Tirzepatide and Levonorgestrel IUD Therapy for EIN and Early-Stage Endometrial Cancer

You may be eligible if

• Inclusion
• 1. Age ≥ 18 years
• 2. Histologically confirmed endometrial intraepithelial neoplasia (EIN) or grade 1 endometrioid EC
• 3. BMI ≥ 30 kg/m2
• 4. Presence of at least one obesity-associated metabolic comorbidity, including:
• a. Hypertension defined as: i. Documented diagnosis of hypertension, regardless of treatment status, documented in the medical records, or ii. Participants receiving antihypertensive therapy, or iii. BP ≥ 130/80 mmHg over 3 independent measurements, or iv. Single BP ≥ 160/100 mmHg b. Hyperlipidemia defined as: i. Documented diagnosis of hyperlipidemia, regardless of treatment status, documented in the medical record, or ii. Participants receiving lipid-lowering therapy, or iii. Triglycerides \> 200 mg/dL, or iv. LDL Cholesterol \> 130 mg/dL c. Type 2 Diabetes defined as: i. Documented diagnosis of Type 2 diabetes mellitus, regardless of treatment status, documented in the medical record, or ii. Receiving glucose-lowering therapy, or iii. Impaired glucose tolerance (Hgb A1c \> 6.0%) d. Diagnosed with sleep apnea
• 5. For participants diagnosed with grade 1 endometrioid endometrial carcinoma: clinical stage 1A disease with MRI-confirmed myometrial invasion \< 50% and no evidence of metastatic disease
• 6. For participants with EIN: no evidence of extrauterine disease based on clinically appropriate evaluation
• 7. Ability to provide informed consent and comply with study procedures and follow-up
• Exclusion
• 1. Mismatch repair-deficient (MMRd) tumors
• 2. p53-abnormal tumors
• 3. Known hypersensitivity or contraindication to either:
• 1. Tirzepatide, or
• 2. LNG-IUD
• 4. Prior LNG-IUD in place at the time of EIN or endometrial cancer diagnosis
• 5. Current systemic progestin therapy
• 6. Current treatment with tirzepatide or another GLP-1 receptor agonist/GLP-1-GIP receptor agonist, or prior treatment with these agents within 1 month before study enrollment
• 7. Type 1 diabetes or a history of pancreatitis, medullary thyroid carcinoma, or Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
• 8. Pregnancy, breastfeeding, or intention to become pregnant during the study treatment
• 9. Concurrent malignancy requiring active treatment (except non-melanoma skin cancer)
• 10. Any medical, psychiatric, or social condition, that in the opinion of the investigator, would interfere with study participation or safety
• 11. Participants with diabetic eye disease, including non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema
• 12. Severe renal impairment, defined as eGFR \< 30 mL/min/1.73m2