What Is Retatrutide? Next-Gen GLP-1 Triple Agonist for Weight Loss Explained (2026)

TRIUMPH-4 Phase 3 Results (Dec 2025)

Record Weight Loss: Participants on the 12mg dose lost an average of 28.7% (71.2 lbs) of their total body weight over 68 weeks.

What is Retatrutide?

Retatrutide is an investigational, once-weekly injectable medicine being studied for chronic weight management (and related conditions). It’s often described as a “triple agonist” because it activates three receptors:

GIP (glucose-dependent insulinotropic polypeptide)
GLP-1 (glucagon-like peptide-1)
Glucagon receptors

This “triple” mechanism is what differentiates retatrutide from today’s most well-known drugs like semaglutide (GLP-1) and tirzepatide (GIP/GLP-1) and why it's often referred to as the "Triple G".

Current status (Dec 2025): Retatrutide is in the Phase 3 TRIUMPH program. A Phase 3 trial (TRIUMPH-4) has reported positive topline results, and additional Phase 3 readouts are expected in 2026. Read our latest update and FDA approval timeline here.

What is the "Triple G" Triple Agonist?

While older medications like Ozempic (Semaglutide) target one receptor and Mounjaro (Tirzepatide) targets two, Retatrutide is the world’s first "Triple G" receptor agonist. It is nicknamed "Triple G" because it simultaneously activates three key metabolic pathways that all begin with the letter G:

GLP-1 (Glucagon-like Peptide-1): Suppresses appetite and slows gastric emptying.
GIP (Glucose-dependent Insulinotropic Polypeptide): Enhances insulin secretion and stabilizes energy balance.
Glucagon: This is the "third G" that sets Retatrutide apart. By activating the glucagon receptor, Retatrutide increases energy expenditure and promotes the breakdown of fat (lipolysis) in the liver.

This triple agonist approach allows for a "multi-pronged" attack on obesity that earlier generations of GLP-1s simply cannot match.

How Retatrutide Works

Retatrutide’s weight-loss potential comes from hitting appetite and metabolism from multiple angles:

1) GLP-1 effects (satiety + slower gastric emptying)

GLP-1 receptor activation tends to:

Increase fullness (satiety)
Reduce hunger and food intake
Slow gastric emptying (food leaves the stomach more slowly), which can reduce appetite

2) GIP effects (incretin signaling + metabolic regulation)

GIP is an incretin hormone involved in insulin response after eating. In combination therapies, GIP activity may enhance weight loss and metabolic outcomes.

3) Glucagon receptor effects (energy expenditure angle)

Glucagon receptor activation is the “extra gear” retatrutide has compared with tirzepatide. In theory, this pathway may help increase energy expenditure and fat utilization—but it can also come with tradeoffs (for example, dose-dependent heart-rate increases were seen in Phase 2).

Bottom line: Retatrutide is designed to combine the appetite suppression of GLP-1/GIP drugs with additional metabolic effects via glucagon receptor activity.

Retatrutide Weight Loss Results

Phase 2 (Obesity, 48 weeks)

In a Phase 2 randomized trial in adults with obesity (or overweight with a weight-related condition), retatrutide produced large average weight loss:

At 24 weeks: up to ~17.5% mean loss (12 mg group) vs ~1.6% placebo
At 48 weeks:
- 12 mg: -24.2%
- 8 mg: -22.8%
- 4 mg (combined): -17.1%
- Placebo: -2.1%

Responder rates at 48 weeks were also strong. For example, ≥15% weight loss occurred in 83% of participants in the 12 mg group (vs 2% placebo).

Phase 3 topline (TRIUMPH-4, 68 weeks; obesity/overweight + knee osteoarthritis)

In Lilly’s reported topline results for TRIUMPH-4 (adults with obesity/overweight and knee osteoarthritis, without diabetes), retatrutide showed:

12 mg: -28.7% mean body weight change at 68 weeks (about -71.2 lbs)
9 mg: -26.4%
Placebo: -2.1%

A notable chunk of participants achieved extremely large losses:

≥30% weight loss: 39.4% (12 mg) vs 0.8% placebo
≥35% weight loss: 23.7% (12 mg) vs 0% placebo

Reality check: These results are impressive, but they come from different trials, different populations, and different time horizons. Until head-to-head trials exist, comparisons to other drugs are indirect.

