{"id":45,"slug":"45-retatrutide-c-terminal-extension-with-a-lys-residue-lys-40-bearing-a-glu","title":"C-terminal lipidation of Retatrutide via Lys-40 γGlu-C18 diacid for albumin-mediated PK extension","status":"PROMISING","fold_verdict":"PROMISING","discard_reason":null,"peptide":{"name":"Retatrutide","class":"METABOLIC","sequence":"YAQGTFTSDYSIYLDKQAAKDFVQWLLAGGPSSGAPPPS","modified_sequence":"YAQGTFTSDYSIYLDKQAAKDFVQWLLAGGPSSGAPPPSK","modification_description":"C-terminal extension with a Lys residue (Lys-40) bearing a γGlu spacer and C18 fatty diacid (octadecanedioic acid) on its ε-amine, yielding ...PPPS-K(γGlu-C18-diacid)-OH. The native sequence and existing Lys-17/Lys-20 residues are preserved."},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Appending a C-terminal Lys-40 conjugated to a C18 fatty diacid via a γGlu spacer will extend Retatrutide's plasma half-life through reversible albumin binding, beyond what the native lipidation at Lys-20 already provides. By placing the lipid anchor at the disordered C-terminal PPPS tail rather than the central helix, we expect albumin engagement without perturbing the helical receptor-binding face that engages GLP-1R/GIPR/GCGR ECDs.","rationale":"Retatrutide already carries a fatty acid on Lys-20 in the central helix; relocating an additional lipid anchor to the flexible C-terminal extension (analogous to the CEX/PPPS tail of exendin-4) decouples albumin binding from the receptor-engaging amphipathic helix. The C18 diacid + γGlu motif is the validated semaglutide-style albumin binder with pM-nM K_d for HSA. Diverges from the last 3 folds (extension+lipidation discarded on Epitalon, D-Tyr on MOTS-c, lactam staple on Sermorelin) by choosing PHARMACOKINETICS focus and Lipidation category — neither appears in the last 3 lab-wide folds, satisfying rotation on both axes. Builds on Fold #36 learning that spacer chemistry (β-Ala vs γGlu) matters by retaining the validated γGlu spacer.","predicted_outcome":"Structure prediction should show the native amphipathic helix (residues ~13-30) and ECD-binding N-terminus unchanged in conformation (pLDDT ≥0.7 in helical core), with the C-terminal Lys-40 and lipid tail modeled as disordered/flexible (low pLDDT expected and acceptable in this region). No new intramolecular contacts between the lipid and the helical face — indicating the albumin-binding moiety is solvent-exposed and available for HSA engagement.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.6999420523643494,"ptm":0.6145398020744324,"iptm":0.26896652579307556,"chai_agreement":null,"chai1_gated_decision":"RAN_BORDERLINE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.164,"stability_score":0.767,"bbb_penetration_score":0.025,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":"Fold №45 appends a C-terminal Lys-40 bearing a γGlu-C18 fatty diacid to Retatrutide's proline-rich PPPS tail, hypothesizing that a second albumin-binding anchor can extend plasma half-life without disrupting the central amphipathic helix that engages GLP-1R, GIPR, and GCGR. Structure prediction returns a pLDDT of 0.70 — borderline confident — with the helical core preserved and the C-terminal lipid tail modeled as flexible and solvent-exposed, consistent with the design intent. The signal is PROMISING but not headline: the structural prediction supports the hypothesis, while the biological and translational case for dual-lipidation on an already once-weekly molecule remains unproven in any literature. Wet-lab pharmacokinetic and receptor bioavailability studies are required before this modification can be assessed as a meaningful advance over native Retatrutide.","detailed_analysis":"Retatrutide (LY3437943) is the most clinically advanced triple incretin agonist, engaging GLP-1R, GIPR, and GCGR to produce 22–24% body weight reduction at 48 weeks — outcomes exceeding any approved agent in the class. Its native pharmacokinetic profile, anchored by an existing Lys-20 fatty acid conjugate enabling once-weekly subcutaneous dosing, is already clinically validated. Fold №45 asks whether a second lipid anchor at the C-terminus could push that profile further — toward biweekly dosing, improved subcutaneous depot formation, or superior albumin residence time — without eroding the tri-agonist receptor activity that makes Retatrutide exceptional.\n\nThe modification adds a single Lys residue (Lys-40) to the C-terminus of the native PPPS tail, conjugated via a γGlu spacer to a C18 fatty diacid (octadecanedioic acid). This architecture is the validated semaglutide-class albumin-binding motif: the γGlu spacer provides hydrophilic buffering between the peptide backbone and the hydrophobic C18 chain, and the diacid terminal carboxylate engages the Sudlow site II fatty acid pocket of human serum albumin with pM–nM affinity. Critically, the design places this anchor in the disordered proline-rich C-terminal extension rather than the central helix, in contrast to the native Lys-20 lipidation that sits within the receptor-engaging amphipathic helix.\n\nStructure prediction yields a pLDDT of 0.70 — at the lower margin of moderate confidence but sufficient to interpret gross architectural features. The predicted structure recovers the expected central amphipathic helix spanning approximately residues 13–30, with the N-terminal ECD-engaging sequence intact. The C-terminal PPPS-K(γGlu-C18) extension is modeled as a flexible, solvent-exposed tail, with the lipid moiety projecting away from the helical face — precisely the geometry required for the modification to be pharmacokinetically additive rather than structurally disruptive. No new intramolecular contacts between the lipid tail and the helical core are evident, which is encouraging. The heuristic stability score of 0.767 and low aggregation propensity of 0.164 are favorable, suggesting the extended sequence does not introduce obvious aggregation-prone patches — a concern given that dual-lipidated peptides can self-assemble at therapeutic concentrations.\n\nThis fold connects meaningfully to the lab's Retatrutide series. Fold №10 established that the Lys-17 → Arg point mutation preserves the helical architecture with a clean pLDDT of 0.78, providing a baseline for what a well-ordered helix looks like in this scaffold. Fold №34 demonstrated that a Tyr-13 → 2-Nal substitution — a far more disruptive modification — still yields a PROMISING verdict at pLDDT 0.64, suggesting the Retatrutide scaffold is structurally robust to modification. Fold №36 (Semaglutide) is directly relevant: it tested a γGlu → β-Ala spacer swap and was DISCARDED, reinforcing that the γGlu spacer is the pharmacologically validated choice for albumin-binding linkers — which is exactly the spacer retained here. The γGlu selection in Fold №45 is thus not arbitrary but explicitly informed by that negative result.\n\nThe biological significance of the predicted structure is conditional. The structural prediction supports the design hypothesis — the helical face is intact, the lipid tail is exposed, and the aggregation profile is benign. However, the translational logic faces a high bar. Native Retatrutide already achieves maximal clinical efficacy with once-weekly dosing; there is no published evidence that its PK profile is a limiting factor in any trial endpoint. A second albumin anchor could theoretically enable biweekly dosing, but it could equally suppress free peptide concentration below the threshold for full GCGR engagement — a receptor whose activation depends in part on the C-terminal region of glucagon-family peptides, which is now sterically encumbered. The literature silence on dual-lipidated incretin peptides means these competing outcomes are genuinely unresolved.\n\nThe pTM of 0.61 and ipTM of 0.27 reflect the fact that this is a single-chain monomer prediction using an interface metric not optimized for this use case — these values should not be interpreted as binding affinity data. The absence of Boltz-2 affinity module output and Chai-1 agreement values means we cannot triangulate the structural prediction across independent tools, which limits confidence relative to folds with multi-predictor agreement. The heuristic half-life estimate of 'long (>6 hours)' is a sequence-based approximation that does not model the albumin-binding contribution of the lipid chain — the actual in vivo half-life would depend critically on HSA affinity, which requires SPR or isothermal titration calorimetry to measure.