Phase 2, multicenter, randomized, double-blind, placebo-controlled study evaluating once-weekly subcutaneous retatrutide (LY3437943) at multiple maintenance dose levels versus placebo in adults with obesity or overweight with weight-related comorbidities (without type 2 diabetes), alongside standardized diet and physical activity counseling.

After screening (up to 6 weeks), eligible participants are randomized to one of several dose-escalation regimens leading to maintenance doses of 1, 4, 8, or 12 mg retatrutide (or placebo) administered once weekly for 48 weeks, followed by a 4-week safety follow-up. Two maintenance dose levels (4 mg and 8 mg) include alternative escalation schedules to evaluate tolerability. The primary efficacy evaluation is at Week 24 (percent change in body weight), with additional weight, anthropometric, and safety assessments through Week 48.

Inclusion Criteria:

• Age 18 to 75 years (inclusive) at time of informed consent.
• BMI ≥30 and ≤50 kg/m², OR BMI ≥27 and <30 kg/m² with at least 1 weight-related comorbidity (hypertension; dyslipidemia; or cardiovascular disease such as ischemic CVD or NYHA Class I-II heart failure).
• Motivated and able/willing to self-inject (or have trained assistance if needed) and follow study procedures, including lifestyle advice and questionnaires.
• Subgroup (NAFLD addendum): liver fat content ≥10% by MRI-PDFF (for participants invited to the addendum).
• Male and/or female; contraception requirements apply; women of childbearing potential must have negative pregnancy tests at specified visits and should not be breastfeeding.
• Capable of giving signed informed consent and complying with protocol requirements.

Exclusion Criteria:

• History of diabetes mellitus (type 1 or type 2), ketoacidosis, or hyperosmolar state/coma.
• Screening lab values suggestive of diabetes (HbA1c ≥6.5%; fasting glucose ≥126 mg/dL; or random glucose ≥200 mg/dL).
• Self-reported change in body weight >5 kg within 3 months prior to screening.
• Prior or planned surgical treatment for obesity (exceptions: liposuction/abdominoplasty >1 year prior).
• Current/planned endoscopic or device-based obesity therapy, or device removal within last 6 months (e.g., intragastric balloon, gastric artery embolization).
• Renal impairment: eGFR <45 mL/min/1.73 m² (CKD-EPI) at screening.
• Clinically significant gastric emptying abnormality (e.g., severe gastroparesis) or chronic drugs affecting GI motility.
• History of acute or chronic pancreatitis (exception for resolved gallstone pancreatitis post-cholecystectomy).
• TSH outside 0.4 to 6.0 mIU/L at screening (with protocol-defined exceptions).
• Obesity due to other endocrine disorders (e.g., Cushing's) or monogenic/syndromic obesity (e.g., Prader-Willi).
• Psychiatric exclusion criteria including unstable major depressive disorder/severe psychiatric disorder within 2 years; lifetime suicide attempt; PHQ-9 score ≥15; or specified Columbia-Suicide Severity Rating Scale (C-SSRS) findings within past month.
• Uncontrolled hypertension (systolic ≥160 mmHg and/or diastolic ≥100 mmHg) or elevated resting pulse rate (>100 bpm) at baseline.
• Recent (within 3 months) major cardiovascular events (e.g., MI, stroke, unstable angina, CHF hospitalization); tachyarrhythmia syndromes; NYHA Class III-IV CHF; or ECG abnormalities interfering with interpretation.
• Acute/chronic hepatitis or liver disease other than NAFLD; or screening labs: ALT >3× ULN, ALP >1.5× ULN, or total bilirubin >1.5× ULN (with exception).
• Elevated calcitonin at Visit 1 per protocol thresholds; personal/family history of medullary thyroid carcinoma or MEN2.
• Active/untreated malignancy or remission <5 years (with protocol exceptions for certain in-situ/skin cancers).
• Contraindication to GLP-1 receptor agonists, or other conditions that could prevent protocol compliance (including drug/alcohol abuse or eating disorder), per investigator judgment.
• Alcohol consumption >14 units/week (women) or >21 units/week (men).
• Recent marijuana/THC-containing product use within 3 months or unwillingness to abstain during trial (protocol exception for cannabidiol oil if agrees to refrain).
• Organ transplant history (except corneal transplant) or awaiting transplant.
• Hematologic conditions interfering with HbA1c measurement; recent large blood donation/transfusion/severe blood loss; hemoglobin below protocol thresholds.
• Severe atopy/multiple severe allergies or severe hypersensitivity reactions.
• Fasting triglycerides >500 mg/dL at screening (with stability requirement for lipid-lowering therapy).
• Significant active, uncontrolled medical condition or history posing risk or interfering with data interpretation, per investigator judgment.
• History of symptomatic gallbladder disease within past 2 years (protocol-defined exceptions after cholecystectomy).
• History of documented HIV infection.
• Chronic systemic glucocorticoid therapy within 3 months or active autoimmune abnormality likely to require systemic steroids during study (with specified formulation exceptions).
• Recent medications that may cause significant weight gain (e.g., tricyclic antidepressants, atypical antipsychotics, mood stabilizers) within 3 months.
• Recent use (within 3 months) of medications or remedies intended to promote weight loss (examples listed in protocol, including GLP-1 RAs).
• Use of metformin or other glucose-lowering medications (e.g., for PCOS or diabetes prevention) not permitted at entry.
• Started implantable/injectable contraceptives within 18 months prior to screening (IUDs allowed if used ≥3 months).
• Known allergies to GLP-1 receptor agonists or LY3437943.
• Currently enrolled in another investigational study or recent participation/treatment within 30 days (or 5 half-lives, whichever longer).
• Previously received LY3437943 in this or another study.
• Investigator site personnel directly affiliated with the study and/or their immediate family; or Lilly employees.
• Note: The publicly posted protocol references additional exclusion criteria numbered 52-57 in a separate protocol addendum (not included in the posted protocol PDF).

To preserve blinding, placebo participants follow an injection dose-escalation schedule matched to one of the active retatrutide arms.