Efficacy of Tirzepatide for Weight Management in Patients With Suboptimal Weight Loss After Bariatric Surgery: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Prior treatment

• Use of a GLP-1 receptor agonist (GLP-1 RA) or any other GLP-1-based therapy at present or within the past 6 months.
• Prescription of a GLP-1 RA or other GLP-1-based therapy within the past 12 months that could not be initiated or maintained due to drug supply shortages.
• Have a planned surgical treatment, endoscopic and/or device-based therapy for obesity during the period of the study.
• Type 2 diabetes currently treated with insulin or sulfonylureas.
• Have a known clinically significant gastric emptying abnormality (for example, severe diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI motility.
• Participation in another clinical study with an investigational product during the last month.
• Are receiving or have received within 3 months prior to screening chronic (\>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have evidence of a significant, active autoimmune abnormality (for example, lupus or rheumatoid arthritis) that has required (within the last 3 months) or is likely to require, in the opinion of the investigator, concurrent treatment with systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular or inhaled preparations) in the next 12 months.

Other illness

• Have had a history of chronic or acute pancreatitis.
• Have NYHA Functional Classification III or IV heart failure.
• Have obesity induced by other endocrinologic disorders (for example, Cushing Syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, Melanocortin 4 Receptor deficiency or Prader Willi Syndrome).
• Have a history of significant active or unstable Major Depressive Disorder or other severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or other serious mood or anxiety disorder) within the last 2 years.
• Have any lifetime history of a suicide attempt.
• Have a family or personal history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia (MEN) Syndrome type 2.
• History of active malignancy within the past 5 years (except adequately treated non-melanoma skin cancer or in situ carcinoma of the cervix).
• Known hypersensitivity or contraindication to tirzepatide or any of its excipients.
• Have severe hepatic impairment (Child-Pugh class C).
• Any condition which, in the investigator's opinion, may jeopardize the subject's safety or compliance with the protocol (e.g., severe psychiatric illness, alcohol or substance abuse).

Lab values

• History of type 1 diabetes or uncontrolled type 2 diabetes (HbA1c \>10%).
• Have severe renal impairment (eGFR \<30 mL/min/1.73 m² using CKD-EPI formula).

Other

• Have thyroid-stimulating hormone (TSH) outside of the reference range at screening visit.
• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
• Unwilling or unable to sign the informed consent form.
• For female patients, pregnancy, breastfeeding, or planning pregnancy during the study period.

• Adults (male or female) aged ≥18 years.
• History of bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) performed ≥12 months before enrollment.
• Current BMI ≥30 kg/m².
• Evidence of suboptimal weight loss, defined as percentage total weight loss (%TWL) since surgery of less than 25% (defined as the percentage of weight loss comparing current body weight with body weight before surgery).
• Absence of recent weight loss (defined as \<5% reduction in body weight over the 6 months prior to screening); participants may be weight stable (\<5% variation in body weight over the 6 months prior to screening) or have experienced weight gain.
• In the investigator's opinion, well-motivated, capable, and willing to comply with study procedures.
• For male participants: male participants with partners of childbearing potential should be willing to use reliable contraceptive methods throughout the study and for 5 half-lives of study drug plus 90 days, corresponding to 4 months after the last injection.
• For female participants:
  • Female participants not of childbearing potential may participate and include those who are: i. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy or tubal ligation), congenital anomaly such as Mullerian agenesis ii. postmenopausal, defined as either:
  • a woman at least 40 years of age with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, AND a follicle-stimulating hormone ≥40mIU/mL; women in this category must test negative in pregnancy test prior to study entry
  • a woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea
  • a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy b. Female participants of child-bearing potential (not surgically sterilized and between menarche and 1-year postmenopausal) must:
  • test negative for pregnancy at Visit 1 based on a serum pregnancy test
  • if sexually active, agree to use 2 forms of effective contraception, where at least 1 form is highly effective, for the duration of the trial and for 30 days thereafter
  • not be breastfeeding
• Provision of written informed consent prior to any study-specific procedures.