Research Dossier on Triple Agonist of GLP-1, GIP, and Glucagon (LY3437943)

(Incretin Mimetics)

(unimolecular, once-weekly triple agonist of GLP-1, GIP, and glucagon receptors)

Classification & Molecular Identity

Molecular class and design

Retatrutide (development code LY3437943) is a synthetic peptide that acts as a single-molecule agonist at three class-B GPCRs: GLP-1R, GIPR, and GCGR (glucagon receptor). Cryo-EM structures show retatrutide engages the orthosteric transmembrane pocket of each receptor with a conserved N-terminal helical segment and receptor-specific contacts that enable triple agonism. The peptide is acylated with a fatty diacid via a linker, conferring albumin association and prolonged half-life; in the cryo-EM analysis, the acylation site is mapped to Lys17 (distinct from sites used by semaglutide and tirzepatide).

Sequence/chemistry notes. Retatrutide is a ~30-amino-acid analog engineered from incretin/glucagon backbones; medicinal-chemistry optimizations include noncanonical residues (e.g., Aib, α-methyl-Leu) that tune receptor selectivity and metabolic stability while retaining the His-Phe-Glu/Asp core interactions characteristic of class-B agonists. Public sources do not uniformly publish the full residue sequence, but the structural biology paper provides residue-level contacts and PDB accessions for the three receptor complexes (GLP-1R: 8YW3, GIPR: 8YW4, GCGR: 8YW5).

Molecular weight & form. The precise molar mass of the clinical peptide depends on the acyl-linker moiety and salt form. Retatrutide is formulated for subcutaneous administration with once-weekly dosing in trials.

Discovery history (lab, year, species)

• Phase 1b (T2D): The first multiple-ascending-dose study in people with type 2 diabetes (12 weeks) established dose-proportional PK, ~6-day half-life, and glycemic/weight-loss signals versus placebo and an active GLP-1RA comparator (dulaglutide 1.5 mg).

• Phase 2 (obesity): The pivotal double-blind RCT in adults with obesity/overweight (338 participants) tested weekly 1, 4, 8, and 12 mg doses for 48 weeks, achieving –24.2% mean weight change at 12 mg (vs –2.1% placebo) and dose-related GI AEs with transient heart-rate increases, peaking around week 24.

• Phase 2 (T2D): A companion phase-2 RCT in people with type 2 diabetes (n≈281) demonstrated HbA1c reductions up to ~–2.0% at 24 weeks and ~17% weight loss at 36 weeks at higher doses, with a GLP-1RA-like AE profile.

Endogenous vs. synthetic origin

• Endogenous: The targets—GLP-1, GIP, and glucagon receptors—are activated physiologically by proglucagon-derived peptides (GLP-1, glucagon) and GIP from K-cells.

• Synthetic: Retatrutide is a designed peptide with a fatty-acyl handle for albumin binding and elements from GIP/GCG backbones to realize balanced multi-receptor agonism.

Homologs, analogs, derivatives

• GLP-1R mono-agonists (e.g., semaglutide).

• Dual agonists: Tirzepatide (GLP-1/GIP).

• Other triple-agonist scaffolds: research peptides such as peptide 20 (MAR423) and others used as structural comparators in cryo-EM studies.

Historical Development & Research Trajectory

Key milestones

• Preclinical rationale: Multi-agonism (GLP-1/GIP/GCGR) was shown to influence appetite, glucose, lipids, and energy expenditure (via glucagon) in animal models—informing human translation.

• Phase 1b (Lancet 2022): Dose-proportional PK, t½ ≈ 6 days, T_max 12–48 h, and candidate weekly dosingwere established; exploratory analyses showed HbA1c, fasting/postprandial glucose, and weight improvements alongside decreases in LDL-C, VLDL-C, and triglycerides at higher doses.

• Phase 2 Obesity (NEJM 2023): Weight loss reached –22.8% (8 mg) and –24.2% (12 mg) at 48 weeks with dose-related GI AEs and heart-rate increases that peaked at week 24 and declined thereafter.

• Phase 2 T2D (Lancet 2023): At 24 weeks, HbA1c decreased up to –2.02% (12 mg escalation), and weight decreased ~16–17% at 36 weeks; tolerability was GLP-1RA-like (GI AEs dominant) and no severe hypoglycemia was observed.

• Mechanisms (2024 cryo-EM): Retatrutide-bound structures of GLP-1R, GIPR, and GCGR resolved the receptor-specific contacts that underpin triple agonism and highlighted acylation-design differences from semaglutide and tirzepatide.

