Once-weekly retatrutide injections to help reduce weight in adults with obesity or overweight

A Phase 2 Study of Once-Weekly LY3437943 Compared With Placebo in Participants Who Have Obesity or Are Overweight With Weight-Related Comorbidities

This trial will test whether once-weekly injections of retatrutide help adults with obesity or overweight (without type 2 diabetes) lose more weight than placebo while following diet and activity advice.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 300 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Hudson Biotech (Industry-sponsored)
• Locations: 1 site (Shenzhen, Guangdong)
• Trial ID: NCT07467447 on ClinicalTrials.gov

What this trial studies

This is a randomized, double-blind, placebo-controlled Phase 2 study testing multiple once-weekly subcutaneous dose regimens of retatrutide (LY3437943) in adults with obesity or overweight and weight-related comorbidities but without type 2 diabetes. After screening, participants are randomized to dose-escalation schedules that reach maintenance doses of 1, 4, 8, or 12 mg (with some arms using alternative escalation for tolerability) or placebo, administered weekly for 48 weeks. All participants receive standardized diet and physical activity counseling, with the primary efficacy endpoint being percent change in body weight at Week 24 and additional assessments through Week 48 plus a 4-week safety follow-up. A NAFLD addendum invites participants with liver fat ≥10% by MRI-PDFF for additional evaluation.

Who should consider this trial

Good fit: Adults aged 18–75 with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity, who are willing to self-inject (or have trained assistance) and follow lifestyle counseling, are the intended participants.

Not a fit: People with type 1 or type 2 diabetes, elevated diabetes-range HbA1c (≥6.5%), pregnant or breastfeeding women, or those unable or unwilling to self-inject or follow the protocol are unlikely to be eligible or benefit from participation.

Why it matters

Potential benefit: If successful, retatrutide could produce substantial weight loss and improve weight-related health measures in adults without type 2 diabetes.

How similar studies have performed: Early clinical work with GLP-1/GIP/dual-agonists and initial retatrutide data have shown large weight-loss effects, so the multi-agonist approach has promising early evidence.

Eligibility criteria

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).

Where this trial is running

Shenzhen, Guangdong

• Peking University Shenzhen Hospital — Shenzhen, Guangdong, China (Recruiting)

Study contacts

• Study coordinator: Seni S Lu, Phd

Conditions Obesity; Retatrutide; LY3437943; triple agonist; GIP receptor agonist; GLP-1 receptor agonist; glucagon receptor agonist; weight loss