Effect of Tirzepatide and Bimagrumab on Body Composition, Insulin Sensitivity, and Bone in Adults With Obesity

Inclusion Criteria:

• BMI ≥30 kg/m2 or ≥27kg/m2 with at least one weight-related medical condition

• Have a history of at least one self-reported unsuccessful behavioral effort to losebody weight

• Have an established primary care provider

Exclusion Criteria:

• Current or prior history of diabetes mellitus based on self-report, use of diabetesmedications, HbA1c ≥6.5%, or fasting glucose ≥126 mg/dL

• Any single serum transaminase level (i.e., ALT, AST, alk phos) ≥3x the upper limitof normal (ULN)

• Serum lipase and/or amylase levels ≥2x ULN

• Serum bilirubin level >1.6 mg/dL

• Chronic kidney disease (e.g., estimated glomerular filtration rate (eGFR) < 45mL/min)

• Total WBC <3000/μL, neutrophils <1500/μL, hemoglobin <12 g/dL, or platelet count <100,000/μL

• Significant coagulopathy, e.g., PT/INR >1.5

• History of familial hypertriglyceridemia or serum fasting triglyceride >500 mg/dL

• Uncontrolled thyroid disease, defined as abnormal TSH with abnormal fT4

• Any chronic active infection (e.g., HIV, hepatitis B or C) or hepatitis C treatmentwithin the previous 6 months

• Known history or presence of severe active acute or chronic liver disease (e.g.,cirrhosis) or conditions with hepatotoxic potential (e.g., gallbladder or bile ductdisease, acute or chronic pancreatitis, exocrine pancreatic insufficiency)

• Active clinically significant gastric emptying abnormality or chronic use of adrug(s) that directly affect GI motility

• History of calcium oxalate kidney stones

• History of clinically significant arrhythmias, unstable angina, myocardialinfarction, stroke, coronary artery bypass graft surgery, percutaneous coronaryintervention, heart failure, valve disorders or defect, pulmonary hypertension,chronic hypotension (<100/50), or chronic uncontrolled hypertension (>160/100)

• Tachycardia, defined as heart rate >100 bpm after 5 minutes resting in a sittingposition

• History of malignancy of any organ system (other than localized squamous or basalcell carcinoma of the skin), treated or untreated, within the previous 5 years

• Confirmed diagnosis of current, significant psychiatric disease (e.g., dementia,Alzheimer's disease, schizophrenia, or bipolar disorder). Individuals withadequately treated depression on stable treatment for at least 3 months areeligible.

• Prior history of suicide attempt

• PHQ-9 score ≥ 15 at screening

• Personal or family history of multiple endocrine neoplasia 2A or 2B or medullarythyroid cancer

• Active alcohol, drug, or tobacco abuse. For alcohol, an average weekly alcoholintake that exceeds 14 units per week (males) or 7 units per week (females) [1 unit = 12 oz or 260 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilledspirits] is exclusionary.

• Cannabis/THC use greater than once a week over the past three months and unwillingto abstain from use of cannabis/THC products for the duration of the study

• Have obesity induced by other endocrinologic disorders (e.g., Cushing syndrome) ordiagnosed monogenetic or syndromic forms of obesity (e.g., Melanocortin 4 Receptordeficiency or Prader Willi syndrome)

• History of weight loss surgery or planned weight loss surgery during the trialperiod

• Use of any anti-obesity medication, nutritional supplement, or over the counter (OTC) product for weight loss within the previous 6 months or during studyparticipation

• Any new dietary intervention or exercise regimen for weight loss started within theprevious 3 months

• Weight instability of >5kg within the previous 3 months

• Weight > 150kg due to limitations of radiology imaging machines

• Use of medications known or suspected to induce weight gain within the previous 3months or during study participation (e.g., anti-androgens, gonadotropin releasinghormone (GnRH) analogs, some anticonvulsant and psychotropic medications (excludinganti-depressant medication) and oral glucocorticoids)

• Use of skeletal muscle anabolic agents within the previous 3 months or during studyparticipation (e.g., hormones such as growth hormone or testosterone, nutritionalsupplements (other than protein) and over-the-counter products labeled as muscleanabolic agents)

• Treatment with glucose-lowering agent(s) within 90 days before screening

• History of hypersensitivity to monoclonal antibodies or drugs in the same compoundclass as the study drugs

• History of fragility fracture or BMD T-score ≤ -2.5 in participants > 50 years old

• Use of IV bisphosphonates within the previous 2 years or other osteoporosismedications within the previous 12 months or during study participation

• Not able or willing to comply with dietary and lifestyle intervention for weightloss, including history of clinically significant condition that precludes regularwalking for exercise or contraindication to following a 500-calorie daily deficit,high protein diet

• Women who are pregnant or breastfeeding

• Women of child-bearing potential, defined as women physiologically capable ofbecoming pregnant, unless they are using an intrauterine device (IUD) from at least 3 months before the baseline visit through at least 4 months after the last drugdose and an additional contraceptive (barrier) method from screening through atleast 4 months after the last drug dose. Women not of child-bearing potential aredefined as individuals who (1) have a congenital anomaly such as Mullerian agenesis,resulting in confirmed infertility, (2) are infertile due to surgical sterilization (defined as documented hysterectomy, bilateral salpingo-oophorectomy, bilateralsalpingectomy, or bilateral oophorectomy), or (3) are post-menopausal. The followinggroups of women are eligible to participate: (a) women who are s/p surgicalbilateral oophorectomy or total hysterectomy at least 6 weeks before taking studytreatment, (b) women who have an IUD (see additional criteria above), (c) women whoare s/p tubal ligation provided that they use an additional barrier form ofcontraception from screening through at least 4 months after the last drug dose, (d)women who are post-menopausal defined as ≥12 months of spontaneous amenorrhea withappropriate clinical and hormonal profile (e.g., age-appropriate, history ofvasomotor symptoms, and/or FSH >40 IU/L), (e) have a congenital anomaly resulting inconfirmed infertility, and (f) do not have a history of sexual activity that couldlead to pregnancy (i.e., total abstinence has been and is their preferred lifestyleor same-sex partners only).

• For men, morning serum testosterone less than 200 ng/dL

• Concurrently enrolled in any other type of medical research judged to bescientifically or medically incompatible with this study

• Plans to move out of the study area within 16 months, or be out of the study areafor >4 weeks, continuously

• Routine MRI exclusion

• Donation or loss of 400 mL or more of blood within past 2 months or plasma donation (> 250 mL) within past 2 weeks

• Major surgery in the trial period

• Any disorder, unwillingness, or inability not covered by any of the other exclusioncriteria, which in the Investigator's opinion, might jeopardize the subject's safetyor compliance with the protocol