamous, transitional cell, sarcomas, or carcinosarcoma histology
* Evidence of extrauterine spread of disease on imaging or during surgical evaluation
* Participants may not be receiving any other investigational agents or anticancer therapies (including chemotherapy, radiation therapy, hormonal, or antibody-based therapy). Prior treatment should have a minimum washout period of 14 days
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the levonorgestrel IUD or any GLP-1 agonist
* Uncontrolled intercurrent illness, or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study. Because of this, a pregnancy test is part of the screening for the study and women who are pregnant or planning pregnancy within 6 months after the end of the study will be excluded. The LNG-IUD is an Food and Drug Administration (FDA)-approved contraceptive agent. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.

Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with tirzepatide, breastfeeding should be discontinued if the mother is treated with tirzepatide

* Women who have any severe and/or uncontrolled medical conditions such as:

  * Unstable angina pectoris, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease,
  * Symptomatic congestive heart failure of New York Heart Association class III or IV,
  * Active (acute or chronic) or uncontrolled severe infection (not responding to antibiotics), liver diseases such as cirrhosis and decompensated liver disease,
  * Known severely impaired lung function (spirometry and diffusion capacity of the lung for carbon monoxide \[DLCO\] 50% or less of normal and oxygen \[O2\] saturation 88% or less at rest on room air), or
  * Active, bleeding diathesis
* Other malignancies within the past 3 years except for basal or squamous cell carcinoma of the skin
* Active (acute or chronic) or uncontrolled severe infections (not responding to antibiotics), including acute pelvic inflammatory disease
* Congenital or acquired uterine anomaly which distorts the uterine cavity
* Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use one additional highly effective method of contraception in addition to the LNG-IUD during the study and 8 weeks after. Acceptable highly effective contraception methods include a combination of any of the following:

  * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
  * Total abstinence or;
  * Male sterilization;
  * Female bilateral tubal ligation or bilateral salpingectomy Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy or tubal ligation at least six weeks prior to study initiation. When the diagnosis of menopause is unclear based on patient history, we will assess follicle-stimulating hormone \\ (FSH) levels for confirmation. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
* Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia (MEN) 2A or 2B. Such women will be excluded
* Participants taking any other prescription medication intended to induce weight loss (i.e., orlistat, phentermine-topiramate, naltrexone-bupropion). A 28-day washout period is required if such women want to enter the study
* Participants on active intermittent fasting
* Participants currently using insulin for glucose control
* Participants who have previously used any glucagon-like peptide (GLP) medications (liraglutide, semaglutide, dulaglutide, exenatide), whether oral or injectable
* Participants diagnosed with Lynch Syndrome