• Ongoing development (2024–2025): Phase 3 studies registered to examine long-term weight-loss maintenance, cardio-renal outcomes, and head-to-head comparisons with established incretins (e.g., tirzepatide).

Paradigm shifts & controversies

• Glucagon as a friend, not a foe: Incorporating GCGR agonism to increase energy expenditure departs from purely GLP-1-centric approaches; nonetheless, GCGR activation may contribute to heart-rate increases and requires careful titration (safety monitoring is ongoing).

• “How much is too much” weight loss? The magnitude of weight reduction (≥20%) raises questions regarding lean mass changes; phase-2 body-composition analyses in T2D indicate fat-mass-dominant loss with proportions of lean loss similar to other anti-obesity agents.

• Generalizability: Early results are promising, but long-term outcomes, maintenance strategies, and benefit–riskin diverse populations remain under evaluation.

Evolution of scientific interest

Initial focus on weight loss in obesity expanded to glycemic control in T2D, lipid/liver fat effects, and broader cardiometabolic endpoints (registered ASCVD/CKD composite trials). Mechanistic structural biology work in 2024 provided a map to refine receptor-bias and balanced activation across GLP-1R/GIPR/GCGR.

Mechanisms of Action

Primary and secondary receptor interactions

• GLP-1R (gut–pancreas–CNS): Incretin signaling enhances glucose-dependent insulin secretion, suppresses glucagon (alpha-cell), slows gastric emptying, and reduces appetite via CNS pathways.

• GIPR (K-cells; adipose/pancreas/CNS): GIP supports postprandial insulin secretion and may augment adipose lipid handling; GIPR co-agonism with GLP-1R potentiates glycemic control and may aid GI tolerability.

• GCGR (alpha-cells; liver): Glucagon mobilizes hepatic glucose and stimulates lipolysis and energy expenditure; in triple agonism, balanced GCGR activation is leveraged for thermogenic and fat-oxidation effects, while GLP-1R/GIPR mitigate hyperglycemia risk.

Cryo-EM structures show retatrutide binding adopts a continuous α-helix with conserved polar/hydrophobic interactions in the TMD and receptor-specific ECL1 contacts that explain tri-receptor potency differences (more potent at GIPR, somewhat less at GCGR and GLP-1R relative to endogenous peptides).

Intracellular signaling pathways

All three receptors are Gs-coupled class-B GPCRs: agonism increases cAMP, activates PKA/EPAC, and drives downstream transcriptional/metabolic programs.

• GLP-1R: β-cell insulin secretion; CNS appetite circuits; gastric motility.

• GIPR: β-cell insulinotropic effects; adipocyte metabolic signaling.

• GCGR: hepatocyte gluconeogenesis and lipid metabolism; systemic energy expenditure.

CNS vs peripheral effects

• CNS: Appetite suppression and nausea are centrally modulated (GLP-1R; potentially GIPR).

• Peripheral: Pancreatic, hepatic, and adipose effects underlie glycemic and lipid/liver changes; HR increases are a known class effect with GLP-1R agonism and may be modulated by GCGR actions.

Hormonal, metabolic, immune interactions

• Glycemic control: Multi-receptor agonism reduces fasting and post-prandial glucose (T2D), lowers HbA1c, and reduces glucagon AUC (phase 1b/2).

• Lipid profile: Dose-dependent decreases in LDL-C, VLDL-C, triglycerides were observed at 12 weeks in phase 1b; liver-fat data from obesity studies and news summaries indicate concomitant reductions (needs phase-3 confirmation).

Evidence grading (A–C)

• A (replicated in controlled trials & structural biology): Tri-receptor agonism, 6-day t½, weekly dosing, large weight-loss and HbA1c effects, dose-related GI AEs and HR increases.

• B (translational, accumulating): Lipid/liver-fat improvements, body-composition analyses in T2D, structural rationale for balanced receptor activation.

• C (uncertain/long-term): MACE/renal outcomes, long-term safety at higher exposures, lean-mass trajectories in prolonged maintenance, and optimal dose-escalation schemes—Not established pending phase-3 programs.

Pharmacokinetics & Stability

ADME profile (human)

• Absorption: After subcutaneous administration, T_max ~12–48 h (phase 1b).

• Distribution: Albumin-binding via fatty-acyl handle yields prolonged exposure (design analogous to other acylated incretins).

• Metabolism & excretion: Peptidic catabolism and reticuloendothelial clearance; detailed metabolite mapping not reported publicly.

• Elimination half-life: ~6 days across dose levels (phase 1b) supporting once-weekly dosing.

Dose proportionality and accumulation

PK is approximately dose-proportional over the ranges studied (phase 1b) with predictable accumulation to steady state under weekly administration.

