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

Endometrial cancer is one of the most common gynecologic malignancies in the United States, with an increasing incidence rate. Obesity has been identified as a major risk factor for endometrial carcinogenesis and is prevalent among patients with endometrial intraepithelial neoplasia (EIN) and early-stage endometrial cancer. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA), can cause meaningful weight loss and improvement in metabolic parameters. Levonorgestrel intrauterine device (LNG-IUD) therapy is a standard hormonal treatment for local EIN and grade 1 endometrioid endometrial carcinoma. This single-arm, single-center investigator-initiated study will evaluate the feasibility, safety, and preliminary efficacy of combining tirzepatide with standard LNG-IUD treatment in patients with EIN or grade 1 endometrioid endometrial carcinoma with co-existing obesity and metabolic risk factors. Eligible participants will be enrolled after initial histological confirmation of either EIN or grade 1 endometrioid endometrial carcinoma. Clinical management will remain at the discretion of the treating physician.

Inclusion

• Age ≥ 18 years
• Histologically confirmed endometrial intraepithelial neoplasia (EIN) or grade 1 endometrioid EC
• BMI ≥ 30 kg/m2
• 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

• 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
• For participants with EIN: no evidence of extrauterine disease based on clinically appropriate evaluation
• Ability to provide informed consent and comply with study procedures and follow-up

Exclusion

• Mismatch repair-deficient (MMRd) tumors
• p53-abnormal tumors
• Known hypersensitivity or contraindication to either:

• Tirzepatide, or
• LNG-IUD
• Prior LNG-IUD in place at the time of EIN or endometrial cancer diagnosis
• Current systemic progestin therapy
• 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
• Type 1 diabetes or a history of pancreatitis, medullary thyroid carcinoma, or Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
• Pregnancy, breastfeeding, or intention to become pregnant during the study treatment
• Concurrent malignancy requiring active treatment (except non-melanoma skin cancer)
• Any medical, psychiatric, or social condition, that in the opinion of the investigator, would interfere with study participation or safety
• Participants with diabetic eye disease, including non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema
• Severe renal impairment, defined as eGFR < 30 mL/min/1.73m2