How Retatrutide Compares to Semaglutide (Wegovy/Ozempic) and Tirzepatide (Mounjaro/Zepbound)

While Retatrutide represents the next generation of weight loss medications, it's important to understand how it stacks up against the currently available options: Semaglutide (Wegovy, Ozempic) and Tirzepatide (Zepbound, Mounjaro).

The Key Difference: Mechanism of Action

The primary distinction lies in how many hormone receptors each medication targets:

Semaglutide (Wegovy/Ozempic): Single agonist targeting GLP-1 receptors only Tirzepatide (Zepbound/Mounjaro): Dual agonist targeting GLP-1 and GIP receptors Retatrutide: Triple agonist targeting GLP-1, GIP, and glucagon receptors

This triple-action approach is what enables Retatrutide's superior weight loss results, but it also introduces new considerations around side effects and safety.

What they have in common

Both are once-weekly injections studied for obesity
Both activate GLP-1 + GIP pathways (major appetite and metabolic signals)

Key difference

Tirzepatide: dual agonist (GLP-1 + GIP)
Retatrutide: triple agonist (GLP-1 + GIP + glucagon)

How do the results compare (indirectly)?

Tirzepatide (SURMOUNT-1, 72 weeks):

Mean weight change at week 72:
- 15 mg: -20.9%
- 10 mg: -19.5%
- 5 mg: -15.0%
- Placebo: -3.1%

Tirzepatide vs Semaglutide (SURMOUNT-5, 72 weeks; head-to-head):

Tirzepatide: -20.2%
Semaglutide: -13.7%

Retatrutide (Phase 2, 48 weeks):

Up to -24.2% at 48 weeks (12 mg)

Retatrutide (TRIUMPH-4 topline, 68 weeks):

Up to -28.7% at 68 weeks (12 mg)

Retatrutide vs. Tirzepatide (Mounjaro/Zepbound): Which is Better?

The "best" medication depends on your timeline, risk tolerance, and weight loss goals. As of 2026, clinical data suggests that Retatrutide may significantly outperform Tirzepatide (Mounjaro/Zepbound) in total weight loss percentage.

While Tirzepatide is the current "gold standard," Retatrutide is the "next-gen" successor. The addition of the Glucagon receptor in Retatrutide helps overcome weight-loss plateaus by keeping the metabolism active even as you eat fewer calories.

Choose Semaglutide if:

You want the most established safety profile (longest market history)
You have cardiovascular disease (proven CV benefits)
You prefer a medication with extensive real-world data
You want to start losing weight immediately

Choose Tirzepatide if:

You want maximum currently available efficacy
You've tried Semaglutide with suboptimal results
You're willing to try a newer medication for better results
You want to start making progress while Retatrutide completes trials

Wait for Retatrutide if:

You're willing to wait 12-18 months for potentially superior results
You have significant weight to lose (100+ lbs)
Other medications haven't achieved your goals
You're prepared for a newer safety profile with unique side effects

The Reality: Most People Don't Need to Wait

While Retatrutide's 28.7% weight loss is impressive, Tirzepatide's 22.5% average represents substantial, life-changing results for most people. For someone weighing 250 lbs, that's a 56-pound loss compared to Retatrutide's projected 72 pounds—both are transformative outcomes.

The additional 12-18 month wait means delaying health improvements, continued strain on joints and cardiovascular system, and postponing the lifestyle changes that come with significant weight loss. For many patients, starting now with a proven medication is the smarter choice.

Side effect profile comparison (high level)

Both drug types commonly cause GI side effects (nausea, diarrhea, constipation, vomiting), especially during dose escalation.
Retatrutide has also shown:

Dose-dependent heart-rate increases in Phase 2
A dysesthesia signal reported in TRIUMPH-4 topline (abnormal sensation/touch)

Practical takeaway: If retatrutide reaches approval, it may be positioned for people who want maximum weight loss, but tolerability and safety will matter just as much as the headline percentage.

Side Effects

Most common side effects seen in retatrutide trials

In TRIUMPH-4 topline results (9 mg and 12 mg), common side effects included:

Nausea: 38.1% / 43.2% (vs 10.7% placebo)
Diarrhea: 34.7% / 33.1% (vs 13.4% placebo)
Constipation: 21.8% / 25.0% (vs 8.7% placebo)
Vomiting: 20.4% / 20.9% (vs 0% placebo)
Decreased appetite: 19.0% / 18.2% (vs 9.4% placebo)

In the Phase 2 obesity trial, adverse events were commonly gastrointestinal, generally mild-to-moderate, and were partially mitigated with a lower starting dose; researchers also observed dose-dependent increases in heart rate that peaked around 24 weeks then declined.

