Efficacy and Safety of Tirzepatide for Weight Management

Common inclusion criteria for both diabetic and non-diabetic individuals:

• Informed consent will be obtained before any trial-related activities.
• Male or female, aged ≥18 years at the time of signing the informed consent form.
• Have a history of at least one self-reported unsuccessful dietary effort to lose body weight.
• Body mass index (BMI):
• ≥30 kg/m² with or without any weight-related comorbidities or
• ≥25-29.9 kg/m² with the presence of at least one of the following weight-related comorbidities (treated or untreated):
• Hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg or currently taking antihypertensive medication).
• Dyslipidemia (treated or with low-density lipoprotein (LDL) ≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL (1.7 mmol/L), or high-density lipoprotein (HDL) \<40 mg/dL (1.0 mmol/L) for men or HDL \<50 mg/dL (1.3 mmol/L) for women).
• Obstructive sleep apnea.
• Cardiovascular disease (more than three months).
• In the investigator's opinion, are well-motivated, capable, and willing to:
• Learn how to self-inject study drug, as required for this protocol (visually impaired persons who are not able to perform the injections must have the assistance of a sighted individual trained to inject study drug; persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject study drug).
• Inject study drug (or receive an injection from a trained individual if visually impaired or with physical limitations).
• Follow study procedures for the duration of the study, including, but not limited to, following lifestyle advice (for example, dietary restrictions and exercise plan) and maintaining a study diary.
• 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 the study drug plus 90 days, corresponding to 4 months after the last injection.
• Female participants:
• Female participants not of childbearing potential may participate and include those who are:
• Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as Mullerian agenesis.
• 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 ≥40 mIU/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.
• Female participants of childbearing 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.

For subjects with T2DM:

• Patients diagnosed with T2DM more than or equal to 180 days prior to the day of screening.
• HbA1c up to 10.0%.

Exclusion Criteria

Common exclusion criteria for both diabetic and non-diabetic individuals:

• Medical criteria:
• 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).
• A self-reported reduction in body weight of more than 5 kg within 30 days before screening, irrespective of medical records.
• Treatment with any medication for the indication of obesity within the past 90 days before screening (e.g., Orlistat, liraglutide, naltrexone/bupropion, diethylpropion, phendimetrazine, semaglutide, and setmelanotide).
• Any previous obesity treatment with surgery or a weight loss device during a lifetime.
• Continued treatment with other GLP-1 agonists, SGLT-2 inhibitors, and/or metformin. However, if these drugs can be stopped based on the best clinical judgment of the investigator, the patient can be recruited after stopping the drug and a washout period of two weeks. In the case of tirzepatide, the washout period will be 8 weeks.
• 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).
• Have current or history of (within 3 months prior to enrollment) treatment with medications that may cause significant weight gain, including but not limited to tricyclic antidepressants, atypical antipsychotics, and mood stabilizers.
• Have started implantable or injectable contraceptives (such as Depo-Provera®) within 18 months prior to screening.
• Past history of pancreatitis.
• Diagnosed case of eating disorders (e.g., Bulimia nervosa).
• Patients with a previous history of suicide attempts and major depressive disorder (MDD) according to DSM-V criteria, schizophrenia, or antipsychotic drug-induced obesity.
• Patients with a personal or family history of medullary thyroid carcinoma (MTC) and/or multiple endocrine neoplasia syndrome type 2 (MEN 2).
• Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years.
• Have uncontrolled hypertension (SBP ≥160 mmHg and/or DBP ≥100 mmHg).
• Have NYHA Functional Classification IV CHF.
• Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an organ transplant.
• Laboratory criteria:
• Incidental diagnosis or uncontrolled thyroid disease, defined as a thyroid-stimulating hormone (TSH) level >6.0 mIU/L or \<0.4 mIU/L as measured by the central laboratory at screening. However, well-controlled thyroid disorder can be included if TSH \<6.0 or >0.4 mIU/L.
• Renal impairment, measured as the estimated glomerular filtration rate (eGFR) \<15 ml/min/1.73 m².

For subjects without T2DM:

• HbA1c more than or equal to 48 mmol/mol (6.5%).

For subjects with T2DM:

• Renal impairment, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m² (less than 60 mL/min/1.73 m² in subjects treated with a sodium-glucose cotransporter 2 inhibitor (SGLT2i)).
• Uncontrolled T2DM (HbA1c >10.0%) as these patients may require insulin or other anti-diabetic drugs which might potentially interfere with the efficacy of tirzepatide.