Storage/reconstitution considerations

Trial publications do not provide CMC details; for research-grade material, follow manufacturer COA. Peer-reviewed sources emphasize once-weekly stability attributable to acylation and albumin interactions rather than formulation specifics.

Preclinical Evidence

Animal/structural studies

• Mechanistic weight-loss drivers: Preclinical analyses suggest retatrutide reduces food intake (GLP-1R/GIPR) and increases energy expenditure (GCGR), contributing to greater weight loss than dual agonists in some models.

• Structural basis: Cryo-EM resolves three active-state complexes demonstrating a shared N-terminal helical binding mode and receptor-specific ECL1 conformations that underlie triple agonism; acylation site differences across peptides are noted (retatrutide at Lys17).

In-vitro receptor pharmacology

• The Nature/Cell Discovery analysis reports the relative potency pattern (vs endogenous peptides): retatrutide is more potent at GIPR (~8.9×) and somewhat less potent at GLP-1R/GCGR (0.3–0.4×) while still achieving robust cAMP signaling at each receptor.

Dose ranges tested (illustrative; all investigational)

• Phase 1b (T2D) weekly: 3, 3/6, 3/6/9/12 mg schedules (vs dulaglutide 1.5 mg and placebo), 12 weeks.

• Phase 2 (obesity) weekly: 1, 4, 8, 12 mg (with different start doses), 48 weeks.

• Phase 2 (T2D) weekly: 0.5, 4, 8, 12 mg maintenance with different escalations, 36 weeks.
  (All of the above are investigational dose used in study X and not approved regimens.)

Comparative efficacy/safety (preclinical & early clinical)

• Efficacy: Large, dose-dependent weight reductions and glycemic improvements.

• Safety: GI AEs (nausea, diarrhea, vomiting, constipation) are common and dose-related; HR increases were observed (peak around week 24 with partial decline thereafter).

Limitations

• Long-term organ-system effects (e.g., gallbladder) require dedicated tracking; GLP-1RA class meta-analyses link higher doses/longer durations to increased gallbladder/biliary disease risk, confounded by rapid weight loss. Retatrutide-specific gallbladder data beyond phase 2 are Not established.

Human Clinical Evidence

Phase 1b—T2D (Lancet 2022)

• Design: Multiple-ascending-dose, randomized, double-blind, placebo- and active-controlled (dulaglutide 1.5 mg) study in people with type 2 diabetes over 12 weeks.

• PK: Dose-proportional; t½ ~6 days; T_max 12–48 h.

• Efficacy: Significant reductions in daily plasma glucose, HbA1c (–1.2% to –1.6% in higher-dose arms at week 12), body weight, and atherogenic lipids in dose-dependent fashion.

• Safety: GI events predominated; overall safety consistent with incretin-based therapeutics.
  (This summary references Urva et al., Lancet 2022—investigational dosing used in study.)

Phase 2—Obesity without diabetes (NEJM 2023; NCT04881760)

• Participants: Adults with BMI ≥30 kg·m⁻², or ≥27 with weight-related condition; n=338.

• Dosing: Once-weekly 1, 4, 8, 12 mg for 48 weeks with escalation schedules (some arms starting at 2 mg).

• Outcomes: Mean weight change at 48 weeks: –8.7% (1 mg), –17.1% (4 mg combined), –22.8% (8 mg), –24.2% (12 mg) vs –2.1% placebo. High percentages achieved ≥5%, ≥10%, ≥15% loss (e.g., at 12 mg: 100%, 93%, 83%respectively).

• Safety: GI AEs were dose-related and mitigated by starting at 2 mg; dose-dependent HR increases peaked at ~24 weeks and decreased thereafter.
  (Investigational doses used in study Jastreboff 2023.)

Phase 2—T2D (Lancet 2023; NCT04867785)

• Design: Randomized, placebo- and dulaglutide-controlled; retatrutide 0.5–12 mg weekly; 36 weeks.

• Glycemia: HbA1c reductions up to –2.02% at 24 weeks; significant improvements vs placebo and (for some arms) vs dulaglutide by week 24.

• Weight: –16–17% by 36 weeks at higher doses vs ~–2–3% with placebo/dulaglutide.

• Safety: Mild–moderate GI AEs frequent; no severe hypoglycemia; HR increases observed (class effect).
  (Investigational doses used in study Rosenstock 2023.)

Body composition—T2D (Lancet Diabetes & Endocrinol. 2025)

A dedicated analysis reported greater total fat-mass reduction and lean-mass proportions similar to other obesity pharmacotherapies despite larger total weight loss—alleviating concerns of disproportionate lean-mass depletion.

