Retatrutide: what it is, how it works and what studies have found

Retatrutide is a triple incretin-glucagon agonist in late-stage clinical development: one peptide chain activates the GIP, GLP-1 and glucagon receptors, combining the appetite and glucose effects of the incretins with the energy-expenditure effects of glucagon. This overview covers its structure, receptor pharmacology and half-life, how it is made, and what the phase 1, phase 2 and 2026 phase 3 TRIUMPH and TRANSCEND trials reported. Retatrutide is investigational; nothing here is medical or usage guidance.

What is retatrutide?

Retatrutide, development code LY3437943, is “a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R)” [3]. It is described in its phase 3 design paper as “a novel synthetic molecule” [8], and in October 2026 as an investigational agent [11]. No retatrutide medicine appears in FDA’s Drugs@FDA data or in EMA’s medicines data [17] [18].

Retatrutide structure and sequence

Property	Retatrutide
INN	Retatrutide [1]
Development code	LY3437943 [1] [3]
CAS number	2381089-83-2 [1] [2]
UNII	NOP2Y096GV [1]
Molecular formula	C221H342N46O68 [2]
Molecular weight	4731.34 [2]
Monoisotopic (exact) mass	4728.47 [2]
Length	39 amino acids [1] [2]
Sequence (one-letter)	Y-Aib-QGTFTSDYSI-αMeL-LDK-K-AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2 [1] [2]
Non-coded residues	Aib at positions 2 and 20; α-methyl-L-leucine at position 13 [1]
Side chain	Lys17 acylated with a C20 fatty di-acid (19-carboxynonadecanoyl) through γ-glutamate and one OEG unit [1]
C-terminus	Serine amide [1]
Receptor targets	GCGR, GIPR, GLP1R [2]

The FDA substance record’s systematic name spells out each residue, including “2-methylalanyl” at positions 2 and 20, “2-methyl-L-leucyl” at position 13 and an N6-[N-(19-carboxy-1-oxononadecyl)-L-γ-glutamyl-2-[2-(2-aminoethoxy)ethoxy]acetyl] group on the second lysine of the Lys16–Lys17 pair [1]. The linker therefore has a single OEG unit, one fewer than tirzepatide’s γGlu-2×OEG linker; that composition is the one that reproduces the published formula C221H342N46O68 [1] [2].

Comparing the KEGG records shows that retatrutide and tirzepatide share the same C-terminal ten residues (GPSSGAPPPS) and the N-terminal tyrosine, but differ at many positions in between, including the third residue (glutamine instead of glutamate), the α-methyl-leucine at 13 and the acylation site (Lys17 instead of Lys20) [2] [21].

Retatrutide mechanism of action

Retatrutide engages three receptors. In vitro it “shows balanced GCGR and GLP-1R activity but more GIPR activity” [3]. The rationale for adding glucagon receptor activity came from the mouse work: in obese mice, “body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction” [3]. In other words, the incretin components reduce intake, and the glucagon component increases expenditure. That attribution comes from animal pharmacology; the separate contribution of each receptor in humans has not been isolated.

Liver fat was examined separately in a phase 2 substudy in people with MASLD, described below [7].

Retatrutide half-life

Parameter	Finding	Evidence level	Ref
Pharmacokinetic profile	Supported once-weekly dosing; weight reduction persisted up to day 43 after a single administration	Phase 1, single ascending dose	[3]
Half-life	Approximately 6 days	Phase 1b, 12 weeks, type 2 diabetes	[4]
Dose proportionality	Pharmacokinetics were dose-proportional	Phase 1b	[4]
Protraction mechanism	C20 fatty di-acid on Lys17 (albumin-binding motif shared with tirzepatide)	Structure	[1] [20]

The about-6-day half-life sits between tirzepatide (about 5 days in its label) and semaglutide (about 1 week) [20] [22]. No approved label exists for retatrutide, so these figures come from early-phase studies only.

Development history and timeline

Retatrutide was discovered and developed by Eli Lilly and Company, which funded each of the trials below.

