Retatrutide: The Triple Agonist Approaching Bariatric Surgery Results

Retatrutide (LY3437943) is the first medication to approach the efficacy of bariatric surgery without the knife. In Eli Lilly's TRIUMPH-4 trial, patients on the 12mg dose lost an average of 28.7% of their body weight—roughly 71 pounds—compared to just 2.1% on placebo.

For context: gastric sleeve surgery typically produces 25-32% weight loss. We're now in territory where a weekly injection can rival major abdominal surgery.

How Triple Agonism Works

Current GLP-1 drugs target one receptor (semaglutide) or two (tirzepatide). Retatrutide targets three: GLP-1, GIP, and Glucagon. Each receptor does something different, and the combination creates synergistic effects beyond any single mechanism.

The Glucagon Paradox

Glucagon seems counterintuitive—it's the hormone that raises blood sugar by triggering glucose release from the liver. But here's the trick: when you activate glucagon alongside GLP-1 and GIP, the potent insulin secretion from those two receptors neutralizes the blood sugar effect. What's left is glucagon's beneficial action: burning liver fat and ramping up metabolic rate.

This is why retatrutide outperforms everything else. You're not just eating less—you're actively burning more, particularly the dangerous visceral fat in and around organs.

Phase 3 Results: The TRIUMPH Program

TRIUMPH-4 Headline Results

The most recent data comes from TRIUMPH-4, which studied patients with obesity and knee osteoarthritis:

• 12mg dose: 28.7% weight loss (~71 lbs) at 68 weeks
• 9mg dose: 26.4% weight loss
• Placebo: 2.1%
• Pain improvement: 76% reduction in WOMAC pain score
• Pain freedom: 12-14% achieved complete pain freedom vs 4.2% placebo

Phase 2 "Super-Responder" Data

Earlier Phase 2 data published in NEJM showed remarkable threshold achievement:

• 100% of patients on 8mg and 12mg achieved ≥5% weight loss
• 26% of patients on 12mg lost ≥30% of body weight

That "super-responder" tier—losing more than 30%—is virtually nonexistent with current GLP-1 medications.

Comparison to Current Options

Side Effects: The Triple Agonist Trade-Off

More efficacy means more side effects. Retatrutide's profile mirrors the incretin class but with glucagon-specific additions:

Discontinuation Rates

In TRIUMPH-4, 18.2% of patients on 12mg discontinued due to adverse events. This is higher than semaglutide (~4-7%) and tirzepatide (~7-10%), reflecting the greater potency and side effect burden.

Dosing & Titration

The introduction of glucagon requires conservative titration to manage side effects:

Flexibility: Patients can remain at 9mg if 12mg isn't tolerated—still achieving >26% weight loss.

Timeline to Approval

The Competition

Novo Nordisk isn't sitting still. In March 2025, they acquired rights to UBT251, a competing triple agonist, for $200 million upfront and up to $1.8 billion in milestones. Early data showed 15.1% weight loss in just 12 weeks—potentially "hotter" than retatrutide's early-phase trajectory.

Hanmi Pharmaceutical is developing HM15211 (triple agonist focused on liver disease) and HM15275 (optimized for muscle preservation during weight loss).