Peptide Evidence Index

Retatrutide

Evidence last reviewed: September 2026

Quick answers

What is it?
Retatrutide is an experimental peptide that activates three hormone receptors at once (GIP, GLP-1, and glucagon) and is not approved as a medicine anywhere.
Why are people interested in it?
Its Phase 2 trial showed larger weight loss at 48 weeks than any single-hormone GLP-1 drug has shown in a comparable trial.
What has actually been studied?
One completed, published randomized Phase 2 trial in 338 adults with obesity; a large Phase 3 program is underway but unpublished.
How strong is the evidence?
Promising but early — the evidence rests on a single mid-sized Phase 2 trial, and the larger Phase 3 program that would normally support approval has not yet reported results.
What don't we know yet?
Whether the Phase 2 effect holds up in Phase 3, long-term cardiovascular and kidney safety, and what happens after stopping the drug.
Where can I read the original research?
Sources at the bottom of this page: the Phase 2 trial (Jastreboff et al., NEJM 2023) and the TRIUMPH-1 registry record.

Plain-English overview

Retatrutide is a synthetic peptide engineered to activate three separate hormone receptors at once: GIP and GLP-1 — the same two targeted by tirzepatide — plus the glucagon receptor, which is theorized to add an energy-expenditure effect on top of the appetite-suppressing and insulin-boosting effects of the other two. It is being developed by Eli Lilly, the same company that makes tirzepatide, and is not approved as a medicine anywhere in the world; it exists only in clinical trials and a registered pre-approval expanded-access program. It is the furthest along of the 'next-generation' incretin drugs, with a published Phase 2 trial showing weight loss larger than any single-hormone GLP-1 drug at 48 weeks, and a large Phase 3 program — including the TRIUMPH trials — underway. The Phase 3 results that will determine its real-world safety profile at scale were still unpublished as of this session.

What researchers are studying it for

Current evidence level

Randomized trials

Regulatory status: Not an approved medicine. Evidence strength and approval are scored separately; approval is a regulatory decision about a specific use, not a measure of how much research exists.

Human research

The only published, completed trial of meaningful size is the Phase 2 study (Jastreboff et al., NEJM 2023), which randomized 338 adults with obesity (BMI 30 or higher, or 27-30 with a weight-related condition) to one of several retatrutide dose arms or placebo, injected weekly for 48 weeks. At 48 weeks, mean weight loss ranged from 8.7% at the lowest studied dose to 24.2% at the highest, versus 2.1% with placebo; at the highest dose, 83% of participants lost at least 15% of body weight, versus 2% on placebo. Heart rate rose in a dose-dependent way, peaking around 24 weeks and declining afterward. Beyond that trial, a large Phase 3 program is underway, including TRIUMPH-1 (obesity and overweight, with knee-osteoarthritis and sleep-apnea subsets, planned enrollment 2,335, primary completion April 2026), TRANSCEND-T2D-1 and -2 (type 2 diabetes), and TRIUMPH-Outcomes (cardiovascular and kidney events in people with obesity and existing disease, planned enrollment 10,000, projected completion February 2029). Several of these, including TRIUMPH-1, had reached their primary completion date by mid-2026, but as of this session none had posted peer-reviewed or registry results. The Phase 2 finding is real and verified; the larger, longer Phase 3 evidence that would normally support an approval decision does not yet exist in published form. 33 studies listing retatrutide as an intervention are registered on ClinicalTrials.gov as of this session.

Animal and preclinical research

The source material reviewed here does not describe specific animal or preclinical studies for retatrutide. As an investigational drug in the same mechanistic family as tirzepatide, its trials follow comparable exclusion practices around thyroid-cancer and pancreatitis history, but no rodent tumor findings specific to retatrutide are described in the material reviewed.

Major findings

What has not been established

Important limitations

Regulatory status

Not approved as a medicine anywhere. Developed by Eli Lilly, retatrutide is in an active Phase 3 program — including the TRIUMPH and TRANSCEND-T2D trials — and a pre-approval expanded-access program has been registered, but as of this session no regulatory agency has approved it for any use. Not on the World Anti-Doping Agency's Prohibited List, though as an unapproved investigational drug its presence in any marketed product would itself be a serious red flag.