Date	Milestone	Ref
Dec 2019 to Dec 2020	Phase 1b multiple-ascending-dose study in type 2 diabetes conducted	[4]
2022	Discovery-to-proof-of-concept paper (Cell Metabolism) and phase 1b results (Lancet) published	[3] [4]
2023	Phase 2 obesity (NEJM) and phase 2 type 2 diabetes (Lancet) trials published	[5] [6]
Jul 2023	TRIUMPH-2 enrolment begins	[10]
2024	MASLD substudy of the phase 2 obesity trial published	[7]
Nov 2025	TRIUMPH-4 (knee osteoarthritis) primary completion	[14]
Apr 2026	TRIUMPH-3 primary completion	[13]
Jun 2026	TRANSCEND-T2D-1 published (Lancet)	[12]
Sep to Oct 2026	TRIUMPH-1 (NEJM), TRIUMPH-2 (Lancet) and the OSA trials (NEJM) published	[9] [10] [11]

Retatrutide clinical trials: key studies and findings

The phase 3 obesity programme is TRIUMPH; the type 2 diabetes programme is TRANSCEND-T2D. TRIUMPH-1 and TRIUMPH-2 are basket trials, with knee osteoarthritis and obstructive sleep apnoea protocols nested inside the weight-management trials, and the four original TRIUMPH trials enrol more than 5,800 participants [8]. Dose levels are omitted below; ranges span the trial’s retatrutide arms.

Study	Phase / design	Population	n	Duration	Primary endpoint	Main finding	Ref
Phase 1b	1b, multiple ascending dose	Type 2 diabetes	72	12 weeks	Safety, tolerability	Half-life about 6 days; body weight up to −8.96 kg vs placebo	[4]
Phase 2 obesity	2, placebo-controlled	Obesity or overweight with a condition	338	48 weeks	% weight change at 24 weeks	−7.2% to −17.5% vs −1.6% at 24 weeks; −8.7% to −24.2% vs −2.1% at 48 weeks	[5]
Phase 2 T2D	2, placebo and dulaglutide controlled	Type 2 diabetes	281	36 weeks	HbA1c change at 24 weeks	−0.43 to −2.02 points vs −0.01 placebo and −1.41 dulaglutide	[6]
MASLD substudy	2a, placebo-controlled	MASLD with ≥10% liver fat	98	48 weeks	Relative liver-fat change at 24 weeks	−42.9% to −82.4% vs +0.3%	[7]
TRANSCEND-T2D-1	3, placebo-controlled monotherapy	Type 2 diabetes on diet and exercise	537	40 weeks	HbA1c change	−1.69 to −1.94 points vs −0.81	[12]
TRIUMPH-1	3, placebo-controlled basket	Obesity, no diabetes	2,339	80 weeks	% weight change; WOMAC pain; AHI	−17.6% to −25.0% vs −3.9%	[9]
TRIUMPH-2	3, placebo-controlled basket	Obesity with type 2 diabetes	1,152	80 weeks	% weight change	−11.9% to −18.8% vs −5.1%	[10]
TRIUMPH-1-OSA / -2-OSA	3, nested placebo-controlled	Moderate to severe OSA	243 / 448	80 weeks	AHI change	Up to −24.4 and −15.1 events/h vs placebo	[11]

Phase 2 obesity trial (NEJM 2023)

The phase 2 obesity trial enrolled 338 adults (51.8% men) with a BMI of 30 or more, or 27 to under 30 with a weight-related condition, and randomised them to one of several once-weekly subcutaneous retatrutide arms or placebo for 48 weeks. At the 24-week primary endpoint, mean weight change ranged from −7.2% in the lowest arm to −17.5% in the highest, versus −1.6% with placebo. By 48 weeks the range was −8.7% to −24.2%, versus −2.1%. In the highest arm, 100%, 93% and 83% of participants reached reductions of at least 5%, 10% and 15%, compared with 27%, 9% and 2% on placebo [5].

The 98 participants with MASLD and at least 10% liver fat formed a substudy. At 24 weeks, relative liver-fat change ranged from −42.9% to −82.4% across arms versus +0.3% with placebo, and up to 86% of participants in the highest arm reached normal liver fat (under 5%) versus none on placebo. The reductions tracked changes in body weight, abdominal fat and insulin-sensitivity measures [7].