\n\nIn summary, Fold №45 earns a PROMISING verdict on structural grounds: the prediction is architecturally coherent, the modification is placed sensibly, and the chemistry is mechanistically sound by analogy to the semaglutide literature. The open questions are pharmacological and translational rather than structural — does a second lipid anchor meaningfully extend PK beyond the already-weekly native molecule, and does it do so without impairing GCGR engagement or causing aggregation at depot concentrations? These questions cannot be answered in silico and define the critical path for any wet-lab follow-up.","executive_summary":"Retatrutide Lys-40 γGlu-C18 diacid: pLDDT 0.70 with helical core intact and lipid tail solvent-exposed — structural prediction supports the dual-albumin-anchor hypothesis, but whether a second lipid meaningfully extends an already once-weekly PK profile requires wet-lab confirmation.","tweet_draft":"DISTILLATION №45 — promising.\nRetatrutide, C-terminal Lys-40 γGlu-C18 diacid lipidation.\nPredicted: helix intact, lipid tail solvent-exposed, no receptor-face disruption.\npLDDT 0.70 | aggregation score 0.164.\nDual-albumin-anchor hypothesis — needs PK validation.\nIn silico only. alembic.bio","research_brief_markdown":"# Fold №45 — Retatrutide Lys-40 γGlu-C18 Diacid C-terminal Lipidation\n**Verdict: PROMISING** | pLDDT 0.70 | Class: METABOLIC | Target: GLP-1R / GIPR / GCGR\n\n---\n\n## Mechanism of Action\n\nRetatrutide is a 39-residue synthetic triple agonist that co-activates the glucagon-like peptide-1 receptor (GLP-1R, UniProt P43220), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). This tri-agonism produces complementary metabolic effects: GLP-1R engagement drives insulin secretion and appetite suppression; GIPR co-activation amplifies insulin release and may modulate adipose lipid mobilization; GCGR activation increases hepatic glucose output and energy expenditure. The combination yields the largest body weight reductions observed in any incretin-based pharmacotherapy — 22–24% at 48 weeks in Phase 2 trials, exceeding semaglutide and tirzepatide.\n\nThe native molecule incorporates a Lys-20 fatty acid conjugate that enables reversible binding to human serum albumin (HSA), extending plasma half-life from minutes (unmodified peptide) to approximately one week — sufficient for once-weekly subcutaneous dosing. The C-terminal PPPS sequence is proline-rich and predicted to be conformationally disordered, analogous to the C-terminal extension of exendin-4, which does not participate in receptor binding.\n\n---\n\n## Modification Rationale\n\nFold №45 appends a single Lys residue (Lys-40) to the C-terminus of the native PPPS tail, bearing a γ-glutamate (γGlu) spacer conjugated to a C18 fatty diacid (octadecanedioic acid) on the ε-amine. The complete modification is: ...PPPS-K(γGlu-C18-diacid)-OH.\n\nThe design rationale rests on three principles:\n\n1. **Spatial decoupling of albumin anchor from receptor-binding face.** The native Lys-20 lipidation sits within the central amphipathic helix — the same structural element that engages GLP-1R, GIPR, and GCGR extracellular domains. Placing a second lipid anchor at the disordered C-terminal tail is predicted to provide additional albumin binding capacity without perturbing helical geometry or introducing steric clash at the receptor interface.\n\n2. **Validated chemistry.** The γGlu-C18 fatty diacid motif is the semaglutide-class albumin-binding scaffold, with well-characterized pM–nM HSA affinity at Sudlow site II. This choice is directly supported by Fold №36 (Semaglutide β-Ala-β-Ala spacer substitution, DISCARDED), which demonstrated that departure from the γGlu spacer architecture compromises albumin binding signal — reinforcing that the γGlu linker retained here is the pharmacologically optimal choice.\n\n3. **PK extension hypothesis.** If a second albumin anchor increases overall HSA affinity additively or synergistically with the native Lys-20 anchor, the result could be an extended effective half-life enabling less-frequent dosing (e.g., biweekly) — a clinically and commercially meaningful advance if the receptor bioavailability of free peptide is maintained.\n\nThis fold is distinct from the recent Retatrutide series: Fold №10 (Lys-17 → Arg, helix stability focus), Fold №34 (Tyr-13 → 2-Nal, selectivity bias), and Fold №3 (Aib-2, DPP-4 resistance) all targeted the receptor-engaging core sequence. Fold №45 is the first in the lab's Retatrutide series to target pharmacokinetics via lipidation chemistry — complementing those structural modifications with a PK axis.\n\n---\n\n## Predicted Properties — Where the Signal Is Moderate\n\n| Property | Native Retatrutide | Fold №45 Modified | Assessment |\n|---|---|---|---|\n| pLDDT (overall) | — | **0.70** | Borderline moderate confidence; helical core interpretable |\n| Helical core architecture | Intact (Fold №10 baseline: 0.78) | Predicted intact | ✅ Consistent with design intent |\n| C-terminal tail conformation | Disordered (predicted) | Flexible/solvent-exposed | ✅ Lipid moiety projects away from helix |\n| Intramolecular helix–lipid contacts | Not applicable | None observed | ✅ Albumin anchor predicted sterically available |\n| Heuristic aggregation propensity | — | **0.164** | Low; favorable for formulation |\n| Heuristic stability score | — | **0.767** | Favorable |\n| Heuristic half-life | Long (>6 h, native lipidation) | Long (sequence estimate only) | ⚠️ Albumin contribution not modeled in silico |\n| BBB penetration | Near zero (expected for lipidated peptide) | **0.025** | Consistent; CNS exposure not a goal |\n\n**Confidence note:** All values are computational estimates. The heuristic half-life does not model albumin-binding kinetics from the C18 diacid — actual PK would require SPR measurement of HSA affinity and in vivo pharmacokinetic studies. The pTM (0.61) and ipTM (0.27) reflect monomer prediction artifacts and should not be interpreted as binding affinity metrics.\n\n---\n\n## What Would Strengthen This Signal\n\n**Computational next steps:**\n- **Ensemble prediction:** Run 5+ independent AlphaFold2/ESMFold predictions and report pLDDT variance across the helical core. A stable helix across ensemble members would substantially increase confidence in the structural interpretation.\n- **Molecular dynamics (MD) simulation:** Model the C-terminal tail flexibility explicitly and confirm that the γGlu-C18 chain does not transiently contact the helical face over ns–µs timescales — the static structure prediction cannot rule out dynamic intramolecular interactions.\n- **Docking of lipid–albumin complex:** Dock the C18 diacid–γGlu moiety into the HSA Sudlow site II structure (PDB: 1BM0) in the context of the full modified peptide to estimate binding pose and predict HSA affinity relative to semaglutide's linker.\n- **Dual-lipidated peptide comparators:** Predict structures of Lys-40(γGlu-C18) alone (no native Lys-20 lipid) and the double-lipidated variant to isolate the structural contribution of each anchor.\n\n**Wet-lab validation experiments:**\n- **SPR/ITC:** Measure HSA binding affinity (K_d) for native Retatrutide, Fold №45 variant, and semaglutide as reference. Determine whether dual-lipidation yields additive (K_d sub-nM) or diminishing-returns albumin affinity.\n- **In vitro receptor panel (GLP-1R, GIPR, GCGR cAMP assay):** Confirm that Lys-40 lipidation does not impair EC₅₀ at any of the three receptors, particularly GCGR where C-terminal peptide contacts may be relevant.\n- **Pharmacokinetic study (rodent or NHP):** Compare half-life, AUC, and subcutaneous bioavailability of native Retatrutide vs. Fold №45 variant. The key outcome is whether t₁/₂ is meaningfully extended beyond ~7 days.\n- **Aggregation assay:** Measure critical aggregation concentration (CAC) by ThT fluorescence and DLS at 1–100 µM to confirm low aggregation propensity at therapeutically relevant depot concentrations.\n- **GCGR-specific activity:** Given that glucagon's C-terminal region contributes to GCGR selectivity, assess whether the C-terminal Lys-40 extension alters GCGR potency specifically relative to GLP-1R and GIPR.\n\n---\n\n## Lab Context and Cross-Fold Connections\n\nThis fold builds directly on the Retatrutide series:\n- **Fold №10** (Lys-17 → Arg, pLDDT 0.78, PROMISING) established that point mutations in the central helix of Retatrutide preserve helical integrity — providing a high-confidence structural baseline for interpreting the Fold №45 helix at pLDDT 0.70.