In-progress/registered trials (examples)

• NCT06859268: weight-loss maintenance after retatrutide-induced loss.

• NCT06662383: retatrutide vs tirzepatide in obesity, 89-week duration.

• NCT06383390: cardiometabolic outcomes in adults with BMI ≥27 and ASCVD/CKD.

• Additional sponsor listings (e.g., Lilly J1I-MC-GZQA) include T2D with renal impairment.
  (All ongoing studies are investigational; results pending.)

Safety signals/adverse events (trial-level)

• Gastrointestinal (nausea, diarrhea, vomiting, constipation): most common, dose-related, mostly mild–moderate; mitigated by slower up-titration.

• Heart rate: Placebo-adjusted increases (~5–7 bpm in phase 2 data) with peak around week 24 and partial decline thereafter.

• Gallbladder/biliary: Incretin-class meta-analysis (GLP-1RAs) links higher doses/longer duration and weight-loss indications to increased gallbladder/biliary risk; retatrutide-specific gallbladder safety beyond phase 2 is Not established.

• Arrhythmias: Secondary summaries report low-frequency arrhythmia AEs; robust adjudication awaits phase-3 disclosure (interpret with caution).

Comparative Context

Related peptides (for orientation)

• Semaglutide (GLP-1R): powerful weight-loss and CV benefit in SELECT; mono-agonist (GLP-1R).

• Tirzepatide (GLP-1R/GIPR): dual agonist with large weight-loss effects (SURMOUNT).

• Retatrutide: aims to add GCGR to GLP-1R/GIPR signaling for greater energy expenditure; phase-2 results suggest additional weight loss versus historical dual-agonist data (indirect comparisons only).

Advantages (research perspective)

• Single molecule achieving three incretin/glucagon axes with a weekly PK profile; large, consistent weight-lossand glycemic signals across phase-2 programs with supportive lipid/liver changes.

• Defined structural basis for balanced tri-receptor activation enables rational design of next-generation analogs.

Disadvantages/constraints

• Class-typical GI AEs and HR elevations require titration strategies and continued safety surveillance.

• Gallbladder/biliary risk requires long-term monitoring (class signal); retatrutide-specific estimates Not established.

• Outcome generalization to diverse populations and long-term maintenance to be established in phase 3.

Research category placement

In research portfolios, retatrutide belongs to incretin-based multi-agonists with metabolic and energy-expenditureactivity, useful for comparative pharmacology and structure-guided design.

Research Highlights

• Weekly PK with t½ ~6 days, T_max 12–48 h, dose-proportional exposure, supporting once-weekly administration (phase 1b).

• Large weight reduction: Up to –24.2% at 48 weeks (12 mg) in obesity phase 2; robust responses at 8–12 mg.

• Glycemic efficacy: HbA1c reductions up to –2.02% at 24 weeks in T2D phase 2 and ~17% weight loss at 36 weeks.

• Body composition: Fat-mass–dominant loss; lean-mass proportions similar to other agents even with greater absolute weight loss.

• Mechanistic structure: Cryo-EM (2.68–3.26 Å) clarifies shared vs receptor-specific interactions enabling tri-agonism; acylation at Lys17 distinguishes retatrutide’s design.

• Lipid/liver: Phase 1b showed LDL-C/VLDL-C/TG reductions; news summaries note liver-fat improvements(awaiting peer-reviewed phase-3 confirmation).

Conflicting/uncertain areas.

• Long-term CV/renal outcomes and gallbladder safety require phase-3 data (Not established).

• Optimal receptor-balance (biasing GLP-1R/GIPR/GCGR) for efficacy vs tolerability will benefit from ongoing structure–activity refinement.

Potential Research Applications (no clinical claims; research-use framing)

1. Receptor-balance mapping
   Use cellular cAMP assays and mutagenesis guided by the cryo-EM fingerprints to quantify how N-terminal/C-terminal modifications alter GLP-1R vs GIPR vs GCGR potency and signaling bias.

2. Energy-expenditure physiology
   In rodent indirect calorimetry, parse food-intake vs EE contributions to weight loss under GLP-1R/GIPR/GCGRselective antagonism or conditional knockouts; integrate liver lipidomics and brown/white adipose thermogenicreadouts.

3. Mechanism-linked safety
   Explore mechanisms of HR elevation and GI AEs under tri-agonism—e.g., GLP-1R antagonism, β-adrenergic blockade, and GCGR modulation—to delineate on- vs off-target drivers.

4. Comparative liver endpoints
   Combine MRI-PDFF, MRE, and plasma lipidomics with tri-agonists vs dual/mono-agonists to identify GCGR-dependent signatures and NAFLD/NASH hypotheses.

