Retatrutide

Mechanism

Retatrutide is a triple receptor agonist targeting GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors simultaneously. This triple mechanism is designed to deliver superior weight loss and metabolic benefits compared to single- or dual-receptor agonists by combining the appetite-suppressing and incretin effects of GLP-1 and GIP with the energy expenditure and lipolysis-promoting effects of glucagon. The addition of glucagon receptor agonism is theorised to increase energy expenditure and promote hepatic fat oxidation, potentially yielding greater fat mass reduction than dual agonists like tirzepatide.

Evidence base

Phase 3 — TRIUMPH-4 Trial (December 2025)

On 11 December 2025, Eli Lilly announced positive topline results from the TRIUMPH-4 Phase 3 trial — the first successful Phase 3 study of retatrutide. The trial enrolled adults with obesity or overweight and knee osteoarthritis, without diabetes.

Key findings:

• 28.7% mean weight loss at 68 weeks with the 12 mg dose (approximately 71.2 lbs / 32.3 kg)
• 75.8% reduction in WOMAC pain score (up to 4.5-point reduction), indicating substantial osteoarthritis pain relief
• The results highlight retatrutide's potential dual benefit: significant weight reduction combined with meaningful improvement in obesity-related osteoarthritis symptoms

Source: Eli Lilly press release, 11 December 2025.

Phase 3 Trial Programme Design

The TRIUMPH programme consists of multiple Phase 3 registrational trials evaluating retatrutide for obesity, obstructive sleep apnoea, and knee osteoarthritis. The rationale and design of these trials was published in 2025 (PMID: 41090431).

Phase 2 — TRIUMPH-1 Trial (Published 2023)

The Phase 2 TRIUMPH-1 trial, published in JAMA in 2023, established retatrutide's dose-response and efficacy signal:

• At 48 weeks, the 12 mg dose achieved 24.2% mean weight loss in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with comorbidities, without diabetes
• Weight loss was still ongoing at the 48-week endpoint, suggesting a plateau had not yet been reached
• Dose-dependent gastrointestinal adverse effects (nausea, diarrhoea, vomiting) were the most common side effects, generally mild to moderate and tapering over time

Source: Jastreboff AM, et al. 'Retatrutide for Obesity — A Phase 2 Trial.' JAMA. 2023;330(14):1339-1350. doi:10.1001/jama.2023.19828

Protocols

Based on the TRIUMPH Phase 2 and 3 trial designs:

• Administration route: Subcutaneous injection (once weekly)
• Dose escalation: Gradual titration — typically starting at 1 mg, escalating through 2 mg, 4 mg, 8 mg, to a target of 12 mg, with dose increases every 4 weeks to improve gastrointestinal tolerability
• Target maintenance dose: 12 mg once weekly (highest dose studied in Phase 2 and 3)
• Treatment duration: Phase 2 assessed 48 weeks; Phase 3 assessed 68 weeks
• Time off / cycling: Not applicable in clinical trial contexts — continuous dosing was used throughout the trial duration

The above describes protocols used in clinical trials and is provided for research and educational purposes only. Retatrutide is not licensed as a medicine in the UK.

UK legal status

Retatrutide is not licensed as a medicine by the MHRA. It is an investigational compound currently in Phase 3 clinical development by Eli Lilly and has not received regulatory approval in the UK or any other jurisdiction.

• UK status: Retatrutide would be classified as a Prescription-Only Medicine (POM) if licensed, as it is an injectable peptide with significant pharmacological activity. Until licensed, it is not legally available as a medicine.
• Research use: Retatrutide may be sold as a research chemical for in vitro or laboratory research purposes, provided it is not marketed for human consumption. Vendors selling retatrutide as a 'research peptide' must not make therapeutic claims.
• MHRA guidance: The MHRA has been actively investigating unlicensed sale of weight-loss injectables. Purchasing unlicensed injectable peptides for self-administration carries legal and health risks.

Vendor notes

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