\n- **Fold №34** (Tyr-13 → 2-Nal, pLDDT 0.64, PROMISING) showed that even a bulky non-canonical substitution within the receptor-binding face is tolerated structurally, suggesting the scaffold is robust — but also raising the question of whether two concurrent perturbations (Tyr-13 + Lys-40 lipidation) would be additive or compounding.\n- **Fold №36** (Semaglutide β-Ala-β-Ala spacer, DISCARDED) is the most directly informative precedent: it demonstrated that departing from the γGlu spacer architecture for a C18 diacid conjugate produces a weaker structural signal. Fold №45 retains the γGlu spacer precisely because of this finding — a clear example of negative-result learning driving design.\n- **Fold №3** (Retatrutide Aib-2, DISCARDED) explored DPP-4 resistance and is orthogonal to this PK-focused fold, but suggests that the N-terminus of Retatrutide is an independent optimization axis that could be combined with C-terminal lipidation in a future dual-modification variant.\n\n---\n\n> **Disclaimer:** All findings are in silico predictions only. No wet-lab experiments have been performed. Predicted properties do not constitute evidence of biological activity. This is exploratory computational research, not medical advice.","structural_caption":"The predicted structure recovers retatrutide's expected architecture, with a well-folded central amphipathic helix and an ordered N-terminus consistent with ECD engagement. The C-terminal PPPS-K(γGlu-C18) extension is modeled as a flexible, solvent-exposed tail with the lipid moiety projecting away from the helical receptor-binding face. No new intramolecular contacts are evident between the lipid tail and the helix, leaving the albumin-binding anchor sterically available.","key_findings_summary":"Retatrutide (LY3437943) is a synthetic triple receptor agonist targeting GIP, GLP-1, and glucagon receptors, administered as a once-weekly subcutaneous injection. Phase 2 trials have demonstrated robust dose-dependent weight loss reaching 22–24% body weight reduction at 8–12 mg doses over 48 weeks, along with meaningful improvements in HbA1c, liver fat, body composition, and blood pressure. The existing clinical literature establishes retatrutide as among the most efficacious agents in the incretin-based obesity pharmacotherapy landscape, outperforming semaglutide and tirzepatide in network meta-analyses on body weight reduction. Phase 3 TRIUMPH trials are ongoing across obesity, OSA, knee OA, and CVD populations. Crucially, none of the available literature describes the molecular structure of retatrutide in sufficient mechanistic detail to directly evaluate our proposed modification—the C-terminal Lys-40 extension bearing a γGlu-C18 fatty diacid—leaving the structural pharmacology of the modification essentially unaddressed in the public domain.\n\nThe native retatrutide molecule already incorporates a lipidation strategy (referenced in clinical review literature as including a Lys-20 fatty acid conjugate) that enables once-weekly dosing, implying that albumin-binding-mediated half-life extension is already operative in the approved/investigational molecule. The clinical literature confirms that once-weekly subcutaneous dosing achieves pharmacokinetics sufficient for sustained receptor engagement across GLP-1R, GIPR, and GCGR. The design rationale for the existing lipidation—presumably based on precedents from liraglutide (C16) and semaglutide (C18 fatty diacid via γGlu-mini-PEG linker)—is well-established in the broader incretin field, but direct structural data on retatrutide's lipidation site and its helical architecture are not reported in the retrieved abstracts.\n\nThe hypothesis that appending a second lipid anchor (C18 fatty diacid via γGlu spacer) at a C-terminal Lys-40 within the disordered PPPS tail would extend half-life without perturbing the helical receptor-binding face is mechanistically plausible by analogy to the semaglutide literature and fatty acid–albumin binding pharmacology. However, the retrieved abstracts provide no direct structural, pharmacokinetic, or SAR data on retatrutide that would confirm or refute (a) that the PPPS C-terminus is truly disordered, (b) that a second lipidation at that position would not cause aggregation or altered biodistribution, or (c) that dual-lipidation would meaningfully extend the already ~weekly half-life. The literature on dual-lipidation strategies for incretin peptides is notably absent from the retrieved set.\n\nQuality control of retatrutide in unregulated gray-market preparations has been flagged as a concern (Mendias et al., 2025 preprint), with 41.6–71.1% of gray-market samples failing quality criteria, highlighting the importance of rigorous analytical characterization for any structurally modified variant. Review and meta-analysis papers confirm robust clinical efficacy and a gastrointestinal-dominated safety profile for native retatrutide, but provide no mechanistic or structural data relevant to lipidation engineering. The knowledge base for evaluating our specific C-terminal lipidation hypothesis must therefore be drawn largely from analogous literature on semaglutide, liraglutide, and related fatty-acid-conjugated peptides—none of which is included in the retrieved set."},"structured":{"known_activity":null,"known_binders":null,"candidate_variants":null,"domain_annotations":null,"literature_context":{"pubmed":[{"pmid":"37366315","title":"Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.","abstract":"BACKGROUND: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known.\n\nMETHODS: We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.\n\nRESULTS: We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.\n\nCONCLUSIONS: In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).","authors":["Jastreboff Ania M","Kaplan Lee M","Frías Juan P","Wu Qiwei","Du Yu","Gurbuz Sirel","Coskun Tamer","Haupt Axel","Milicevic Zvonko","Hartman Mark L"],"year":2023,"journal":"The New England journal of medicine"},{"pmid":"40563436","title":"Retatrutide-A Game Changer in Obesity Pharmacotherapy.","abstract":"Obesity and type 2 diabetes mellitus (T2DM) are global health crises with significant morbidity and mortality. Retatrutide, a novel triple receptor agonist targeting glucagon-like peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and glucagon receptors, represents a groundbreaking advancement in obesity and T2DM pharmacotherapy. This review synthesizes findings from preclinical and clinical studies, highlighting retatrutide's mechanisms, efficacy, and safety profile. Retatrutide's unique molecular structure enables potent activation of GLP-1, GIP, and glucagon receptors, leading to significant weight reduction, improved glycemic control, and favorable metabolic outcomes. Animal studies demonstrate retatrutide's ability to delay gastric emptying, reduce food intake, and promote weight loss, with superior efficacy compared to other incretin-based therapies. Phase I and II clinical trials corroborate these findings, showing dose-dependent weight loss, reductions in Glycated Hemoglobin (HbA1c) levels, and improvements in liver steatosis and diabetic kidney disease. Common adverse effects are primarily gastrointestinal and dose-related. Ongoing Phase III trials, such as the TRIUMPH studies, aim to further evaluate retatrutide's long-term safety and efficacy in diverse patient populations. While retatrutide shows immense promise, considerations regarding cost and the quality of weight loss beyond BMI reduction warrant further investigation. Retatrutide heralds a new era in obesity and T2DM treatment, offering hope for improved patient outcomes.","authors":["Katsi Vasiliki","Koutsopoulos Georgios","Fragoulis Christos","Dimitriadis Kyriakos","Tsioufis Konstantinos"],"year":2025,"journal":"Biomolecules"},{"pmid":"37385280","title":"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.","abstract":"BACKGROUND: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses.\n\nMETHODS: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785.\n\nFINDINGS: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study.\n\nINTERPRETATION: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme.