You've seen clinics advertising "GLP-3 peptide" as the next breakthrough in weight loss, something beyond semaglutide and tirzepatide.

Here's what they're not telling you: there is no GLP-3 in human biology.

What clinics call "GLP-3" is actually retatrutide (LY3437943), an investigational triple receptor agonist developed by Eli Lilly that's still in Phase 3 clinical trials. The "GLP-3" label is marketing, not science.

This guide cuts through the confusion to explain what retatrutide actually is, how it differs from approved medications, what the clinical data shows, and what you should know before considering this treatment.

The truth about "GLP-3 peptide"

Human biology produces only two glucagon-like peptides from the proglucagon gene: GLP-1 and GLP-2. That's it. There is no third human GLP.

The only true GLP-3 exists in cartilaginous fish like sharks, where it regulates ketone metabolism. It has no relevance to human obesity treatment.

When clinics advertise "GLP-3 peptide," they're using a nickname for retatrutide that implies a logical progression: GLP-1 leads to GLP-2 leads to GLP-3. This is misleading. Retatrutide doesn't work on some newly discovered "GLP-3 receptor"—it works on three existing receptor systems simultaneously.

What retatrutide actually is

Retatrutide is a 39-amino acid synthetic peptide that activates three hormone receptors at once:

1. GLP-1 receptor (glucagon-like peptide-1)

2. GIP receptor (glucose-dependent insulinotropic polypeptide)

3. GCG receptor (glucagon)

This triple mechanism is why it's called a "triple agonist" or "tri-agonist"—not because it targets some mythical third glucagon-like peptide.

Current status: Retatrutide is in Phase 3 clinical trials. It is NOT FDA-approved for any indication. Clinics offering it are providing an investigational compound outside of official trials.

For context on approved weight loss peptides, see our best peptides for weight loss guide.

How retatrutide works: the triple mechanism

Understanding retatrutide's three-pronged approach explains both its impressive efficacy and its potential.

GLP-1 receptor activation

GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) have transformed obesity treatment. Retatrutide includes this mechanism:

Effects:

• Slows gastric emptying (you feel full longer)

• Reduces appetite through brain signaling

• Increases insulin secretion when blood sugar is elevated

• Improves blood sugar control

This is the foundation that makes GLP-1 medications effective for weight loss. Retatrutide builds on it.

GIP receptor activation

Glucose-dependent insulinotropic polypeptide (GIP) is the second receptor target, similar to tirzepatide (Mounjaro, Zepbound):

Effects:

• Enhances insulin release from the pancreas

• Works synergistically with GLP-1 for appetite control

• May influence fat storage and energy balance

• Improves glucose regulation

Tirzepatide's success as a dual GLP-1/GIP agonist demonstrated that adding GIP to GLP-1 enhances weight loss beyond GLP-1 alone.

Glucagon receptor activation

This is what sets retatrutide apart from tirzepatide. Glucagon receptor (GCG) activation adds:

Effects:

• Increases energy expenditure

• Promotes fat oxidation (burning fat for fuel)

• Signals satiety through brain-gut communication

• May enhance liver fat reduction

• Potentially greater effects on body composition

The glucagon component matters: Research shows that glucagon signaling through the vagal nerve creates feelings of fullness, and glucagon receptor activation in the liver stimulates FGF21 secretion—a hormone that helps burn fat without necessarily reducing food intake.

Why three is more than one plus one plus one

The combination isn't just additive—it may be synergistic:

• GLP-1 and GIP together enhance appetite suppression more than either alone

• Glucagon increases metabolic rate and fat burning

• The combined effect on energy balance exceeds what any single mechanism achieves

• Different pathways may reduce the body's ability to adapt and plateau

This helps explain why Phase 2 trials showed weight loss exceeding 24%—greater than approved single or dual agonists.

Clinical trial results: what the data shows

Retatrutide has demonstrated impressive results in clinical trials, though it's important to understand these are still research findings, not real-world outcomes.

Phase 2 obesity trial (NEJM 2023)

The landmark study published in the New England Journal of Medicine tested retatrutide in adults with obesity over 48 weeks.

