礼来公司的“三重G”Retatrutide减重达27%: 减重手术的终结？

The numbers are in, and they are staggering.

Eli Lilly’s Phase 3 data for retatrutide—its experimental “triple G” agonist—shows participants losing an average of 27% of their body weight, or roughly 71.2 lbs. For context, that is not just “better than Ozempic” (which typically hits ~15%) or Mounjaro (~21%); it is statistically indistinguishable from the outcomes of invasive bariatric surgery.

But the headline number isn’t the most interesting part of this story. The real breakthrough lies in how it achieves this. Retatrutide isn’t just suppressing appetite; it is fundamentally altering human metabolism by engaging a third receptor that its predecessors ignored: Glucagon.

This is the physics of why “Triple G” changes the game.

The “Triple G” Mechanism: Why Three is Better Than Two

To understand why retatrutide is so potent, you have to look at the evolution of incretin hormones.

1. Generation 1 (Semaglutide/Wegovy): Targets one receptor (GLP-1). It slows gastric emptying and signals satiety to the brain.
2. Generation 2 (Tirzepatide/Zepbound): Targets two receptors (GLP-1 + GIP). The addition of GIP (glucose-dependent insulinotropic polypeptide) enhances insulin secretion and further modulates fat metabolism.
3. Generation 3 (Retatrutide): Targets three receptors (GLP-1 + GIP + Glucagon).

The Glucagon Paradox

Adding Glucagon to a weight loss drug sounds counterintuitive. Historically, glucagon is known as the “anti-insulin”—a hormone that raises blood sugar by telling the liver to release stored glucose. Why would you want that in a metabolic drug?

The answer lies in energy expenditure.

While GLP-1 and GIP primarily focus on reductive mechanisms (eating less), Glucagon activates brown adipose tissue and increases the resting metabolic rate. It essentially turns up the body’s thermostat.

$\text{Weight Loss} = \text{Calories In (GLP-1 + GIP)} - \text{Calories Out (Glucagon)}$

By activating the glucagon receptor in the liver, retatrutide increases fatty acid oxidation (burning fat for fuel) and energy expenditure. It is attacking the obesity equation from both sides: aggressively lowering intake while simultaneously boosting output. This is why we see that jump from 21% (Tirzepatide) to 27% (Retatrutide). It is the metabolic equivalent of adding a turbocharger to an already efficient engine.

Beyond Weight: The Osteoarthritis Unlock

One of the most critical findings in the Phase 3 trial wasn’t just on the scale—it was in the knees.

The study focused on patients with obesity and osteoarthritis (OA) of the knee. The results showed “substantial relief” from OA pain, a finding that is strategically massive for Eli Lilly.

Why? Reimbursement.

Insurance companies have been hesitant to cover GLP-1s purely for “weight loss,” often categorizing it as a cosmetic or lifestyle drug. However, they do cover treatments for specific medical conditions like Type 2 Diabetes to prevent costly complications.

By proving that retatrutide treats osteoarthritis—a debilitating condition that leads to expensive knee replacement surgeries—Lilly is building a fortress of clinical data to mandate insurance coverage. If a $1,000/month drug can prevent a $50,000 knee replacement, the economic argument shifts from “vanity” to “value.”

The Hidden “Fourth” Benefit: Liver Health

While the scale captures the headlines, the most medically significant impact of retatrutide may be occurring in the liver.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as fatty liver disease, affects nearly 25% of the global population. It is a silent killer, leading to fibrosis, cirrhosis, and eventually liver failure. Currently, there are no FDA-approved drug treatments specifically for it.

This is where the Glucagon receptor shines again.

Glucagon directly stimulates hepatic (liver) fatty acid oxidation. In Phase 2 trials, retatrutide didn’t just reduce liver fat—it obliterated it. Patients saw a >80% reduction in liver fat, with nearly 90% of participants achieving total resolution of steatosis (fatty liver) at the highest dose.

This “two-birds-with-one-stone” effect—treating obesity and curing fatty liver—positions retatrutide not just as a weight loss drug, but as a hepatoprotective agent. This is a massive differentiator from Semaglutide, which has shown benefits but not the same aggressive clearance of hepatic fat that the triple-agonist mechanism achieves.

The Competitor Landscape: Lilly vs. Amgen

The market is not standing still. While Lilly pushes the envelope with efficacy (27-28% weight loss), a new challenger is emerging with a completely different philosophy: Amgen.