Primary research sources

Jastreboff AM et al., Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
NEJM 2023; PMID 37366315; ClinicalTrials.gov NCT04881760
TRIUMPH-1 (Phase 3, obesity/overweight with knee-osteoarthritis and sleep-apnea subsets)
ClinicalTrials.gov NCT05929066; status completed, primary completion April 2026; results not yet posted
TRIUMPH-Outcomes (Phase 3, cardiovascular and kidney outcomes)
ClinicalTrials.gov NCT06383390; status active, not recruiting; projected completion February 2029; results not yet posted
Full evidence entry (complete data, registry records, dosing evidence)
Randomized trials
Supported by randomized controlled trials

At a glance

Also known as
LY3437943
Class
Triple hormone-receptor agonist (GIP/GLP-1/glucagon)
Derived from
A synthetic peptide engineered to activate three receptors at once — GIP, GLP-1, and the glucagon receptor — combining the mechanisms of dual-incretin drugs like tirzepatide with an added glucagon-receptor effect on energy expenditure
Registered human trials
33
…with published results
at least the Phase 2 trial below; several completed Phase 3 trials (including TRIUMPH-1) have not yet posted peer-reviewed or registry results as of this session
Largest human trial
2,335 adults without type 2 diabetes who have obesity or overweight (TRIUMPH-1, a Phase 3 master protocol; primary completion April 2026) is the largest registered retatrutide trial, but its results were not yet published as of this session; the largest published trial remains the 338-person Phase 2 study below
Studied for
chronic weight management in overweight/obesity (Phase 3, unapproved), type 2 diabetes glycemic control (Phase 3, unapproved), cardiovascular and kidney event reduction in adults with obesity and existing cardiovascular or kidney disease (Phase 3, ongoing through 2029)
Dosing evidence
Doses used in trialsAll human dosing data comes from company-run Phase 1-3 trials using supervised escalation schedules; there is no FDA-approved label or dose for retatrutide anywhere, for any use.
Regulatory status
Not approved as a medicine anywhere. Retatrutide, developed by Eli Lilly, is in an active Phase 3 program — including the TRIUMPH and TRANSCEND-T2D trials — and a pre-approval expanded-access program has been registered, but as of this session no regulatory agency has approved it for any use.
Anti-doping status
Not on the World Anti-Doping Agency's Prohibited List — though as an unapproved investigational drug, its presence in any marketed product would itself be a serious red flag

What it is

Retatrutide is a synthetic peptide engineered to activate three separate hormone receptors at once: GIP and GLP-1 — the same two targeted by tirzepatide — plus the glucagon receptor. Glucagon is usually thought of as insulin's opposite, raising blood sugar, but agonizing its receptor alongside GIP and GLP-1 is theorized to add an energy-expenditure effect on top of the appetite-suppressing and insulin-boosting effects of the other two. It is being developed by Eli Lilly, the same company that makes tirzepatide.

It is not approved as a medicine anywhere in the world. It exists only in clinical trials and a registered pre-approval expanded-access program.

What the studies actually found

The only published, completed trial of meaningful size is the Phase 2 study (Jastreboff et al., NEJM 2023; PubMed PMID 37366315, DOI), which randomized 338 adults with obesity (BMI 30 or higher, or 27-30 with a weight-related condition) to one of several retatrutide dose arms or placebo, injected weekly for 48 weeks. At 48 weeks, mean weight loss ranged from 8.7% at the lowest studied dose to 24.2% at the highest, versus 2.1% with placebo. At the highest dose, 83% of participants lost at least 15% of body weight, versus 2% on placebo. Heart rate rose in a dose-dependent way, peaking around 24 weeks and declining afterward.