Phase 2 type 2 diabetes trial (Lancet 2023)

At 42 US centres, 281 adults with type 2 diabetes were randomised to placebo, dulaglutide or one of six retatrutide arms. At 24 weeks HbA1c changed by −0.43% to −2.02% with retatrutide, −0.01% with placebo and −1.41% with dulaglutide. At 36 weeks body weight fell by up to 16.94% with retatrutide versus 3.00% with placebo and 2.02% with dulaglutide. No severe hypoglycaemia and no deaths were reported, and the data informed phase 3 dose selection [6].

TRIUMPH-1 and TRIUMPH-2 (phase 3, 2026)

TRIUMPH-1 randomised 2,339 adults with obesity and without diabetes to one of three once-weekly retatrutide arms or placebo for 80 weeks. Mean weight change was −17.6%, −23.7% and −25.0% across the arms versus −3.9% with placebo. In the 574 participants with knee osteoarthritis, WOMAC pain scores improved more than with placebo (differences of −1.6 and −1.8 points for the two arms in the primary analysis), and in the 243 with obstructive sleep apnoea the apnoea-hypopnoea index fell further than with placebo [9].

TRIUMPH-2 enrolled 1,152 adults with obesity and type 2 diabetes at 92 centres in eight countries. At week 80, weight change was −11.9%, −16.8% and −18.8% across arms versus −5.1% with placebo, with improvements in glycaemic control [10]. The nested OSA analyses (243 participants in TRIUMPH-1-OSA, 448 in TRIUMPH-2-OSA, baseline AHI 58.6 and 55.9 events per hour) found AHI reductions versus placebo of up to 24.4 events per hour in the population without diabetes and 15.1 in the population with diabetes [11].

TRANSCEND-T2D-1 (phase 3, 2026)

TRANSCEND-T2D-1 tested retatrutide as monotherapy in 537 adults with type 2 diabetes at 48 sites in the USA, Mexico and India. At 40 weeks, HbA1c changed by −1.69% to −1.94% versus −0.81% with placebo, and body weight by −11.5% to −15.3% versus −2.6%. Discontinuations for adverse events were 2–5% with retatrutide and 0% with placebo, and no severe hypoglycaemia was reported [12].

Ongoing phase 3 trials

Trial	Question	Enrolment	Status (Oct 2026)	Ref
TRIUMPH-3, NCT05882045	Obesity with cardiovascular disease	1,946	Completed; primary completion April 2026	[13]
TRIUMPH-4, NCT05931367	Obesity with knee osteoarthritis	445	Completed; primary completion November 2025	[14]
TRIUMPH-5, NCT06662383	Head-to-head versus tirzepatide in obesity	800	Active, not recruiting	[15]
NCT06383390	Cardiovascular and kidney outcomes in obesity	10,000	Active, not recruiting; primary completion expected 2029	[16]

Safety findings reported in studies

Gastrointestinal adverse events dominate. In the phase 1b study they were the most frequent treatment-emergent events [4]. In the phase 2 obesity trial they were dose-related, mostly mild to moderate, and partly mitigated by a lower starting level; dose-dependent heart-rate increases peaked at 24 weeks and then declined [5]. In the phase 2 diabetes trial, gastrointestinal events occurred in 35% of retatrutide participants overall, 13% on placebo and 35% on dulaglutide [6].

The phase 3 data add detail. In TRIUMPH-2, diarrhoea occurred in 27–34% with retatrutide versus 13% with placebo and nausea in 14–28% versus 8%. Hypotension (1–6% vs under 1%) and dysaesthesia (4–7% vs 1%) were more frequent with retatrutide, and permanent discontinuation because of adverse events or death reached 12% in one of the higher arms versus 5% with placebo. All deaths were judged by investigators to be unrelated to treatment [10]. Long-term cardiovascular safety will come from the outcomes trial, which is not expected to complete until 2029 [16].

