Retatrutide

LY3437943 · “Reta” · S-tier (Dr. Alex Tatem) · Strong evidence

The most powerful weight-loss drug tested so far. It works like tirzepatide but adds glucagon, which appears to raise energy use as well as cut appetite. The phase 3 data is excellent, but it isn’t approved, so every vial available today comes from an unregulated source.

Dr. Tatem’s take

S-tier: “truly the goat of cutting agents” and “probably the first fat burner that won’t land you in the ICU.” On Diary of a CEO he predicted it will be a trillion-dollar drug. His main worries are gray-market purity and the dose-dependent rise in heart rate. He said he has not used it himself.

In Dr. Tatem’s tier list

• Context: insulin was one of the first commercialized peptides, but the modern era began with semaglutide (Ozempic/Wegovy). Lilly’s tirzepatide added GIP activity and became far more powerful.
• Retatrutide adds a third target — the glucagon receptor — on top of GLP-1 and GIP.
• With semaglutide, critics are right that weight loss is mostly eating less. With retatrutide, “you will burn more fat with retatrutide on a certain caloric intake than you would on just that caloric restriction alone.”
• It’s unprecedented that a future blockbuster is available on the gray market before approval: you can get it “from a peptide website in China, but you can’t get it from your doctor yet.”
• Safety looks in line with other GLP-1 drugs. Verdict: the first S tier — “truly the goat of cutting agents.”

History & background

Retatrutide (LY3437943) was designed by Eli Lilly in Indianapolis as a single molecule that activates three receptors. Its phase 2 obesity results (NEJM, June 2023) showed 24% average weight loss at 48 weeks — then a record.

The phase 3 TRIUMPH program followed. In 2026 Lilly reported up to 28.7% average weight loss (TRIUMPH-4, knee osteoarthritis) and 28.3% at 80 weeks (TRIUMPH-1). As of October 2026 it is still investigational in the US; FDA has named it repeatedly in warning letters to “research use only” sellers.

Benefits

• Largest average weight loss of any drug tested: 28.3% of body weight at 12 mg over 80 weeks (TRIUMPH-1).
• Cut knee-arthritis pain by up to about 76% in people with obesity (TRIUMPH-4).
• Improves blood sugar control in type 2 diabetes (phase 2).
• Glucagon activity may raise fat burning beyond appetite suppression alone.

Risks

• Gastrointestinal effects are common: nausea in 28–43% and vomiting in 11–25% of trial participants.
• Abnormal skin sensations (dysesthesia) in up to 20.9% at 12 mg (TRIUMPH-4).
• Resting heart rate rises with dose.
• 11–18% of people on the top dose quit trials because of side effects.
• Presumed GLP-1 class risks (pancreatitis, gallbladder disease, thyroid C-cell warning). There’s no label yet, so these are assumed rather than confirmed.

Dosing protocols (informational, labeled by evidence)

• Clinical trial / label: Phase 2 obesity trial — 1, 4, 8 or 12 mg/wk; 12 mg arm started at 2 mg and stepped 2→4→8→12, SubQ, Weekly, 48 wk
• Clinical trial / label: Phase 3 TRIUMPH-1 — 4, 9 or 12 mg/wk maintenance, SubQ, Weekly, 80 wk
• Community (bro science): Gray-market use — Start ~1 mg/wk (some 0.5 mg); settle at 2–4 mg/wk, SubQ, Weekly, Ongoing

Status: Investigational. Not FDA-approved (Eli Lilly, phase 3). FDA has named it in several warning letters to research-peptide sellers.

Grade and commentary: Dr. Alex Tatem. Watch: The Truth About Popular Peptides (What Works, What’s Overhyped) | Peptide Tier List pt.1, Retatrutide Dosing Explained (Doctor Breaks Down the Data), Doctor Explains Retatrutide: The Most Powerful GLP-1 Weight Loss Drug Yet, Peptide Expert: What Do Peptides Actually Do? (EXPLAINED) - Dr Alex Tatem. Subscribe: @DrAlexTatem.