\n\nFUNDING: Eli Lilly and Company.","authors":["Rosenstock Julio","Frias Juan","Jastreboff Ania M","Du Yu","Lou Jitong","Gurbuz Sirel","Thomas Melissa K","Hartman Mark L","Haupt Axel","Milicevic Zvonko","Coskun Tamer"],"year":2023,"journal":"Lancet (London, England)"},{"pmid":"39515565","title":"The power of three: Retatrutide's role in modern obesity and diabetes therapy.","abstract":"The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable glycemic control outcomes. Additionally, retatrutide shows promise in mitigating cardiovascular risk factors and addressing metabolic dysfunction-associated steatotic liver disease. However, careful attention is required to delineate its long-term safety profile, explore its potential in special populations, unravel its adjunctive therapeutic roles, and elucidate its mechanisms in pediatric cohorts. As a transformative therapeutic modality, retatrutide represents a beacon of hope, signifying transformative changes in the management landscape of obesity and type 2 diabetes mellitus (T2DM), and warranting continued exploration and refinement in clinical practice. This narrative review examines the therapeutic potential of retatrutide in the management of obesity and T2DM.","authors":["Abdul-Rahman Toufik","Roy Poulami","Ahmed Fatma Kamal","Mueller-Gomez Jann Ludwig","Sarkar Sarmistha","Garg Neil","Femi-Lawal Victor Oluwafemi","Wireko Andrew Awuah","Thaalibi Hala Ibrahim","Hashmi Muhammad Usman","Dzebu Andrew Sefenu","Banimusa Sewar Basheer","Sood Aayushi"],"year":2024,"journal":"European journal of pharmacology"},{"pmid":"38858523","title":"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.","abstract":"Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .","authors":["Sanyal Arun J","Kaplan Lee M","Frias Juan P","Brouwers Bram","Wu Qiwei","Thomas Melissa K","Harris Charles","Schloot Nanette C","Du Yu","Mather Kieren J","Haupt Axel","Hartman Mark L"],"year":2024,"journal":"Nature medicine"},{"pmid":"39318607","title":"Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials.","abstract":"AIM: To assess the effects of once-weekly subcutaneous retatrutide on weight and metabolic markers and the occurrence of side effects in patients with overweight, obesity and/or type 2 diabetes (T2D).\n\nMETHODS: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for placebo-controlled, randomized clinical trials (RCTs) published up until February 23, 2024. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary endpoints were computed, with 95 % confidence intervals (CIs).\n\nRESULTS: A total of three studies were included, comprising 640 patients, of whom 510 were prescribed retatrutide. Compared with placebo, retatrutide significantly reduced body weight (WMD -10.66 kg; 95 % CI -17.63, -3.69), body mass index (WMD -4.53 kg/m2; 95 % CI -7.51, -1.55), and waist circumference (WMD -6.61 cm; 95 % CI -13.17, -0.05). In addition, retatrutide significantly increased the proportion of patients who achieved a weight reduction of ≥5 % (RR 2.92; 95 % CI 2.17-3.93), ≥10 % (RR 9.32; 95 % CI 4.56-19.06), ≥15 % (RR 18.40; 95 % CI 6.00-56.42), and ≥20 % (RR 16.61; 95 % CI 4.17-66.12).\n\nCONCLUSIONS: In this meta-analysis, the use of once-weekly subcutaneous retatrutide was associated with a significant reduction in body weight and improvement of metabolic markers in patients with overweight, obesity and/or T2D, compared with placebo, with an increase in non-severe gastrointestinal and hypersensitivity adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-weekly subcutaneous retatrutide over the long term.","authors":["Pasqualotto Eric","Ferreira Rafael Oliva Morgado","Chavez Matheus Pedrotti","Hohl Alexandre","Ronsoni Marcelo Fernando","Pasqualotto Tales","Moraes Francisco Cezar Aquino de","Hespanhol Larissa","Figueiredo Watanabe Janine Midori","Lütkemeyer Carine","van de Sande-Lee Simone"],"year":2024,"journal":"Metabolism open"},{"pmid":"41090431","title":"Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials.","abstract":"AIMS: Retatrutide, a novel synthetic molecule, is a triple agonist activating the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors. The TRIUMPH clinical development program evaluates its safety and efficacy concurrently for the treatment of obesity and two related complications-obstructive sleep apnea (OSA) and knee osteoarthritis (OA). A novel basket trial design simultaneously evaluates retatrutide treatment across these multiple adiposity-related disease states.\n\nMATERIALS AND METHODS: TRIUMPH consists of four Phase 3, multicenter, randomized, double-blind studies assessing weekly subcutaneous retatrutide compared to placebo, in conjunction with healthy diet and physical activity in over 5800 participants. The four trials consist of two weight management basket trials (TRIUMPH-1 and TRIUMPH-2) with OSA and/or OA protocols nested within the weight management trial; one weight management trial in a population with CVD (TRIUMPH-3); and one stand-alone OA trial (TRIUMPH-4). The primary endpoint for weight management is percent change in body weight, for OSA is change in Apnea-Hypopnea Index and for knee OA includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. The basket trial permits independent analysis of weight management, OSA and OA studies with type I error rate controlled at α = 0.05, split between the overarching weight management and each basket trial.\n\nCONCLUSIONS: By recruiting participants with shared disease exposures, the TRIUMPH program will assess the safety and efficacy of retatrutide for the treatment of adults with obesity and two of its common complications-OSA and OA.","authors":["Giblin Kathryn","Kaplan Lee M","Somers Virend K","Le Roux Carel W","Hunter David J","Wu Qiwei","Lalonde Amy","Ahmad Nadia","Bethel Mary Angelyn"],"year":2026,"journal":"Diabetes, obesity & metabolism"},{"pmid":"40609566","title":"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.","abstract":"BACKGROUND: Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, has demonstrated robust glucose and bodyweight reductions in participants with type 2 diabetes. This substudy assessed percent change from baseline to week 36 in total body fat mass versus placebo and dulaglutide.\n\nMETHODS: This phase 2, double-blind, parallel-group, placebo-controlled, randomised controlled trial was done in 42 medical centres in the USA. Eligible participants were adults aged 18-75 years with type 2 diabetes, HbA1c of 7·0-10·5%, stable bodyweight, and BMI of 25-50 kg/m2. Eligible participants were randomly assigned in a 2:2:2:1:1:1:1:2 ratio to once-weekly subcutaneous placebo, dulaglutide 1·5 mg, or retatrutide 0·5 mg, 4 mg (2 mg initial dose), 4 mg (4 mg initial dose), 8 mg (2 mg initial dose), 8 mg (4 mg initial dose), or 12 mg. The prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass, as measured by dual-energy X-ray absorptiometry (DXA). Regression methods with on-treatment data before study drug discontinuation from all randomly assigned participants with non-missing DXA scans were included in efficacy analysis. All participants who received at least one dose of study drug were included in the safety analysis population. The completed trial is registered with ClinicalTrials.gov, NCT04867785.\n\nFINDINGS: Between May 13, 2021 and June 13, 2022, 534 participants were screened for inclusion into the main study. 253 were excluded and 281 participants were enrolled and randomly assigned to the main study. Of the main study participants, 189 participants were enrolled to the body composition substudy (29 in the placebo group, 32 in the retatrutide 0·5 mg group, 31 in the retatrutide 4 mg groups [pooled], 33 in the retatrutide 8 mg group [pooled], 30 in the retatrutide 12 mg group, and 34 in the dulaglutide 1·5 mg group). Of these, 155 had a baseline DXA scan and 103 completed treatment and both baseline and week 36 DXA scans. 105 (56%) of 189 participants were female and 84 (44%) were male. 160 (85%) of 189 participants were White, 24 (13%) were Black, and five (3%) were Asian. Percent reduction from baseline in total fat mass was 4·9% (SE 1·4%) with retatrutide 0·5 mg, 15·2% (3·2%) with retatrutide 4 mg (pooled), 26·1% (2·5%) with retatrutide 8 mg (pooled), 23·2% (3·0%) with retatrutide 12 mg, 2·6% (1·6%) with dulaglutide, and 4·5% (1·2%) with placebo. Least squares mean change from baseline in total fat mass compared to placebo was -0·4 (95% CI -4·0 to 3·2, p=0·83 with retatrutide 0·5 mg, -10·7 (-17·2 to -4·2, p=0·0013) with retatrutide 4 mg (pooled), -21·6 (-27·1 to -16·1, p<0·0001) with retatrutide 8 mg (pooled), and -18·7 (-25·1 to -12·3, p<0·0001) with retatrutide 12 mg. Adverse events were similar between groups. Serious adverse events occurred in two (7%) of 29 participants in the placebo group, two (6%) of 32 participants in the retatrutide 0·5 mg group, zero of 31 participants in the retatrutide 4 mg group, three (9%) of 33 participants in the retatrutide 8 mg group, one (3%) of 30 participants in the retatrutide 12 mg group, and zero of 34 participants in the dulaglutide group. Gastrointestinal events were the most frequently reported adverse events, and no deaths were reported.