Everything We Know About Retatrutide So Far (2025 Clinical Updates)

Introduction

Weight-loss medicine has evolved faster in the past five years than in the previous five decades. Drugs like Semaglutide and Tirzepatide have already changed how doctors approach obesity – but Eli Lilly’s investigational therapy Retatrutide might push those limits even further.

If early data hold up, Retatrutide could deliver an average 24% body-weight reduction in less than a year – numbers previously seen only after bariatric surgery.

So, what exactly is Retatrutide, how does it work, and how does it stack up against the current heavyweights in this space? Let’s dig into what 2025 clinical data tell us.

What Is Retatrutide and How Does It Work?

Retatrutide (LY-3437943) is a triple hormone receptor agonist developed by Eli Lilly. Unlike existing GLP-1 drugs that target a single hormone pathway, Retatrutide activates three:

• GLP-1 (Glucagon-Like Peptide-1) – regulates appetite and slows digestion.
• GIP (Glucose-Dependent Insulinotropic Polypeptide) – supports insulin release and metabolic efficiency.
• Glucagon receptor – helps burn fat by promoting energy expenditure.

In simpler terms, Retatrutide aims to suppress appetite, improve insulin function, and boost metabolism – a “triple-threat” mechanism that may explain its strong weight-loss results.

The drug is still in Phase 3 trials as of late 2025, but early data have drawn serious attention from the medical community and investors alike.

As Dr. Ania Jastreboff of Yale School of Medicine, lead investigator of the landmark 2023 NEJM study, explained:

“The magnitude of weight loss with Retatrutide is something we’ve never seen before in obesity pharmacotherapy.”

Clinical Results: What the Studies Show

Phase 2 Results (NEJM, 2023)

The pivotal Phase 2 trial published in The New England Journal of Medicine followed 338 adults with obesity (without diabetes) for 48 weeks. Participants received weekly injections of Retatrutide or placebo.

Average weight loss after 48 weeks:

• 1 mg – 8.7%
• 4 mg – 17.1%
• 8 mg – 22.8%
• 12 mg – 24.2%
• Placebo – 2.1%

At the top dose (12 mg), participants lost nearly a quarter of their body weight – an average of about 58 pounds (26 kg). For context, that’s roughly equivalent to outcomes seen after sleeve-gastrectomy surgery.

In addition to weight loss, researchers observed improvements in:

• Blood pressure
• Cholesterol levels
• Insulin sensitivity
• Liver fat reduction (a promising sign for MASLD/NASH patients)

Source: Jastreboff AM et al., NEJM 2023; 389(17): 1628–1639.

Phase 3 Trials (Ongoing in 2025)

As of 2025, Eli Lilly is running several Phase 3 programs:

• TRIUMPH-1 (NCT06859268) – weight management in non-diabetic adults
• TRIUMPH-2 – comparison with Tirzepatide in obesity
• TRIUMPH-3 – long-term maintenance and rebound tracking

Preliminary updates indicate that weight loss trends remain consistent with Phase 2 – with sustained reductions and acceptable tolerability. Final results are expected in 2026.

Dosing and Administration

Retatrutide is administered once weekly by subcutaneous injection, much like Semaglutide (Wegovy) or Tirzepatide (Zepbound).

In trials, doses were gradually escalated to limit side effects. The highest studied dose, 12 mg per week, produced the greatest weight reduction.

If approved, experts expect Lilly to recommend stepwise dose escalation (for example, 2 mg → 4 mg → 8 mg → 12 mg) over several weeks, to improve tolerability and reduce gastrointestinal discomfort.

Side Effects and Safety

Like other GLP-1-based therapies, the most common side effects are gastrointestinal.

Reported adverse events include:

• Nausea (around 30–40% of patients)
• Diarrhea or constipation
• Vomiting (typically during dose titration)
• Mild increase in heart rate (around 3–5 bpm)

Most side effects are mild or moderate and tend to lessen as the body adapts. So far, there have been no major safety concerns such as severe pancreatitis or thyroid cell abnormalities.

Eli Lilly has confirmed that its Phase 3 studies will include dedicated cardiometabolic safety endpoints to assess long-term effects.

How Does Retatrutide Compare to Semaglutide (Ozempic) and Tirzepatide (Zepbound)?

To understand Retatrutide’s potential, it helps to compare it with the current market leaders in GLP-1-based therapy:

Semaglutide (Ozempic, Wegovy):

• Mechanism: GLP-1 agonist
• Average weight loss: ~15%
• Duration: 68 weeks
• Proven standard

Tirzepatide (Zepbound)

• Mechanism: GLP-1 + GIP dual agonist
• Average weight loss: ~20–21%
• Duration: 72 weeks
• Superior to Semaglutide in SURMOUNT-1 trial

Retatrutide (RETA)

• Mechanism: GLP-1 + GIP + Glucagon triple agonist
• Average weight loss: ~24%
• Duration: 48 weeks
• Status: Investigational (Phase 3)

In short, Retatrutide extends the mechanism of Zepbound by adding glucagon activation – encouraging the body to burn energy rather than merely suppressing appetite.

Whether this triple mechanism can maintain safety and comfort long-term is the question 2026 studies aim to answer.

Why Retatrutide Matters

If Retatrutide delivers on its promise, it could mark the start of a new era in metabolic medicine – one where pharmacological weight loss matches surgical results with fewer risks.

Beyond appearance or body weight, this could have far-reaching public health impacts:

• Lower rates of type 2 diabetes
• Reduced cardiovascular disease
• Reversal of fatty liver disease
• Improved mobility and quality of life

While questions around cost, coverage, and long-term weight stability remain, Retatrutide’s data suggest a turning point in obesity care – a future where medication can achieve results once possible only through surgery.

Conclusion

By now, most people have heard of Ozempic, Wegovy, and Zepbound, but Retatrutide may soon join, or even surpass, that list. With promising clinical results and a unique triple-agonist approach, it stands out as one of the most powerful next-generation therapies in development.

Still, caution is warranted. Long-term safety, accessibility, and real-world adherence will determine whether Retatrutide becomes a lasting breakthrough or simply a major stepping stone in obesity care.

As Dr. Karen Miller, an endocrinologist at Brigham and Women’s Hospital, noted:

“We’re entering an era where obesity can finally be managed as a metabolic disease, not a personal failure.”