Amgen’s MariTide (Maridebart Cafraglutide)

While retatrutide is a “gas pedal” (activating three receptors), Amgen’s experimental drug, MariTide, acts as a brake and a gas pedal simultaneously. It is an antibody-drug conjugate that:

1. Activates the GLP-1 receptor (like Ozempic).
2. Blocks the GIP receptor (anti-Synergistic?).

Wait, retatrutide activates GIP, but MariTide blocks it?

This scientific divergence is the biggest bet in biotech right now. Amgen believes that blocking GIP might produce longer-lasting effects after the drug is stopped. Early Phase 2 data suggests MariTide could be dosed monthly (or even less frequently) compared to retatrutide’s weekly injection.

The Showdown:

• Retatrutide (Lilly): Maximum efficacy (27%), potentially higher side effects (HR), weekly dosing. The “Nuclear Option.”
• MariTide (Amgen): High efficacy, lower dosing frequency (monthly), unique GIP antagonism. The “Convenience Option.”

Detailed Safety Profile: The Heart Rate Question

The primary concern hanging over retatrutide is cardiovascular safety. Glucagon is a sympathomimetic—it activates the “fight or flight” pathways to mobilize energy.

In the TRIUMPH-1 and Phase 2 data, this manifested as an increase in resting heart rate.

• Observations: Patients on high-dose retatrutide saw a mean heart rate increase of ~5-10 beats per minute (bpm), peaking at 24 weeks before stabilizing.
• Arrhythmias: A small percentage of participants experienced cardiac arrhythmias, though mostly benign.

The FDA will heavily scrutinize this. While a slightly elevated heart rate is often acceptable in exchange for massive weight loss (which itself lowers cardiovascular risk), the long-term stress on the heart is an unknown variable. Lilly has implemented aggressive titration protocols (starting low and going slow) to mitigate this, which seems to have reduced the discontinuation rate due to adverse events.

Unlike GLP-1 monotherapies (Ozempic), where nausea is the main limiting factor, retatrutide’s limiting factor may well be this cardiac signal. It is likely that the drug will carry a warning or be contraindicated for patients with specific pre-existing heart conditions.

The “Super-Responder” Phenotype

It is important to look at the distribution of weight loss, not just the average.

• The Average: ~27% loss.
• The Super-Responders: In sub-groups, nearly 40% of participants taking the high dose are expected to lose >=30% of their body weight.

At 30% weight loss, we are entering territory where the biology of the patient is fundamentally reset. Metabolic parameters—blood pressure, A1C, lipids—often normalize completely. This pushes the conversation beyond “managing obesity” to “reversing the metabolic syndrome.”

The Context: A History of Escalation

We are witnessing a rapid escalation in the “biotech arms race” for metabolic dominance.

• 2017: Ozempic approves. The world realizes GLP-1s work.
• 2023: Zepbound approvals. The “Dual Agonist” era begins, pushing weight loss ceilings to ~20%.
• 2025/2026: Retatrutide. The “Triple Agonist” era effectively solves obesity for the vast majority of patients without surgery.

The gap between pharmaceutical intervention and surgical intervention has closed. Bariatric surgery, once the gold standard for severe obesity (BMI > 40), typically results in 25-30% weight loss. Retatrutide hitting 27% means we have effectively bottled the surgery.

Forward-Looking Analysis: The Safety Hurdle

The only thing standing between retatrutide and market dominance is the safety profile. Specifically, the “Glucagon effect” can increase heart rate.

In Phase 2 trials, retatrutide was associated with a dose-dependent increase in heart rate, peaking at around 24 weeks. The Phase 3 data will need to be scrutinized heavily by the FDA to ensure that the increased sympathetic nervous system activity (driven by glucagon) doesn’t translate to adverse cardiovascular events long-term.

However, if the safety profile holds—particularly with the titration protocols Lilly has developed—we are looking at the new king of the hill.

What comes next?

The Phase 3 data is the green light. Expect a full NDA filing with the FDA in early 2026.

If approved, retatrutide creates a new tier in the obesity market:

1. Tier 1 (Semaglutide/Wegovy): ~15% loss. For BMI 27-30 or cosmetic use.
2. Tier 2 (Tirzepatide/Zepbound): ~21% loss. For BMI 30-35.
3. Tier 3 (Retatrutide): ~27-30% loss. For BMI > 35, or those with comorbidities like Osteoarthritis and Fatty Liver.

The “Triple G” era effectively closes the chapter on the first generation of obesity drugs. We are no longer just suppressing appetite; we are engineering metabolism. With retatrutide, Eli Lilly hasn’t just built a better mousetrap; they’ve built a trap that burns the mouse’s fat while it waits.