Primary Prevention and Uterine Preservation in Premenopausal Women With Obesity and Endometrial Hyperplasia

Inclusion Criteria:

• Diagnosis of histologically confirmed non-atypical endometrial hyperplasia (EH) orcomplex atypical endometrial hyperplasia (AEH).

• Patients with a previous diagnosis of EH or AEH who are already being followedwith conservative management with oral or LNG-IUD progestin therapy areeligible provided they have not previously been on a GLP-1R agonist within 3months prior to enrollment.

• For patients with a previous diagnosis of EH or AEH who have been placed onprogestin prior to study entry, the duration of IUD or oral progestin use priorto trial entry should be less than or equal to 6 months.

• Premenopausal woman with a uterus.

• At least 18 years of age and no more than 45 years of age.

• Interested in uterine preservation/fertility-sparing treatment.

• BMI ≥ 30 kg/m2.

• Prior or current receipt of progestin is allowed as above. Willingness to undergoplacement of LNG-IUD at the time of study entry.

• Prior or current receipt of metformin is allowed.

• Ability to understand and willingness to sign an IRB approved written informedconsent document.

Exclusion Criteria:

• Prior use of GLP-1 receptor agonist (exenatide, liraglutide, or other) orpramlintide or any DPP-4 inhibitor in the 3 months prior to date of registration.

• History of type 1 diabetes.

• History of type 2 diabetes requiring use of insulin.

• Acute decompensation of glycemic control.

• Concomitant use of other weight management drugs or drugs for short-term weightloss.

• History of surgery or use of a device to treat obesity.

• Uncontrolled thyroid disease

• Acute coronary or cerebrovascular event in the previous 60 days.

• Currently planned coronary, carotid, or peripheral artery revascularization.

• Chronic heart failure (NYHA class IV).

• Evidence of renal dysfunction as defined by creatinine clearance < 60 ml/minute.

• History of solid organ transplant or awaiting solid organ transplant.

• Diagnosis of any malignant neoplasm or current, active treatment with chemotherapyor radiation.

• Family or personal history of multiple endocrine neoplasia syndrome type 2 (MEN 2)or familial medullary thyroid carcinoma (MTC).

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to progestin, semaglutide, or other agents used in the study.

• History of diabetic retinopathy.

• Recent history of pancreatitis, defined as less than 6 months prior to enrollment.

• History of suicidal attempts or active suicidal ideation.

• Significant active psychiatric disease, including recent psychiatric inpatientadmission or use of any psychiatric medications that are not stabilized.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, orcardiac arrhythmia.

• Pregnant and/or breastfeeding. Participants must have a negative serum pregnancytest within 7 days of date of registration.

• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL,they have a history of AIDS-defining opportunistic infection within the 12 monthsprior to registration, or they are receiving anti-retrovirals that affect progestinlevels. Concurrent treatment with effective ART according to DHHS treatmentguidelines is recommended.