Retatrutide Phase 3 Trials: What We Know and What It Means for Prescribers

Retatrutide (LY3437943) is Eli Lilly's triple receptor agonist — acting on GLP-1, GIP, and glucagon receptors simultaneously. The Phase 2 data generated significant excitement in the obesity medicine community, and Phase 3 trials are now underway. For prescribers and practices that are already offering compounded retatrutide, understanding the clinical evidence base is essential.

The Phase 2 trial of retatrutide (published in The New England Journal of Medicine in 2023) enrolled 338 adults with obesity. Key findings:

Weight loss outcomes: At the highest dose (12 mg weekly), participants lost an average of 24.2% of body weight over 48 weeks. This compares to approximately 15% for semaglutide (Wegovy) and 20–22% for tirzepatide (Zepbound) in their respective trials.

Dose-response relationship: The trial showed a clear dose-response relationship, with higher doses producing greater weight loss.

Metabolic markers: Improvements in blood pressure, lipids, and glycemic markers were observed across dose groups.

Tolerability: GI side effects (nausea, vomiting, diarrhea) were the most common adverse events, consistent with other GLP-1 class compounds. The incidence was dose-dependent.

Understanding why retatrutide may produce greater weight loss than semaglutide or tirzepatide requires understanding the three receptor mechanisms:

GLP-1 receptor agonism: Reduces appetite, slows gastric emptying, increases insulin secretion. This is the mechanism shared with semaglutide and tirzepatide.

GIP receptor agonism: Enhances insulin secretion, may have direct effects on adipose tissue. Shared with tirzepatide but not semaglutide.

Glucagon receptor agonism: This is what distinguishes retatrutide. Glucagon increases energy expenditure and promotes fat oxidation. The addition of glucagon receptor agonism is thought to contribute to the enhanced weight loss observed with retatrutide.

The theoretical concern with glucagon receptor agonism is increased blood glucose — but the GLP-1 and GIP components appear to counterbalance this effect in practice.

Eli Lilly's Phase 3 program for retatrutide (the TRIUMPH program) is testing the compound across several populations and indications:

TRIUMPH-1: Adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. Primary endpoint: weight loss at 72 weeks.

TRIUMPH-2: Adults with type 2 diabetes and obesity. Testing both weight loss and glycemic control endpoints.

TRIUMPH-3: Cardiovascular outcomes trial. Testing whether retatrutide reduces major adverse cardiovascular events (MACE) in high-risk patients.

TRIUMPH-4: Adolescents with obesity. Pediatric indication.

Results from the Phase 3 program are expected in 2026–2027, with potential FDA approval filing to follow.

Retatrutide is not yet FDA-approved. It is available as a compounded preparation through licensed 503A facilities for patient-specific prescriptions.

The strong Phase 2 data and active Phase 3 program have driven significant prescriber interest in compounded retatrutide — particularly among practices that want to offer patients the most advanced options available.

Key considerations for prescribers:

Evidence base: The Phase 2 data is compelling, but Phase 3 results are not yet available. Prescribers should counsel patients that the long-term safety and efficacy data is still accumulating.

Regulatory status: Compounded retatrutide is available under 503A for patient-specific prescriptions. The regulatory basis for compounding will evolve as the FDA approval process progresses.

Patient selection: Given the strong Phase 2 data, retatrutide may be particularly appropriate for patients who have not achieved adequate response to semaglutide or tirzepatide.

Monitoring: As with all GLP-1 class compounds, appropriate monitoring for GI side effects, heart rate changes, and other class effects is important.

Retatrutide is our most requested special order. We supply it in lyophilized powder, pre-constituted injectable, and wet mix forms. We have particular expertise serving California-based practices.

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This content is for informational and educational purposes only. Retatrutide is not FDA-approved. Compounded retatrutide is available as a patient-specific 503A preparation. Prescribers should review current literature and use clinical judgment.