Retatrutide (LY3437943)

Verified against FDA GSRS substance record UNII NOP2Y096GV supplied the CAS registry number, INN 12350, USAN JK-35 and the 39-residue sequence and full systematic name. PubChem was queried for 'retatrutide' and 'LY3437943' and returned no CID, so that field is null rather than guessed. The GSRS record carries an automatically calculated formula of C187H281N43O60 (MW 4091.5), which corresponds to the unmodified 39-residue backbone only; the formula given above adds the two Aib residues, the α-methyl-leucine, the C-terminal amide and the Lys17 lipidation described in the same GSRS systematic name. See the conflicting-figures table below. Fields marked “not verified” are ones we could not confirm against a primary chemical database — we leave them blank rather than guess.

Identity and development status

Retatrutide is a synthetic peptide of 39 amino acids carrying three non-standard residues — 2-aminoisobutyric acid at positions 2 and 20, and α-methyl-leucine at position 13 — plus a C-terminal amide. The lysine at position 17 is acylated with a twenty-carbon diacid attached through a γ-glutamyl spacer and an AEEA linker, the same lipidation strategy used to extend circulating half-life in other long-acting incretin peptides. The FDA Global Substance Registration System lists it under UNII NOP2Y096GV with CAS registry number 2381089-83-2, INN 12350 and USAN code JK-35.

The compound is investigational. As of August 2026 it has not been approved by the FDA for any indication. ClinicalTrials.gov lists 33 registered studies naming retatrutide or LY3437943, all sponsored by Eli Lilly, spanning phase 1 pharmacokinetic and drug-interaction work through the phase 3 TRIUMPH and TRANSCEND programmes, plus a pre-approval expanded access record (NCT07629401). Several phase 3 trials have passed their primary completion dates without a peer-reviewed publication yet appearing, so the published evidence base is currently narrower than the registered one. Anything presented as a retatrutide finding should be checked against whether the trial it came from has actually reported.

The receptor combination under study

The MeSH supplementary concept record for retatrutide (C000729679) describes it as a triple agonist peptide at the glucagon receptor, the glucose-dependent insulinotropic polypeptide receptor and the glucagon-like peptide-1 receptor. All three are class B G-protein-coupled receptors that signal principally through Gs and cyclic AMP accumulation, which is why cell-based cAMP readouts are the standard assay for characterising this class.

What distinguishes the triple-agonist design from single and dual agonists is the inclusion of glucagon receptor activity. Glucagon receptor signalling has effects on hepatic glucose output and energy expenditure that run in a different direction from GLP-1 receptor signalling on insulin secretion, so a molecule engaging both is being studied for a net effect that neither component predicts on its own. This is the pharmacological rationale investigators state; it is not a demonstrated mechanism of any clinical outcome.

No published head-to-head receptor-potency comparison between retatrutide and the marketed dual agonist tirzepatide was located in PubMed during preparation of this page. Claims about the relative balance of the three activities in retatrutide circulate widely in secondary summaries but were not traceable to a primary characterisation paper indexed in PubMed.

What the phase 2 trials measured

Two phase 2 trials anchor most of what is publicly known. In the obesity trial (NCT04881760), 338 adults with a BMI of 30 or higher, or 27 to under 30 with at least one weight-related condition, were randomised across six retatrutide dose arms and placebo for 48 weeks. Jastreboff and colleagues reported least-squares mean body weight change at 48 weeks of −24.2% in the 12 mg group against −2.1% with placebo, with 83% of the 12 mg group and 2% of the placebo group reaching a reduction of 15% or more.

In the type 2 diabetes trial (NCT04867785), 281 adults with HbA1c between 7.0% and 10.5% received placebo, dulaglutide 1.5 mg, or one of six retatrutide regimens. Rosenstock and colleagues reported HbA1c change at 24 weeks of −2.02% in the 12 mg group against −0.01% with placebo and −1.41% with dulaglutide, and body weight change at 36 weeks of −16.94% against −3.00% with placebo.

A substudy of the obesity trial examined 98 participants with metabolic dysfunction-associated steatotic liver disease and at least 10% liver fat. Sanyal and colleagues reported a relative change in liver fat at 24 weeks of −82.4% in the 12 mg group against +0.3% with placebo.

The first published phase 3 readout

TRANSCEND-T2D-1 (NCT06354660) is the first retatrutide phase 3 trial to appear in the peer-reviewed literature. Bajaj and colleagues reported it in The Lancet in June 2026. The trial randomised 537 adults with type 2 diabetes inadequately controlled by diet and exercise alone, HbA1c between 7.0% and 9.5%, and BMI of at least 23, across 48 sites in the United States, Mexico and India. Participants received once-weekly subcutaneous retatrutide at 4 mg, 9 mg or 12 mg, or placebo, over 40 weeks.

Mean change in HbA1c from baseline to week 40 was −1.94% at 12 mg against −0.81% with placebo, an estimated treatment difference of −1.12% (95% CI −1.39 to −0.85). Mean percentage change in body weight was −15.3% at 12 mg against −2.6% with placebo. Ninety-one percent of participants completed the treatment period on study drug.

Two deaths occurred during the trial, both in the 4 mg group, and the investigators recorded them as unrelated to the study drug. Discontinuation attributable to adverse events ran at 2–5% across the retatrutide arms and 0% on placebo. No severe hypoglycaemia was recorded.

Adverse events recorded in the published trials

Gastrointestinal events were the most frequently recorded category across the programme. In the type 2 diabetes phase 2 trial, nausea, diarrhoea, vomiting or constipation were reported in 67 of 190 participants across the retatrutide arms (35%), against 6 of 45 on placebo (13%) and 16 of 46 on dulaglutide (35%). Within the retatrutide arms the frequency ranged from 13% at 0.5 mg to 50% in the 8 mg fast-escalation group, indicating a dose relationship. In the obesity trial these events were likewise dose-related and were recorded as partially reduced by a lower starting dose.

The obesity trial also recorded dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. This is a signal specific to the glucagon receptor component of the molecule's activity and is one of the reasons the phase 3 cardiovascular outcome trial (NCT06383390, 10,000 participants, primary completion February 2029) exists.

Long-term safety data are not yet available. The longest published exposure is 48 weeks. Trials in participants with renal impairment, established cardiovascular disease and chronic kidney disease are registered and active but have not reported.

What is not known

The published record covers a maximum of 48 weeks of exposure. No long-term safety, durability or discontinuation data exist. The large outcome trials that would establish whether the metabolic changes translate into cardiovascular or kidney events — NCT06383390 with 10,000 participants and NCT05882045 with 1,946 — have not reported; the former is not due to complete until February 2029. Body composition has not been publicly characterised, so the proportion of the recorded weight change attributable to fat mass against lean mass is unknown. The phase 3 obesity trials TRIUMPH-1 (2,335 participants) and the master protocol NCT05929079 (1,152 participants) have passed primary completion without publication, meaning the largest obesity datasets are not yet in the literature. Trial populations skewed heavily toward White participants — 84% in the phase 2 diabetes trial — and the published trials excluded people with type 1 diabetes, severe renal impairment at entry, and pregnancy. No published data address use during pregnancy or lactation, in adolescents, or in adults over 75. Retatrutide is not an approved medicine in any jurisdiction, and material sold outside a registered trial has not been subject to the identity, purity or sterility controls that apply to investigational supply.

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