Beyond that trial, Eli Lilly has a large Phase 3 program underway, including TRIUMPH-1 (obesity and overweight, with knee-osteoarthritis and sleep-apnea subsets), TRANSCEND-T2D-1 and -2 (type 2 diabetes), and TRIUMPH-Outcomes (cardiovascular and kidney events in people with obesity and existing disease). Several of these — including TRIUMPH-1 — had reached their primary completion date by mid-2026, but as of this session none had posted peer-reviewed or registry results. The Phase 2 finding above is real and verified; the larger, longer Phase 3 evidence that would normally support an approval decision does not yet exist in published form.

What exists in humans

33 studies listing retatrutide as an intervention are registered on ClinicalTrials.gov as of this session, spanning Phase 1 pharmacokinetic and drug-interaction studies, the Phase 2 obesity trial above, and a wide Phase 3 program in obesity, type 2 diabetes, chronic kidney disease, knee osteoarthritis, sleep apnea, and cardiovascular/kidney outcomes. This is a substantially smaller and younger trial record than any of the approved drugs profiled alongside it — retatrutide's largest published trial (338 participants) is smaller than the smallest pivotal trial behind any approved GLP-1 drug covered here.

The Phase 2 trial and the Phase 3 obesity program both exclude, as is standard for this drug class, people with a history of pancreatitis, a personal or family history of medullary thyroid carcinoma or MEN2, and recent significant change in body weight. A registered expanded-access program (for patients who do not qualify for or cannot access a trial) exists, which is itself a signal the sponsor considers the drug close to a filing decision — but expanded access is not the same as approval, and it does not mean the drug has been shown safe and effective for general use.

What doses have been studied in humans

The Phase 2 trial gave 338 adults with obesity a weekly subcutaneous injection, escalated over several weeks to one of six dose levels (1 mg up to 12 mg, with different starting-dose strategies), continued for 48 weeks; the primary endpoint was percent change in body weight at 24 weeks, with 48-week change as a secondary measure. The ongoing Phase 3 trials use comparable weekly, escalated regimens over longer durations — TRIUMPH-1 ran its primary treatment period to 80 weeks, with an optional extension to 104 weeks.

Because retatrutide has no approved label anywhere, there is no dose "approved for" any use — every dose that exists in the human record is a trial-protocol dose, administered under direct research supervision with structured monitoring. That is a materially different situation from the five approved drugs profiled alongside it, and it means there is no legitimate real-world source for a retatrutide dose outside a clinical trial.

What remains unknown

  • Whether the Phase 2 effect holds up in Phase 3. Phase 2 obesity trials for other drugs in this class (including tirzepatide's own Phase 2) have generally translated into similar or somewhat smaller Phase 3 effects, but this has not yet been confirmed for retatrutide because Phase 3 results were unpublished as of this session.
  • Cardiovascular and kidney safety at scale. TRIUMPH-Outcomes, the trial designed to answer this question directly in people with existing cardiovascular or kidney disease, is not expected to complete before 2029.
  • What happens after stopping. No dedicated withdrawal trial comparable to semaglutide's STEP 1 extension or tirzepatide's SURMOUNT-4 has been published for retatrutide.
  • The heart-rate increase seen in the Phase 2 trial was dose-dependent and did not fully resolve within the 48-week trial window; its long-term clinical significance is not yet established.
  • Regulatory status. Retatrutide is not approved anywhere. Any product claiming to contain it outside a registered clinical trial or the registered expanded-access program is not a legitimate source of the studied drug.

Registry and study records

Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
ClinicalTrials.gov NCT04881760 · n=338, completed 2022, results posted; Jastreboff et al., NEJM 2023
TRIUMPH-1 (Phase 3, obesity/overweight, with knee osteoarthritis and sleep apnea subsets)
ClinicalTrials.gov NCT05929066 · n=2,335, status COMPLETED, primary completion April 2026; no results posted on the registry as of this session
TRIUMPH-Outcomes (Phase 3, cardiovascular and kidney outcomes)
ClinicalTrials.gov NCT06383390 · planned n=10,000, status ACTIVE_NOT_RECRUITING, projected completion February 2029; no results posted
See the full Evidence Index →

Related research

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Topic hubs

TopicWeight & Metabolism

Evidence last reviewed: September 2026. Peptide Proof reports what studies found. We do not give medical advice, dosing guidance, or treatment recommendations.