Trial Overview
In June 2023, the New England Journal of Medicine published the results of a Phase 2 clinical trial of Retatrutide (LY3437943) for overweight and obesity — authored by Ania M. Jastreboff and colleagues. The trial, officially titled "Triple Hormone Receptor Agonist (LY3437943) for Obesity — A Phase 2 Randomized Trial," enrolled 338 adults and randomized them across seven treatment arms (six active doses plus placebo). It is the defining document establishing Retatrutide's efficacy profile.
Source: Jastreboff AM et al. "Triple Hormone Receptor Agonist for Obesity." New England Journal of Medicine. June 2023. doi: 10.1056/NEJMoa2301972.
Study Design
Trial Structure
- Design: Randomized, double-blind, placebo-controlled, dose-ranging Phase 2 trial
- Sites: Multiple international sites
- Duration: 24-week dose-escalation period + 24-week maintenance period = 48 weeks total
- Sample size: 338 participants randomized
Inclusion Criteria
- Adults aged 18–75
- Body mass index (BMI) ≥30, or BMI ≥27 with at least one weight-related comorbidity
- Stable body weight (≤5% change in prior 3 months)
- No Type 2 diabetes (participants with pre-diabetes were eligible)
Dose Arms
Participants were randomized to weekly subcutaneous injections of Retatrutide at doses of 1 mg, 2 mg, 4 mg, 8 mg (up to 8), 8 mg (up to 12), 12 mg (up to 12), or placebo. The primary analysis focused on the highest-dose group (12 mg target).
Primary Endpoint — Weight Loss
The primary endpoint was percent change in body weight at 24 weeks (end of dose-escalation period). The key secondary endpoint was percent change at 48 weeks. Both showed strongly significant, dose-dependent weight reduction.
Results by Dose Group
Retatrutide showed clear dose-response across all active arms — weight loss increased with dose, and the highest dose groups had not reached a plateau at 48 weeks. Below is the approximate weight loss by arm:
The trajectory for the 12 mg group shows continued steep decline between week 24 and week 48 — indicating that dose escalation through the maintenance period drives continued weight loss, and that no plateau had been reached by trial end.
Secondary Endpoints — The Full Picture
Waist Circumference
Mean waist circumference reduction of 17.5 cm at the highest dose — a reduction in visceral fat that correlates strongly with reduced cardiovascular and metabolic disease risk.
Systolic Blood Pressure
Reductions of 7–9 mmHg in systolic blood pressure were observed at higher doses — clinically meaningful changes that could reduce cardiovascular event risk if sustained.
Fasting Lipids
Significant reductions in triglycerides (approximately 30–35% reduction at highest dose) and LDL cholesterol, alongside increases in HDL cholesterol — consistent with improved overall cardiometabolic health.
Fasting Insulin & Glucose
Dose-dependent reductions in fasting insulin and fasting glucose, with improvements in insulin sensitivity. The glucose-lowering effect is relevant to pre-diabetes research even in the non-diabetic trial population.
Liver Fat (Metabolic Syndrome Subgroup)
A substudy of participants with metabolic syndrome showed a 46% reduction in liver fat content — a dramatic finding that positions Retatrutide as a highly promising research candidate for non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
Safety & Tolerability
The safety profile was broadly consistent with the GLP-1 receptor agonist class:
- Nausea: Most common adverse event, dose-dependent, typically transient and highest during dose-escalation phases
- Vomiting and diarrhea: Secondary GI events, similar pattern to semaglutide and tirzepatide
- Decreased appetite: Intended pharmacological effect, reported as adverse event in some participants
- No new safety signals: The glucagon receptor addition did not introduce unexpected safety signals not already associated with the GLP-1/GIP class
- Injection site reactions: Mild, transient, consistent with subcutaneous peptide administration
Trial discontinuation due to adverse events was broadly comparable to rates observed in semaglutide Phase 3 trials.
Phase 3 Status
Following the remarkable Phase 2 results, Eli Lilly initiated Phase 3 clinical trials for Retatrutide. Phase 3 trials are larger (thousands of participants), longer (72–104 weeks), and designed to confirm efficacy and safety for regulatory submission. Phase 3 Retatrutide trials are expected to include:
- Obesity primary endpoints (TRIUMPH-1 type registration trial)
- Type 2 diabetes indication arms
- Cardiovascular outcomes endpoints (MACE)
- NASH/NAFLD dedicated liver disease trial
If Phase 3 data replicates the Phase 2 weight loss trajectory through 72 weeks, Retatrutide could achieve mean weight loss exceeding 30% — entering territory that approaches surgical outcomes.
Scientific Significance
The Retatrutide Phase 2 trial is one of the most significant publications in the history of obesity pharmacology research. For the first time, a pharmacological agent demonstrated weight loss approaching what bariatric surgery has historically achieved — without the surgical risks, recovery, or lifestyle restrictions.
The 24.2% mean weight loss at the highest dose, combined with the continued declining trajectory at 48 weeks, suggests that Retatrutide's full weight loss potential — if studies ran to 72 or 96 weeks — may substantially exceed even this historic result.
For researchers, this data represents the current frontier of what pharmacological intervention can achieve in metabolic disease. Research-grade Retatrutide is available from QSC Peptides with ≥99% purity verification.
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