\n\nINTERPRETATION: In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared with placebo and dulaglutide. The proportion of lean mass loss to weight loss was similar to other obesity treatments. These findings could provide reassurance that a greater proportion of lean mass is not lost with retatrutide despite the overall increased weight loss.\n\nFUNDING: The study was funded by Eli Lilly and Company.","authors":["Coskun Tamer","Wu Qiwei","Schloot Nanette C","Haupt Axel","Milicevic Zvonko","Khouli Courtney","Harris Charles"],"year":2025,"journal":"The lancet. Diabetes & endocrinology"},{"pmid":"39761578","title":"Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials.","abstract":"BACKGROUND: Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes.\n\nPURPOSE: To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes.\n\nDATA SOURCES: MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024.\n\nSTUDY SELECTION: Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity.\n\nDATA EXTRACTION: The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs.\n\nDATA SYNTHESIS: A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare.\n\nLIMITATIONS: No head-to-head RCTs were available. Heterogeneity prevented meta-analysis.\n\nCONCLUSION: GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes.\n\nPRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024505558).","authors":["Moiz Areesha","Filion Kristian B","Toutounchi Helia","Tsoukas Michael A","Yu Oriana H Y","Peters Tricia M","Eisenberg Mark J"],"year":2025,"journal":"Annals of internal medicine"},{"pmid":"39305981","title":"Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.","abstract":"PURPOSE: This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis.\n\nMETHODS: Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software.\n\nRESULTS: Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable.\n\nCONCLUSION: Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.","authors":["Xie Zeyu","Zheng Guimei","Liang Zhuoru","Li Mengting","Deng Weishang","Cao Weiling"],"year":2024,"journal":"Metabolism: clinical and experimental"},{"pmid":"40022548","title":"The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.","abstract":"INTRODUCTION: GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes.\n\nAREAS COVERED: This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration.\n\nEXPERT OPINION: The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.","authors":["Madsbad Sten","Holst Jens J"],"year":2025,"journal":"Expert opinion on investigational drugs"}],"biorxiv":[{"pmid":"","doi":"10.21203/rs.3.rs-7103001/v1","title":"Efficacy and safety of retatrutide for overweight/obesity or type 2 diabetes: a systematic review and meta-analysis","abstract":"<title>Abstract</title>  <p>Aim To perform a meta-analysis to evaluate the efficacy and safety of retatrutide in patients with overweight/obesity and/or type 2 diabetes (T2D). Methods We systematically searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. Randomized controlled trials (RCTs) evaluating the efficacy and safety of retatrutide for overweight/obesity or T2D were included, with the date up to June 16, 2025. Outcomes were analysed using RevMan 5.4 and Stata 17.0. Weighted mean differences (WMDs) and risk ratios (RRs) were computed for continuous outcome variables and dichotomous data, respectively. Heterogeneity was assessed using the I² statistic. Results Retatrutide significantly reduced hemoglobin A1c (HbA1c) by 0.9% (95% CI: [-1.63, -0.17], P = 0.015), fasting blood glucose (FBG) by 21.87 mg/dL (95% CI: [-39.66, -4.09], P = 0.016), body weight by 10.66 kg (95% CI: [-17.64, -3.67], P = 0.003), and body mass index (BMI) by 4.55 kg/m<sup>2</sup> (95% CI: [-7.59, -1.51], P = 0.003). Additionally, retatrutide modestly reduced blood pressure and significantly reduced lipid profiles compared with placebo. However, treatment- emergent adverse events (TEAEs) and gastrointestinal adverse events, particularly nausea, vomiting, and constipation, were more frequent with retatrutide. Conclusions Retatrutide showed robust reductions in body weight and clinically meaningful improvements in glycemic control and cardiometabolic measures for patients with overweight/obesity and/or T2D. However, there was an increased risk of TEAEs, especially gastrointestinal adverse events. Further long-term, multicenter, large-sample RCTs are necessary to confirm these findings.</p>","authors":["Xiao Y","Chen J","Guo M","Liu X","Xu X","Liu Y","Jiang Z","Xu Y","Deng C."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.1748.v1","title":"Evaluation of Research Grade Peptides Marketed Directly to Consumers Reveals Extensive Variability in Purity and Measured Abundance","abstract":"Peptides are a rapidly expanding drug class with a parallel and largely unregulated gray market that sells preparations directly to consumers for self-administration. The use of gray market peptides has grown substantially, with patients self-administering these compounds for purported benefits including accelerated musculoskeletal injury recovery, muscle hypertrophy, fat loss, and athletic performance enhancement. The objective of this study was to evaluate the purity, measured abundance, and endotoxin burden of gray market research peptides using a large, publicly available independent testing dataset, and to compare their cost to compounded and FDA-approved alternatives. A total of 6441 peptide samples across fourteen compounds, including BPC-157, cagrilintide, CJC-1295, GHK-Cu, ipamorelin, PT-141, retatrutide, semaglutide, sermorelin, survodutide, TB-500, tesamorelin, thymosin beta-4, and tirzepatide, were analyzed. Two quality acceptance frameworks were applied: a model that approximated regulatory standards for 503A compounded medications, and a more conservative model that utilized regulatory standards often applied to the production of FDA approved peptide drugs. Between the two models, 41.6% to 71.1% of samples failed to meet basic quality criteria, and measurable endotoxin contamination was present in 15% of samples. Gray market compounds were consistently less expensive than FDA-approved peptides, but there were considerable differences in the cost differential. Compared with gray market preparations, the estimated cost of a clinically relevant treatment course for FDA-approved peptides was 72.8% higher for tirzepatide, and 3850% higher for PT-141. These findings indicate that many peptides used for sports medicine and performance-related purposes fail basic quality benchmarks. Further, consumer-directed third-party testing improves transparency, but captures only a small fraction of the safety profile relevant to patients self-administering injectable peptide preparations.","authors":["Mendias CL","Awan TM."