Regulatory status by region

Region	Status (October 2026)	Ref
United States	Not approved; no Drugs@FDA application record	[17]
European Union	Not authorised; no entry in EMA medicines data	[18]
Global	Investigational; INN and USAN assigned; phase 3 trials completed and ongoing	[1] [2] [11]

Retatrutide in laboratory research

Retatrutide is used in research as a tool for dissecting three-receptor pharmacology. Typical applications, following the published discovery work, include:

• Receptor activity profiling: cAMP or binding assays at GCGR, GIPR and GLP-1R expressed in cell lines, to reproduce the reported balance of activities [3].
• Energy-balance models: diet-induced obese mice measuring food intake and energy expenditure, the models used to separate incretin and glucagon contributions [3].
• Liver research: liver fat and lipid metabolism endpoints, following the MASLD substudy [7].
• Analytical characterisation: reversed-phase HPLC or UPLC for purity and related substances, LC-MS intact mass against the theoretical exact mass of about 4728.47 [2], peptide mapping to confirm Aib2, αMeL13, Aib20 and the acylation site, and counter-ion, water and peptide-content testing. Correct placement of the side chain on Lys17 rather than Lys16 is a specific identity question for this molecule.

How is retatrutide made? Synthesis, purity and impurities

The developer has not published a manufacturing process. The structure itself sets the constraints. A 39-residue chain with three α,α-disubstituted or α-methylated residues (Aib2, αMeL13, Aib20) requires forcing coupling conditions at those positions, and the side chain must go onto Lys17 but not the adjacent Lys16, which in Fmoc solid-phase peptide synthesis (SPPS) is normally handled with an orthogonally protected lysine that is deprotected and acylated on resin, or by coupling a pre-formed lipidated lysine building block. The crude peptide is then purified by preparative reversed-phase HPLC and lyophilized. Route options are compared in SPPS vs LPPS.

The most relevant impurity classes are deletion sequences at the hindered couplings, insertion and truncated sequences, diastereomers, the regio-isomer acylated at Lys16, side-chain variants with a missing γGlu or OEG unit, and oxidation or deamidation products. The EU synthetic peptide guideline, effective 1 June 2026, names deletion, truncated and insertion sequences among the impurity types to characterise [19]. For how these are specified and controlled see peptide API impurities and specifications.

Storage and stability of lyophilized retatrutide

Research and API material is a white to off-white lyophilized powder. As with other lipidated peptides, the dry form limits hydrolysis and aggregation; keep it frozen, sealed and protected from light and moisture, and avoid repeated warming and cooling of the same vial. The underlying science and handling practice are covered in lyophilised peptide stability and storage.

Retatrutide vs tirzepatide and other incretin peptides

Property	Retatrutide	Tirzepatide	Semaglutide
Receptors	GIPR, GLP-1R, GCGR [2] [3]	GIPR, GLP-1R [20]	GLP-1R [22]
Length	39 residues [2]	39 residues [21]	31 residues [22]
Non-coded residues	Aib2, αMeL13, Aib20 [1]	Aib2, Aib13 [20]	Aib8 [22]
Lipid and linker	C20 di-acid, γGlu-OEG, Lys17 [1]	C20 di-acid on Lys20 [20]	C18 di-acid on Lys26 [22]
Half-life	About 6 days [4]	About 5 days [20]	About 1 week [22]
Status (Oct 2026)	Investigational [17]	Approved	Approved

The direct clinical comparison, TRIUMPH-5, had not reported by October 2026 [15]. For the dual agonist see the tirzepatide overview; for an amylin-based approach being studied alongside incretins, see cagrilintide.

How Winhycare Pharma supplies retatrutide

Winhycare Pharma supplies retatrutide as research-use-only material for laboratories and, separately, as API to licensed pharmaceutical manufacturers and developers. Material is supplied at ≥99% purity by HPLC with a certificate of analysis for every batch, and custom synthesis (specified salt forms, purity grades, reference-standard quantities) is available. Specifications are on the retatrutide supplier page; to request a quotation, use the peptide API enquiry form.

For laboratory research use only. Not for human or veterinary use.