Weight loss results:

Key findings:

• At the highest dose (12 mg), participants lost an average of 24.2% of body weight

• Weight loss had not plateaued at 48 weeks—participants were still losing

• 72% of participants with prediabetes reverted to normal blood sugar

• Improvements in blood pressure, lipids, and other metabolic markers

Context: These results exceed those seen with semaglutide (~15-17% in trials) and are comparable to or slightly better than tirzepatide (~21% at highest doses).

Phase 3 TRIUMPH-4 trial

The most recent Phase 3 results, announced in December 2025, tested retatrutide in people with obesity and knee osteoarthritis.

Results:

Additional findings:

• 14.1% (9 mg) and 12.0% (12 mg) achieved complete freedom from knee pain

• Significant reductions in cardiovascular risk markers

• 14.0 mmHg reduction in systolic blood pressure at highest dose

• Reductions in non-HDL cholesterol, triglycerides, and inflammatory markers

Liver fat reduction (MASLD substudy)

A separate analysis looked at retatrutide's effect on metabolic dysfunction-associated steatotic liver disease (formerly NAFLD):

Liver fat reduction at 24 weeks:

Achievement of normal liver fat (<5%):

• 86% achieved normal liver fat at 12 mg dose

• 0% in placebo group

These results suggest retatrutide may be particularly effective for fatty liver disease, though dedicated trials are ongoing.

Type 2 diabetes trial

In people with type 2 diabetes, retatrutide showed:

• Significant reductions in HbA1c (blood sugar marker)

• Weight reductions that did not plateau by 36 weeks

• Improvements in blood pressure and lipids

• Results superior to placebo and the comparator dulaglutide

For more on metabolic peptides, see our peptides for blood sugar guide.

Retatrutide dosage: what trials used

Since retatrutide isn't approved, there's no official dosing.

However, clinical trials provide insight into what protocols researchers have tested.

Clinical trial dosing protocols

Phase 2 obesity trial escalation:

Key principles:

• Once-weekly injection: Subcutaneous, like semaglutide and tirzepatide

• Slow titration: Gradual dose increases over 8-16 weeks

• Target doses: 8-12 mg for maximum efficacy

• Individualized pace: Some participants stayed at lower doses longer if experiencing side effects

Why titration matters

Rapid dose escalation is associated with:

• Severe nausea and vomiting

• Treatment discontinuation

• Poor tolerance leading to missed doses

Starting low and increasing gradually allows the body to adapt, significantly reducing gastrointestinal side effects.

Half-life and pharmacokinetics

• Half-life: Approximately 6 days

• Peak concentration: 12-72 hours after injection

• Steady state: Achieved after several weeks of consistent dosing

• Metabolism: Primarily hepatic, does not interact with cytochrome P450 enzymes

For general dosing guidance on peptides, see our peptide dosage calculator.

Retatrutide side effects

Like all incretin-based medications, retatrutide causes side effects, predominantly gastrointestinal.

Common side effects

From clinical trials:

Important context:

• Most GI side effects occur during dose escalation

• Severity is typically mild to moderate

• Side effects often decrease with continued use

• Slow titration significantly reduces incidence

Other reported side effects

• Injection site reactions (redness, irritation)

• Fatigue

• Headache

• Skin sensitivity (7% vs 1% placebo, but not serious)

• Decreased appetite (which is also a desired effect)

What wasn't seen

Notably, Phase 2 trials did NOT report:

• Hypoglycemia (low blood sugar) events

• Thyroid cancer signals

• Pancreatitis at significant rates

However, the sample sizes are still relatively small, and long-term safety data is limited.

Managing side effects

Strategies that may help:

• Eat smaller, more frequent meals

• Avoid high-fat and fried foods

• Stay well-hydrated

• Take medication at the same time each week

• Slow down dose escalation if needed

• Communicate with your healthcare provider

For comprehensive safety information, see our peptide safety guide.

Retatrutide vs. other weight loss medications

How does retatrutide compare to approved options?

Retatrutide vs. semaglutide (Ozempic/Wegovy)

Retatrutide vs. tirzepatide (Mounjaro/Zepbound)

The weight loss hierarchy

Based on clinical trial data:

1. Retatrutide (~24-29% weight loss) - Not yet approved

2. Tirzepatide (~21-22% weight loss) - FDA approved

3. Semaglutide (~15-17% weight loss) - FDA approved

Important caveat: Clinical trial populations and protocols differ, making direct comparisons imperfect. Real-world results often differ from trial results.