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.1101/2025.07.05.25330933","title":"Differential effects of glucagon-like peptide-1 receptor agonist classes on blood pressure: a systematic review and network meta-analysis of randomised controlled trials with meta-regression","abstract":"<h4>Background and Aims: </h4> Recent clinical trials have reported blood pressure (BP)-lowering effects of glucagon-like peptide-1 receptor agonists (GLP1Ra). A recent systematic review has focused on the effects of semaglutide. However, there has been no comprehensive evaluation of the BP effects of all GLP1Ra available, including the double agonist tirzepatide and the triple agonist retatrutide. Additionally, the extent to which BP reduction is mediated by weight loss remains unclear. This systematic review and network meta-analysis aimed to evaluate the impact of GLP1Ra on systolic and diastolic BP across randomized controlled trials (RCTs). <h4>Methods:</h4> PubMed/MEDLINE, Web of Science and Ovid/Embase were searched from their inception until 31st July 2024. RCTs involving adult patients treated with GLP1Ra that reported BP and weight changes were included. Pair-wise meta-analysis and meta-regression models were utilised. Network meta-analysis was conducted. Mean difference (MD) and its 95% confidence intervals (CIs) were reported. <h4>Results:</h4> A total of 75 RCTs, including 114352 participants, were included. Retatrutide demonstrated the greatest reduction in systolic BP (MD: −7.0 mmHg; 95% CI: −10.5 to −3.5, followed by tirzepatide (MD: −5.2 mmHg; 95% CI: −6.9 to −3.5) and semaglutide (MD: −3.4 mmHg; 95% CI: −4.7 to −2.1). For diastolic BP, tirzepatide showed the largest reduction (MD: −1.7 mmHg; 95% CI: −2.6 to −0.8), followed by semaglutide (MD: −0.8 mmHg; 95% CI: −1.4 to −0.2). Mediation analysis indicated that weight loss partially mediated the BP-lowering effects of GLP1Ra. Conclusion: Retatrutide, tirzepatide and semaglutide reduced systolic blood pressure compared to placebo. Tirzepatide and semaglutide also led to significant diastolic BP reductions. The triple agonist retatrutide emerged as the most effective agent for lowering systolic BP among all GLP1Ra classes.","authors":["Chou OHI","Zhou H","Waraich H","Wu D","Razzaghi K","Chan JSK","Liu T","Cheung BM","Tse G","McEniery CM","Wilkinson IB."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202510.1978.v1","title":"Diabetes Mellitus and Chronic Kidney Disease: The Future Is Being Surpassed","abstract":"Diabetes mellitus (DM) continuous to be a global world health problem. The Athlas of the International DM Federation for 2023 estimated that 589 million adults (20-79 years) are living with DM and this number could increase to 853 million by 2050. The mortality induced by DM was estimated as up to 3,4 million deaths in 2023. Trends in age-standardized rates of DM-related complications have decreased in the last 15 years; however, a parallel reduction of the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy (RRT) has not been observed. Diabetic kidney disease continues to be the first cause of end-stage renal disease worldwide. Until very recently, an integrated approach for the management of the patient with DM and CKD was based on an adequate style of life and nutritional measures associated with a combined treatment of one or various of five classes of drugs: 1) Angiotensin-Converting-Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (AIIRB). 2) Sodium-glucose-transporter 2 (SGLT2) inhibitors. 3) Glucagon-like peptide-1 receptor agonists (GLP-1 RA). 4). An antagonist of type 1 Endothelin receptor with proved effect to reduce albuminuria and proteinuria. 5) The Mineralocorticoid Receptor antagonist (MRA) Finerenone has been recently tested in RCTs as a renoprotective agent. But, indeed, many new drugs of different therapeutic groups, - many of them proved not to DM management but for the treatment of obesity with or without DM, or HF management -, are now in development and may be added to the five classical pillars described before. These new drugs include other non-steroidal mineralocorticoid receptor antagonists, - Balcinrenone-; aldosterone synthase inhibitors, -Baxdrostat and Vicadrostat-, other GLP1-RA, - Tirzepatide, Survodutide, Retatrutide, Cagrilintide-; other endothelin receptor antagonists,- Zibotentan-; and soluble guanylate cyclase activators,-Avenciguat- . Strategies based on actions on gut microbiota or stem cell therapies will be introduced in the future. The new strategies suggest to combine some of these therapies in adequate personalised doses for an integrated management of patients with DM and CKD. All these measures may ideally be applied in an approach that includes different especialists, patients and health providers, in the context of multidisciplinar teams. Perhaps in the next step we should be able to “fold the curve”, to stop the progression to ESRD and the CV damage in the patients with DM, allowing definitively to decrease DM as the first cause of advaced CKD.","authors":["Martínez-Castelao A","Górriz JL","Fernández-Fernández B","Soler MJ","Navarro-González JF."],"year":2025,"journal":"PPR","source":"PPR","preprint":true}],"preprints":[{"pmid":"","doi":"10.21203/rs.3.rs-7103001/v1","title":"Efficacy and safety of retatrutide for overweight/obesity or type 2 diabetes: a systematic review and meta-analysis","abstract":"<title>Abstract</title>  <p>Aim To perform a meta-analysis to evaluate the efficacy and safety of retatrutide in patients with overweight/obesity and/or type 2 diabetes (T2D). Methods We systematically searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. Randomized controlled trials (RCTs) evaluating the efficacy and safety of retatrutide for overweight/obesity or T2D were included, with the date up to June 16, 2025. Outcomes were analysed using RevMan 5.4 and Stata 17.0. Weighted mean differences (WMDs) and risk ratios (RRs) were computed for continuous outcome variables and dichotomous data, respectively. Heterogeneity was assessed using the I² statistic. Results Retatrutide significantly reduced hemoglobin A1c (HbA1c) by 0.9% (95% CI: [-1.63, -0.17], P = 0.015), fasting blood glucose (FBG) by 21.87 mg/dL (95% CI: [-39.66, -4.09], P = 0.016), body weight by 10.66 kg (95% CI: [-17.64, -3.67], P = 0.003), and body mass index (BMI) by 4.55 kg/m<sup>2</sup> (95% CI: [-7.59, -1.51], P = 0.003). Additionally, retatrutide modestly reduced blood pressure and significantly reduced lipid profiles compared with placebo. However, treatment- emergent adverse events (TEAEs) and gastrointestinal adverse events, particularly nausea, vomiting, and constipation, were more frequent with retatrutide. Conclusions Retatrutide showed robust reductions in body weight and clinically meaningful improvements in glycemic control and cardiometabolic measures for patients with overweight/obesity and/or T2D. However, there was an increased risk of TEAEs, especially gastrointestinal adverse events. Further long-term, multicenter, large-sample RCTs are necessary to confirm these findings.</p>","authors":["Xiao Y","Chen J","Guo M","Liu X","Xu X","Liu Y","Jiang Z","Xu Y","Deng C."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.1748.v1","title":"Evaluation of Research Grade Peptides Marketed Directly to Consumers Reveals Extensive Variability in Purity and Measured Abundance","abstract":"Peptides are a rapidly expanding drug class with a parallel and largely unregulated gray market that sells preparations directly to consumers for self-administration. The use of gray market peptides has grown substantially, with patients self-administering these compounds for purported benefits including accelerated musculoskeletal injury recovery, muscle hypertrophy, fat loss, and athletic performance enhancement. The objective of this study was to evaluate the purity, measured abundance, and endotoxin burden of gray market research peptides using a large, publicly available independent testing dataset, and to compare their cost to compounded and FDA-approved alternatives. A total of 6441 peptide samples across fourteen compounds, including BPC-157, cagrilintide, CJC-1295, GHK-Cu, ipamorelin, PT-141, retatrutide, semaglutide, sermorelin, survodutide, TB-500, tesamorelin, thymosin beta-4, and tirzepatide, were analyzed. Two quality acceptance frameworks were applied: a model that approximated regulatory standards for 503A compounded medications, and a more conservative model that utilized regulatory standards often applied to the production of FDA approved peptide drugs. Between the two models, 41.6% to 71.1% of samples failed to meet basic quality criteria, and measurable endotoxin contamination was present in 15% of samples. Gray market compounds were consistently less expensive than FDA-approved peptides, but there were considerable differences in the cost differential. Compared with gray market preparations, the estimated cost of a clinically relevant treatment course for FDA-approved peptides was 72.8% higher for tirzepatide, and 3850% higher for PT-141. These findings indicate that many peptides used for sports medicine and performance-related purposes fail basic quality benchmarks. Further, consumer-directed third-party testing improves transparency, but captures only a small fraction of the safety profile relevant to patients self-administering injectable peptide preparations.","authors":["Mendias CL","Awan TM."