5. Structure-guided analog design
   Build sequence libraries around residues highlighted in the ECL1/TMD recognition maps to create analogs with tunable receptor ratios, then evaluate efficacy–tolerability surfaces in translational models.

Safety & Toxicology

Preclinical/early clinical signals

• GI AEs (nausea, vomiting, diarrhea, constipation) dominate; titration mitigates severity.

• Heart-rate increases (peak around week 24) were seen in both obesity and T2D phase-2 programs, consistent with incretin class effects and possibly augmented by GCGR activity; clinical significance Unknown pending outcomes.

• Gallbladder/biliary: GLP-1RA class meta-analysis links higher dose/longer duration to biliary events; retatrutide-specific risk Not established.

• Hypoglycemia: No severe hypoglycemia reported in phase 2 T2D.

Long-term and population-specific safety

• Not established; phase 3 trials are designed to evaluate maintenance, cardio-renal endpoints, and broader safety signals across ASCVD/CKD strata.

Limitations & Controversies

• Outcome evidence beyond phase 2: durability of weight loss, CV/renal outcomes, and quality-of-life benefits require phase 3 confirmation.

• Generalizability: Additional data are needed in older, multi-morbid, and diverse ancestry groups, and in pediatrics.

• Mechanistic trade-offs: The GCGR component may drive EE but also HR and glycemic counter-regulation—fine-tuning receptor balance is an active area of optimization.

• Comparative effectiveness: Head-to-head studies vs tirzepatide and high-dose semaglutide are underway; until those read out, cross-trial comparisons remain indirect.

Future Directions

• Phase 3 programs across obesity and T2D with ASCVD/CKD enrollment (e.g., NCT06383390, NCT06662383, NCT06859268) to address maintenance, safety, and outcomes.

• Mechanistic imaging (e.g., brown-fat thermogenesis, hepatic fat by MRI-PDFF) to quantify EE contributions under tri-agonism.

• Structure-driven analogs exploiting ECL1/TMD determinants to adjust receptor-balance for specific indications (e.g., NASH vs obesity).

• Integrated safety strategy focusing on HR, gallbladder/biliary, and GI endpoints—with refined dose escalationalgorithms and co-therapy hypotheses where appropriate.

References

1. Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med.2023. (Primary obesity RCT; NCT04881760; dose–response, HR signal, GI AEs, –24.2% at 48 weeks.) PMID: 37366315.

2. Rosenstock J, et al. Retatrutide… for people with type 2 diabetes: phase 2 trial. Lancet. 2023;402:529-544. (HbA1c up to –2.02% at 24 weeks; ~–17% weight at 36 weeks; safety GLP-1RA-like.) PMID: 37385280.

3. Urva S, et al. LY3437943 (retatrutide) in T2D: phase 1b multiple-ascending dose. Lancet. 2022;400:1869-81. (t½ ~6 days; T_max 12–48 h; LDL/VLDL/TG reductions.) PDF.

4. Li W, et al. Structural insights into retatrutide triple agonism at GLP-1R, GIPR, GCGR. Cell Discovery. 2024. (Cryo-EM mechanisms; acylation at Lys17; PDB 8YW3/4/5.).

5. Coskun T, et al. Effects of retatrutide on body composition in people with type 2 diabetes. Lancet Diabetes Endocrinol. 2025. (Fat-mass reductions; lean-mass proportionality similar to other agents.) PMID: 40609566.

6. Zheng Z, et al. GLP-1 receptor: mechanisms and therapeutic implications. Signal Transduct Target Ther. 2024. (GLP-1R biology overview.).

7. Grant R, et al. IV NAD⁺ infusion kinetics (context for metabolic readouts in incretin studies). Nutrients. 2019. (Methodologic reference for metabolic biomarker dynamics.).

8. He L, et al. GLP-1RA use and gallbladder/biliary diseases (meta-analysis). JAMA Intern Med. 2022. (Class signal; informs monitoring needs.) PMID: 35344001.

9. Sanyal AJ, et al. Retatrutide for metabolic disease (editorial context). Nat Med. 2024. (Summarizes large weight-loss effects and mechanistic rationale.).

10. NCT06859268, NCT06662383, NCT06383390 — ClinicalTrials.gov entries for maintenance, head-to-head vs tirzepatide, and ASCVD/CKD outcomes, respectively.

(Additional context citations used inline: NEJM PubMed abstract details for HR/GI AEsPubMed; phase 1b PDF for PK and lipid changesSIO Società Italiana Obesità; expert commentary on HR changesPubMed.)

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.