Understanding GLP-2: the actual intestinal peptide

While "GLP-3" is marketing fiction, GLP-2 is a real and important peptide.

Understanding it helps clarify the confusion.

What GLP-2 actually does

GLP-2 is a 33-amino acid peptide produced by L-cells in the intestine. Unlike GLP-1 (which affects appetite and blood sugar), GLP-2 focuses on gut health:

GLP-2 functions:

• Stimulates growth of intestinal lining

• Increases villus height and crypt depth

• Improves nutrient absorption

• Slows gastric emptying

• Reduces gastric acid secretion

• Enhances intestinal blood flow

Teduglutide (Gattex): the GLP-2 analog

FDA-approved for: Short bowel syndrome (SBS)

Teduglutide is a GLP-2 analog with an extended half-life (about 1.3 hours vs 7 minutes for natural GLP-2).

What it treats:

• Short bowel syndrome

• Intestinal failure requiring IV nutrition

• Severe malabsorption conditions

Key point: GLP-2/teduglutide is NOT a weight loss medication. It's for serious intestinal conditions where the gut cannot absorb nutrients properly.

Why some clinics mention GLP-2 with weight loss

Some clinics suggest GLP-2 analogs for "gut healing" or "leaky gut" alongside weight loss treatments. This is largely off-label and not supported by robust evidence for weight management.

The legitimate connection:

• Retatrutide is being studied for metabolic dysfunction-associated steatotic liver disease

• GLP-2 has anti-inflammatory effects in the gut

• Some research explores GLP-2 for inflammatory bowel disease

But these are distinct from marketing GLP-2 as a weight loss adjunct.

For legitimate gut health peptides, see our BPC-157 guide and KPV peptide benefits.

The regulatory reality: why this matters

Understanding retatrutide's regulatory status is crucial for making informed decisions.

Current status (as of late 2025)

• Phase 3 trials: Multiple ongoing (TRIUMPH program)

• FDA approval: NOT approved for any indication

• Expected timeline: Potentially 2027 or later for approval

• Availability: Only through clinical trials or off-label compounding

What "investigational" means

When a drug is investigational:

• It hasn't completed the full FDA approval process

• Long-term safety data is limited

• Manufacturing may not meet FDA standards (for compounded versions)

• Insurance won't cover it

• Legal protections for patients may be limited

The compounding pharmacy question

Some clinics obtain retatrutide through compounding pharmacies. Important considerations:

Potential concerns:

• Purity and potency may vary

• Not manufactured under FDA oversight

• No guarantee the product matches clinical trial formulations

• Quality control varies between compounders

This isn't unique to retatrutide, compounded versions of semaglutide and tirzepatide have similar concerns during shortages.

Making an informed decision

If you're considering retatrutide:

1. Ask specifically: "Is this FDA-approved?" The answer is no.

2. Understand the source: Where does the compound come from?

3. Weigh risks: Investigational drugs have unknown long-term effects

4. Consider alternatives: FDA-approved options exist with established safety profiles

5. Monitor closely: More frequent check-ins if using investigational compounds

Who might consider retatrutide

Despite the regulatory uncertainties, there are people for whom retatrutide (once approved) or early access might be considered.

Potential candidates

Based on clinical trial inclusion criteria:

• BMI ≥30 (obesity)

• BMI ≥27 with weight-related conditions (hypertension, dyslipidemia, etc.)

• Type 2 diabetes with obesity

• Knee osteoarthritis with obesity

• Metabolic dysfunction-associated steatotic liver disease (MASLD)

• Sleep apnea with obesity

Who might benefit most

Retatrutide may be particularly relevant for:

• Those who haven't achieved goals with GLP-1 or GLP-1/GIP medications

• People with significant liver fat

• Those needing substantial weight loss (>20%)

• Patients with multiple metabolic conditions

Who should avoid it

Contraindications based on trial exclusions:

• Personal or family history of medullary thyroid carcinoma

• Multiple endocrine neoplasia syndrome type 2

• Pregnancy or planning pregnancy

• Severe kidney disease

• History of pancreatitis

• Active gallbladder disease

For women-specific considerations, see our peptides for menopause guide.

Frequently asked

Is GLP-3 a real peptide?