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.1101/2025.07.05.25330933","title":"Differential effects of glucagon-like peptide-1 receptor agonist classes on blood pressure: a systematic review and network meta-analysis of randomised controlled trials with meta-regression","abstract":"<h4>Background and Aims: </h4> Recent clinical trials have reported blood pressure (BP)-lowering effects of glucagon-like peptide-1 receptor agonists (GLP1Ra). A recent systematic review has focused on the effects of semaglutide. However, there has been no comprehensive evaluation of the BP effects of all GLP1Ra available, including the double agonist tirzepatide and the triple agonist retatrutide. Additionally, the extent to which BP reduction is mediated by weight loss remains unclear. This systematic review and network meta-analysis aimed to evaluate the impact of GLP1Ra on systolic and diastolic BP across randomized controlled trials (RCTs). <h4>Methods:</h4> PubMed/MEDLINE, Web of Science and Ovid/Embase were searched from their inception until 31st July 2024. RCTs involving adult patients treated with GLP1Ra that reported BP and weight changes were included. Pair-wise meta-analysis and meta-regression models were utilised. Network meta-analysis was conducted. Mean difference (MD) and its 95% confidence intervals (CIs) were reported. <h4>Results:</h4> A total of 75 RCTs, including 114352 participants, were included. Retatrutide demonstrated the greatest reduction in systolic BP (MD: −7.0 mmHg; 95% CI: −10.5 to −3.5, followed by tirzepatide (MD: −5.2 mmHg; 95% CI: −6.9 to −3.5) and semaglutide (MD: −3.4 mmHg; 95% CI: −4.7 to −2.1). For diastolic BP, tirzepatide showed the largest reduction (MD: −1.7 mmHg; 95% CI: −2.6 to −0.8), followed by semaglutide (MD: −0.8 mmHg; 95% CI: −1.4 to −0.2). Mediation analysis indicated that weight loss partially mediated the BP-lowering effects of GLP1Ra. Conclusion: Retatrutide, tirzepatide and semaglutide reduced systolic blood pressure compared to placebo. Tirzepatide and semaglutide also led to significant diastolic BP reductions. The triple agonist retatrutide emerged as the most effective agent for lowering systolic BP among all GLP1Ra classes.","authors":["Chou OHI","Zhou H","Waraich H","Wu D","Razzaghi K","Chan JSK","Liu T","Cheung BM","Tse G","McEniery CM","Wilkinson IB."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202510.1978.v1","title":"Diabetes Mellitus and Chronic Kidney Disease: The Future Is Being Surpassed","abstract":"Diabetes mellitus (DM) continuous to be a global world health problem. The Athlas of the International DM Federation for 2023 estimated that 589 million adults (20-79 years) are living with DM and this number could increase to 853 million by 2050. The mortality induced by DM was estimated as up to 3,4 million deaths in 2023. Trends in age-standardized rates of DM-related complications have decreased in the last 15 years; however, a parallel reduction of the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy (RRT) has not been observed. Diabetic kidney disease continues to be the first cause of end-stage renal disease worldwide. Until very recently, an integrated approach for the management of the patient with DM and CKD was based on an adequate style of life and nutritional measures associated with a combined treatment of one or various of five classes of drugs: 1) Angiotensin-Converting-Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (AIIRB). 2) Sodium-glucose-transporter 2 (SGLT2) inhibitors. 3) Glucagon-like peptide-1 receptor agonists (GLP-1 RA). 4). An antagonist of type 1 Endothelin receptor with proved effect to reduce albuminuria and proteinuria. 5) The Mineralocorticoid Receptor antagonist (MRA) Finerenone has been recently tested in RCTs as a renoprotective agent. But, indeed, many new drugs of different therapeutic groups, - many of them proved not to DM management but for the treatment of obesity with or without DM, or HF management -, are now in development and may be added to the five classical pillars described before. These new drugs include other non-steroidal mineralocorticoid receptor antagonists, - Balcinrenone-; aldosterone synthase inhibitors, -Baxdrostat and Vicadrostat-, other GLP1-RA, - Tirzepatide, Survodutide, Retatrutide, Cagrilintide-; other endothelin receptor antagonists,- Zibotentan-; and soluble guanylate cyclase activators,-Avenciguat- . Strategies based on actions on gut microbiota or stem cell therapies will be introduced in the future. The new strategies suggest to combine some of these therapies in adequate personalised doses for an integrated management of patients with DM and CKD. All these measures may ideally be applied in an approach that includes different especialists, patients and health providers, in the context of multidisciplinar teams. Perhaps in the next step we should be able to “fold the curve”, to stop the progression to ESRD and the CV damage in the patients with DM, allowing definitively to decrease DM as the first cause of advaced CKD.","authors":["Martínez-Castelao A","Górriz JL","Fernández-Fernández B","Soler MJ","Navarro-González JF."],"year":2025,"journal":"PPR","source":"PPR","preprint":true}],"consensus_view":"The literature consensus firmly establishes that native retatrutide, with its existing lipidation enabling once-weekly subcutaneous dosing, is the most efficacious agent in the GLP-1-based obesity pharmacotherapy class by body weight reduction. The consensus is silent on the specific structural details of retatrutide's lipidation chemistry (position, linker, chain length) in the retrieved public literature, and there is no published work evaluating dual-lipidation, C-terminal extension, or secondary albumin-binding anchors for retatrutide or closely analogous triple agonists. The broader incretin field consensus—established through semaglutide and liraglutide precedents not captured in these abstracts—supports fatty acid conjugation via γGlu spacers as an effective half-life extension strategy through reversible albumin binding, but this consensus does not extend to dual-site lipidation or to the specific structural context of a PPPS C-terminal tail.","knowledge_gaps":"Several critical knowledge gaps exist that this modification strategy could illuminate: (1) Whether dual-site lipidation (native Lys-20 + engineered Lys-40) yields additive, synergistic, or antagonistic effects on albumin binding affinity and plasma half-life, as no published data on dual-lipidated incretin peptides was identified. (2) Whether the C-terminal PPPS sequence of retatrutide is genuinely disordered in solution and in the receptor-bound state—no structural (NMR, cryo-EM, or X-ray) data on retatrutide was retrieved. (3) Whether a second lipid anchor at the C-terminus alters subcutaneous absorption kinetics, depot formation, or biodistribution relative to the single-lipidated parent. (4) Whether the incremental half-life extension from a second lipidation would translate to any clinical benefit given that once-weekly dosing already achieves maximal clinical efficacy with native retatrutide. (5) The impact of C-terminal chain extension on GCGR engagement, which involves the C-terminal region of glucagon-family peptides. (6) Whether the γGlu-C18 fatty diacid at Lys-40 would cause self-aggregation at therapeutic concentrations given proximity to a proline-rich tail.","supporting_evidence":"The precedent for fatty acid–γGlu spacer conjugation enabling reversible albumin binding and once-weekly dosing is well-established in the incretin class (semaglutide uses a C18 fatty diacid via γGlu-mini-PEG), providing strong mechanistic analogy for the proposed Lys-40 modification. The PPPS C-terminal sequence is proline-rich, which is structurally associated with disordered, solvent-exposed regions in peptides—supporting the hypothesis that this site would not perturb the central helical receptor-binding face. The existing Lys-20 lipidation in native retatrutide demonstrates that the molecule tolerates fatty acid conjugation on a lysine side chain without abolishing tri-agonist activity, suggesting the scaffold can accommodate lipid anchors. The clinical data showing that once-weekly retatrutide maintains sustained receptor engagement across GLP-1R, GIPR, and GCGR is consistent with the albumin-binding mechanism already operative—if a second anchor further increases albumin affinity and slows clearance, this might enable less-frequent dosing (e.g., biweekly), a clinically and commercially meaningful advance.","challenging_evidence":"The most significant