Draft entry. Written from the cited papers but not yet reviewed by a person. Check the references before relying on any claim.

Retatrutide

also LY3437943 · Triple G · GTPL13769

Retatrutide is an experimental once-weekly injected peptide from Eli Lilly that activates three hormone receptors: GIP, GLP-1 and glucagon [1]. In a 48-week phase 2 trial in adults with obesity, the 12 mg dose lowered body weight by 24.2%, against 2.1% on placebo [2]. The first phase 3 trial, in type 2 diabetes, confirmed large falls in HbA1c and weight [3]. It is not approved; in the cited literature its phase 3 obesity trials are still under way [4].

Very large weight losses in phase 2 and confirmed glucose effects in phase 3, but the obesity phase 3 results, long-term safety data and any approval are still to come.

C₂₂₁H₃₄₂N₄₆O₆₈4731 g/molCID 171390338 ↗

Human RCTs10 papers · 2020–2026 · 8 journals · 8 in humans

meta-analysis
RCT
trial
observational
preclinical / case
review / patent / other
retracted

in its favour

+ About 24% average weight loss at 48 weeks on the top dose in phase 2
+ Large HbA1c reductions in type 2 diabetes, confirmed in phase 3
+ Liver fat fell by more than 80% on higher doses in people with fatty liver

watch for

− Dose-related nausea, vomiting and diarrhoea, reduced by starting at a lower dose
− Heart rate rises with dose
− Not approved; long-term safety data are not yet published

Overview

Retatrutide (LY3437943) is a single peptide that activates the glucagon, GIP and GLP-1 receptors. In a phase 1 study its pharmacokinetics supported once-weekly dosing, and weight was still reduced 43 days after a single dose [1]. It is in development for type 2 diabetes, obesity and related complications [3].

Obesity. In a 48-week phase 2 trial, 338 adults with obesity or overweight took 1, 4, 8 or 12 mg or placebo. Weight fell by 8.7%, 17.1%, 22.8% and 24.2%, against 2.1% on placebo. On 12 mg, 83% lost at least 15% of their weight [2]. A meta-analysis of the three randomised trials then available (878 people) put the extra weight reduction over placebo at 14.3%, with systolic blood pressure 9.9 mmHg lower [5]. The phase 3 TRIUMPH programme, with more than 5,800 participants, is testing it for obesity, sleep apnoea and knee osteoarthritis [4].

Type 2 diabetes. In a 36-week phase 2 trial, HbA1c fell by up to 2.02 points on 12 mg, against 1.41 on dulaglutide, and weight fell by up to 16.9% [6]. In the first phase 3 trial (537 people on diet and exercise alone), HbA1c fell by 1.69–1.94 points against 0.81 on placebo, and weight by 11.5–15.3% against 2.6% over 40 weeks [3].

Body composition and liver. In a substudy, total fat mass fell by 23–26% on 8 or 12 mg. The share of weight lost as lean mass was similar to other obesity treatments [7]. In participants with fatty liver, liver fat fell by 81–82% on 8 or 12 mg at 24 weeks, and 79–86% reached normal liver fat, against none on placebo [8].

Mechanism

Retatrutide combines three hormone signals in one molecule. In cell assays it acts more strongly at the GIP receptor than at the glucagon and GLP-1 receptors [1]. It is less potent than the body's own glucagon and GLP-1 (0.3 and 0.4 times as active) and 8.9 times as potent as native GIP [8].

In obese mice, GIP and GLP-1 receptor activity cut food intake, and glucagon receptor activity added a rise in energy expenditure. Together they caused more weight loss [1]. In the fatty-liver substudy, the drop in liver fat tracked weight loss and improvements in insulin sensitivity and fat metabolism [8].

Direct targetswhat the molecule itself binds or acts on

GIP receptoractivates
about 8.9 times as potent as native GIP in cell assays [8]
strong
GLP-1 receptoractivates
about 0.4 times as potent as native GLP-1 [8]; together with GIP, drives the fall in food intake in mice [1]
strong
Glucagon receptoractivates
about 0.3 times as potent as native glucagon [8]; added energy expenditure on top of reduced intake in obese mice [1]
moderate

Dosing

as studied or commonly reported; not a recommendation

Doses below are what studies used or, where marked, what is commonly reported. None is a recommendation.