Beyond Weight Loss: Retatrutide and Joint Health (TRIUMPH-4 Trial)

One of the most exciting breakthroughs in the TRIUMPH-4 Phase 3 trial (released Dec 2025) was Retatrutide’s impact on Knee Osteoarthritis (OA).

Obesity and joint pain are inextricably linked, but Retatrutide showed benefits that went beyond just taking the weight off the joints:

75% Pain Reduction: Participants reported a staggering 75.8% reduction in WOMAC pain scores.
Complete Pain Relief: In a post-hoc analysis, approximately 1 in 8 participants reported being completely free of knee pain by week 68.
Improved Mobility: Functional scores improved by over 70%, allowing patients to return to activities they had previously abandoned due to chronic inflammation and joint stress.

If you are struggling with "obesity-induced knee pain," Retatrutide represents a significant leap forward in dual-purpose therapy for both metabolic and musculoskeletal health.

Dysesthesia (TRIUMPH-4 topline signal)

TRIUMPH-4 reported dysesthesia in:

8.8% (9 mg) and 20.9% (12 mg) vs 0.7% placebo

Retatrutide and Muscle Mass: Can it Preserve Lean Tissue?

A major concern with rapid weight loss is "sarcopenia" or the loss of muscle mass. Early research into Retatrutide indicates a unique potential for muscle-sparing body recomposition.

Because Retatrutide activates the Glucagon receptor, it promotes higher energy expenditure and fat oxidation. While all weight loss involves some lean mass reduction, Retatrutide’s metabolic "revving" effect may help the body prioritize burning stored fat over muscle tissue when combined with high-protein intake and resistance training. This makes it a highly discussed "body comp" peptide among researchers and clinicians looking for "quality" weight loss rather than just a lower number on the scale.

Is it safe to buy Retatrutide online?

Safety warning about “research” products sold online

Because retatrutide is not approved, some sellers push “research only” versions. The FDA has explicitly warned consumers about illegally marketed, unapproved GLP-1-related products — including ones containing retatrutide — often sold online with dosing instructions despite “not for human consumption” labeling.

Who It’s Best For

Right now (Dec 2025): retatrutide is only available via clinical trials—not legally as a prescribed, FDA-approved medication.

If it becomes approved, the data suggests it may be best suited for adults who:

Have obesity (BMI ≥30) or overweight (BMI ≥27 with a weight-related condition)—the populations used in trials
Want very large weight loss (e.g., targeting 20%+) and can tolerate dose escalation and GI effects
Have obesity-related complications being studied (for example, knee osteoarthritis in TRIUMPH-4)

Not a good fit (common-sense filter):

Anyone trying to source “research” peptides online (quality + legality + safety risks are real).
Anyone who can’t tolerate significant GI side effects or who is at higher risk from the known tolerability issues seen in incretin-style therapies (needs clinician judgment)

FAQs

Is retatrutide FDA approved?

No. As of Dec 11, 2025, retatrutide is not FDA-approved.

When will retatrutide be available?

There’s no official public approval date. Lilly reported TRIUMPH-4 topline results and says multiple Phase 3 trials are expected to complete in 2026.
Some media physicians speculate it’s unlikely to be available until late 2026 or later, depending on trial completion and FDA review.

How is retatrutide taken in studies?

In trials, it’s been studied as a once-weekly subcutaneous injection, with gradual dose escalation to improve tolerability.

How much weight can people lose on retatrutide?

In published Phase 2 obesity data, average losses reached up to 24.2% at 48 weeks at higher doses.
In TRIUMPH-4 topline Phase 3 results (knee osteoarthritis population), Lilly reported up to 28.7% at 68 weeks (12 mg).

Is it safe to buy retatrutide online as a “research chemical”?

Don’t. The FDA warns that unapproved GLP-1-related drugs sold online may be counterfeit, contain wrong ingredients, wrong doses, or no active ingredient—and has specifically warned about products containing retatrutide being sold under “research use” labels.

What’s the closest FDA-approved alternative today?

If you want a “closest analog” in terms of mechanism and results, tirzepatide is a GLP-1/GIP dual agonist with strong obesity outcomes (e.g., ~20% average loss in multiple studies).
A clinician can help decide what’s appropriate based on your health profile and access.