There is no GLP-3 in human biology. "GLP-3" is a marketing term for retatrutide, a triple receptor agonist targeting GLP-1, GIP, and glucagon receptors. The only true GLP-3 exists in sharks and other cartilaginous fish, where it regulates ketone metabolism.

Is retatrutide FDA-approved?

No. Retatrutide is still in Phase 3 clinical trials. It has not been approved by the FDA for any indication. Approval is potentially years away, pending successful trial completion and regulatory review.

How much weight can you lose on retatrutide?

In Phase 2/3 clinical trials, participants lost an average of 24-29% of body weight at the highest doses (8-12 mg) over 48-68 weeks. Individual results vary, and real-world outcomes may differ from clinical trial results.

What are the side effects of retatrutide?

The most common side effects are gastrointestinal: nausea (38-43%), diarrhea (33-35%), constipation (22-25%), and vomiting (20-21%). These typically occur during dose escalation and often improve with continued use.

How is retatrutide different from semaglutide?

Semaglutide targets one receptor (GLP-1), while retatrutide targets three (GLP-1, GIP, and glucagon). In clinical trials, retatrutide produced greater weight loss (~24-29%) compared to semaglutide (~15-17%). However, semaglutide is FDA-approved with established long-term safety data, while retatrutide is still investigational.

How is retatrutide different from tirzepatide?

Tirzepatide targets two receptors (GLP-1 and GIP), while retatrutide adds a third (glucagon). Early data suggests retatrutide may produce slightly more weight loss and greater liver fat reduction, but both are effective options. Tirzepatide is FDA-approved; retatrutide is not.

Can I get retatrutide now?

Retatrutide is only officially available through clinical trials. Some clinics and compounding pharmacies offer it, but this is outside FDA oversight. The compound's quality, purity, and safety in these settings is not guaranteed.

How much does retatrutide cost?

Since retatrutide isn't approved, there's no established retail price. Clinics offering it through compounding may charge $300-800+ per month, though prices vary widely. Insurance does not cover investigational drugs.

When will retatrutide be approved?

If Phase 3 trials are successful, Eli Lilly could potentially file for FDA approval in 2026, with approval possible in 2027. However, timelines can shift based on trial results and regulatory requirements. Market analysts predict 2027 approval with projected sales of $15.6 billion by 2031.

Is "GLP-3" better than GLP-1 medications?

The "GLP-3" (retatrutide) appears more effective for weight loss in clinical trials than GLP-1-only medications. However, "better" depends on individual factors including side effect tolerance, availability, cost, and the value of established long-term safety data. For many people, approved GLP-1 or GLP-1/GIP medications may be the more appropriate choice.

The bottom line on "GLP-3"

"GLP-3 peptide" doesn't exist in human biology. When clinics use this term, they mean retatrutide—an investigational triple receptor agonist with impressive clinical trial results that is NOT yet FDA-approved.

What we know:

• Retatrutide activates GLP-1, GIP, and glucagon receptors simultaneously

• Phase 2/3 trials show 24-29% weight loss at highest doses

• Side effects are similar to other incretin medications (mainly GI)

• It may be particularly effective for liver fat reduction

• FDA approval is potentially years away

What to consider:

• Approved alternatives (semaglutide, tirzepatide) have established safety profiles

• "GLP-3" marketing may oversimplify or mislead

• Investigational drugs carry unknown long-term risks

• Quality control for compounded versions is variable

• Clinical trial results don't always translate to real-world outcomes

The bigger picture: Retatrutide may represent a genuine advance in obesity treatment—the data is genuinely impressive. But the "GLP-3" branding obscures what it actually is and its current regulatory status. Being informed about what you're considering is the first step to making a decision that's right for you.

Related guides

• Best peptides for weight loss – Comprehensive weight management options

• Peptide safety guide – Understanding risks

• Peptide dosage calculator – Accurate dosing

• Retatrutide dosage chart – Detailed dosing protocols

• BPC-157 guide – Gut healing peptide

• KPV peptide benefits – Anti-inflammatory gut support

• Peptides for menopause – Women's metabolic support

• Peptides for blood sugar – Glucose management

• How to reconstitute peptides – Preparation guide

• Peptide storage guide – Keeping peptides stable

• Getting started with peptides – Beginner's introduction

In case I don’t see you, good afternoon, good evening, and good night. Take care of yourself. <3