Subcutaneous injection

1, 4, 8 or 12 mg (starting at 2 or 4 mg)
adults with obesity or overweight without diabetes (phase 2)
once weekly · 48 weeks
human study[2]
0.5, 4, 8 or 12 mg (starting at 2 or 4 mg)
type 2 diabetes (phase 2)
once weekly · 36 weeks
human study[6]
4, 9 or 12 mg
type 2 diabetes on diet and exercise alone (TRANSCEND-T2D-1)
once weekly · 40 weeks
human study[3]
0.5 mg up to 12 mg by stepwise escalation
type 2 diabetes (phase 1b)
once weekly · 12 weeks
human study[9]

Timing and food: Once weekly. In phase 2, gastrointestinal side effects were partly reduced by starting at 2 mg rather than 4 mg [2]. The phase 3 obesity trials reach 4, 9 or 12 mg through a fixed escalation, and allow a permanent dose reduction for side effects [4].
Time to effect: Weight was still falling at 48 weeks on the higher doses (22.8–24.2%, against 17.3–17.5% at 24 weeks) [2].
Notes: No approved dose exists. Retatrutide sold online is not the trial product.

Pharmacokinetics

what the body does with it

Half-life	About 6 days [9]
Steady state	Exposure rises in proportion to dose [9]
Metabolism	The peptide is joined to a fatty diacid chain, and its long half-life suits once-weekly dosing [8]

Safety

risks and cautions, not medical advice

Side effects are mainly gastrointestinal and dose-related. They are mostly mild to moderate, and a lower starting dose partly reduced them [2]. In type 2 diabetes, 35% of retatrutide users had gastrointestinal events, ranging from 13% on 0.5 mg to 50% on the fastest 8 mg escalation [6]. In phase 3, 2–5% stopped because of side effects, against none on placebo, and no severe hypoglycaemia occurred [3].

Heart rate rose with dose, peaked at 24 weeks and then declined [2]. The fatty-liver substudy found no signs of liver toxicity through 48 weeks [8]. The phase 3 programme monitors ECGs, pancreatic markers, calcitonin, and depression and suicidal thoughts [4]. Long-term outcome data have not been published.

Adverse effects

reported, not universal

Nausea, vomiting, diarrhoea and constipation, dose-related and mostly mild to moderate [2][6]
Dose-dependent rise in heart rate that peaked at 24 weeks [2]

Cautions

who should think twice

Not approved for any use; it is still in phase 3 trials [4]
Products sold online as retatrutide are unregulated and their content is unverified

Limits of the evidence

what has not been shown

The obesity results are phase 2 (338 people, 48 weeks); phase 3 obesity trials have not yet reported in the cited literature [2][4]
Every trial was funded by Eli Lilly, and most authors are company employees [2][3][7]
The meta-analysis pooled only three trials [5]

Interactions

documented pairs only, not exhaustive

Tirzepatide
avoid
Both activate the GLP-1 and GIP receptors [1][10]; no trial has combined them, and their gastrointestinal side effects overlap.

FAQ

Is retatrutide approved?: No. It is still being tested in phase 3 trials for obesity, sleep apnoea, knee osteoarthritis and type 2 diabetes [3][4].
How is it different from tirzepatide?: It also activates the glucagon receptor. In mice this added a rise in energy expenditure on top of reduced food intake [1].
How much weight did people lose?: In the phase 2 obesity trial, 24.2% on average after 48 weeks on 12 mg, against 2.1% on placebo [2].

References

entry last reviewed 2026-09-19

[1]
LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.
Coskun T, Urva S, Roell WC et al.Cell Metab 2022clinical trial · humanPMID 35985340◌ unreviewed
[2]
Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.
Jastreboff AM, Kaplan LM, Frías JP et al.N Engl J Med 2023RCT · humanPMID 37366315◌ unreviewed
[3]
Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.
Bajaj HS, Welch M, Shah P et al.Lancet 2026RCT · humanPMID 42250575◌ unreviewed
[4]
Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials.
Giblin K, Kaplan LM, Somers VK et al.Diabetes Obes Metab 2026otherPMID 41090431◌ unreviewed
[5]
Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials.
Abdrabou Abouelmagd A, Abdelrehim AM, Bashir MN et al.Proc (Bayl Univ Med Cent) 2025meta-analysis · humanPMID 40291085◌ unreviewed
[6]
Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.
Rosenstock J, Frias J, Jastreboff AM et al.Lancet 2023RCT · humanPMID 37385280◌ unreviewed
[7]
Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.
Coskun T, Wu Q, Schloot NC et al.Lancet Diabetes Endocrinol 2025RCT · humanPMID 40609566◌ unreviewed
[8]
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.
Sanyal AJ, Kaplan LM, Frias JP et al.Nat Med 2024RCT · humanPMID 38858523◌ unreviewed
[9]
LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.
Urva S, Coskun T, Loh MT et al.Lancet 2022RCT · humanPMID 36354040◌ unreviewed
[10]
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.
Willard FS, Douros JD, Gabe MB et al.JCI Insight 2020preclinical · cellPMID 32730231◌ unreviewed