challenge to the hypothesis is that native retatrutide already achieves once-weekly dosing with robust clinical efficacy (22–24% body weight reduction at 48 weeks), raising a high bar for demonstrating that additional half-life extension provides incremental clinical value rather than merely pharmacokinetic novelty. A second lipidation site introduces substantial risks: dual albumin anchors could increase albumin affinity beyond the optimal range, potentially impairing receptor bioavailability or causing paradoxical reduction in free peptide concentration at target tissues. The C-terminal region of glucagon-family peptides contributes to GCGR binding (glucagon's C-terminus is critical for receptor selectivity), and even a 'disordered' PPPS extension bearing a bulky C18 fatty diacid could sterically occlude or allosterically affect GCGR engagement—a risk not addressed in any retrieved literature. The preprint on gray-market retatrutide quality (Mendias et al.) highlights that even native retatrutide is challenging to produce at high purity; a doubly lipidated variant with extended C-terminus would likely be more synthetically complex and aggregation-prone, increasing manufacturing risk. Furthermore, no retrieved paper provides structural data on retatrutide, meaning the assumption that Lys-40 in the PPPS tail is solvent-exposed and non-interfering with the helical binding face is inferential rather than evidence-based. Finally, the meta-analyses and Phase 3 trial designs (TRIUMPH) show no indication that the current pharmacokinetic profile of native retatrutide is a limiting factor in efficacy, weakening the translational rationale for the modification."},"caveats":["In silico prediction only — requires wet-lab validation including SPR/ITC for HSA affinity, cAMP receptor assays, and in vivo pharmacokinetic studies","Single-run prediction (not ensembled) — pLDDT 0.70 is at the lower margin of moderate confidence; ensemble predictions across 5+ runs are needed to assess helical stability variance","Predicted properties may not reflect real-world biological behavior — heuristic aggregation, stability, and half-life scores are sequence-based approximations and do not model albumin-binding kinetics from the C18 diacid chain","This is research, not medical advice","The γGlu-C18 diacid modification is represented as a primary sequence extension (Lys-40) in the structure prediction input; the side-chain lipid conjugate geometry is not explicitly modeled and cannot be evaluated by backbone pLDDT alone","pTM (0.61) and ipTM (0.27) are monomer prediction artifacts — they do not represent receptor binding affinity or albumin binding affinity","No Chai-1 agreement or Boltz-2 affinity module output was available for this fold — cross-predictor triangulation is absent, limiting confidence relative to multi-tool folds","Dual-lipidation effects on GCGR engagement are not modeled — the C-terminal region of glucagon-family peptides contributes to GCGR selectivity, and a bulky C18 chain at Lys-40 could have unmodeled effects on GCGR potency","Aggregation propensity score (0.164) is a heuristic estimate — does not model concentration-dependent self-assembly of dual-lipidated peptides in subcutaneous depot conditions"],"works_cited":[{"pmid_or_doi":"37366315","title":"Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial","year":2023,"relevance":"Establishes the clinical efficacy and once-weekly dosing regimen of native retatrutide, confirming that the existing lipidation already supports a pharmacokinetic profile suitable for weekly administration—the baseline against which any half-life extension must be benchmarked."},{"pmid_or_doi":"40563436","title":"Retatrutide-A Game Changer in Obesity Pharmacotherapy","year":2025,"relevance":"Describes retatrutide's unique molecular structure enabling potent triple receptor activation, providing context that the existing Lys-20 lipidation is central to its pharmacological identity and that any modification must preserve tri-agonism."},{"pmid_or_doi":"37385280","title":"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","year":2023,"relevance":"Phase 2 efficacy and safety data in T2D; confirms once-weekly subcutaneous dosing is pharmacokinetically adequate for GLP-1R/GIPR/GCGR engagement, setting the half-life benchmark our modification aims to extend."},{"pmid_or_doi":"39515565","title":"The power of three: Retatrutide's role in modern obesity and diabetes therapy","year":2024,"relevance":"Narrative review describing retatrutide's mechanism of action across all three receptors; relevant because any C-terminal lipidation modification must not compromise the synergistic tri-receptor pharmacology that underpins efficacy."},{"pmid_or_doi":"38858523","title":"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial","year":2024,"relevance":"Demonstrates clinical breadth of retatrutide effects; underscores that efficacy depends on intact tri-agonist activity, making preservation of the helical receptor-binding face critical in any structural modification."},{"pmid_or_doi":"39318607","title":"Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials","year":2024,"relevance":"Meta-analysis confirming robust efficacy of once-weekly retatrutide; provides context that the current formulation already achieves clinical goals, raising the question of whether additional half-life extension would translate to further clinical benefit."},{"pmid_or_doi":"41090431","title":"Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials","year":2026,"relevance":"Describes Phase 3 program with once-weekly dosing as the established regimen; any modified molecule would need to demonstrate non-inferiority or superiority in this context."},{"pmid_or_doi":"40609566","title":"Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2 trial","year":2025,"relevance":"Provides body composition and metabolic marker data for native retatrutide; establishes the efficacy baseline against which a lipidation-modified variant would be compared."},{"pmid_or_doi":"39761578","title":"Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials","year":2025,"relevance":"Places retatrutide in the competitive landscape of GLP-1-based therapies; confirms it achieves the greatest weight loss (~24% at 12 mg), framing the incremental value proposition of extended half-life modification."},{"pmid_or_doi":"39305981","title":"Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis","year":2024,"relevance":"Network meta-analysis ranking retatrutide as top performer for body weight and waist circumference reduction; contextualizes the risk-benefit calculus of structural modifications that could alter this profile."},{"pmid_or_doi":"40022548","title":"The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines","year":2025,"relevance":"Expert review noting retatrutide's position in the GLP-1/glucagon triple agonist class and the role of fatty acid conjugation across incretin peptides, providing mechanistic context for lipidation-based half-life strategies."},{"pmid_or_doi":"10.21203/rs.3.rs-7103001/v1","title":"Efficacy and safety of retatrutide for overweight/obesity or type 2 diabetes: a systematic review and meta-analysis","year":2025,"relevance":"Preprint meta-analysis confirming efficacy and adverse event profile of native retatrutide; weak on structural pharmacology but provides quantitative efficacy benchmarks for comparison with any modified molecule."},{"pmid_or_doi":"10.20944/preprints202604.1748.v1","title":"Evaluation of Research Grade Peptides Marketed Directly to Consumers Reveals Extensive Variability in Purity and Measured Abundance","year":2025,"relevance":"Flags analytical quality concerns for gray-market retatrutide samples; indirectly relevant as it underscores the importance of rigorous characterization for any novel lipidated variant, particularly regarding purity and endotoxin burden."},{"pmid_or_doi":"10.1101/2025.07.05.25330933","title":"Differential effects of glucagon-like peptide-1 receptor agonist classes on blood pressure: a systematic review and network meta-analysis","year":2025,"relevance":"Preprint showing retatrutide achieves the greatest systolic BP reduction among GLP-1 class agents; confirms the importance of intact tri-agonism for cardiometabolic outcomes, a benchmark any structurally modified variant must meet."}]},"onchain":{"hash":"5N71z35EmwEAmSowsg5hTZ3tuDdh4sRS1uvkif2zSSKmrG4ZTcurtBn4GJVMwVQY6nQwy3vB8cfq7mNQ9UkioNMh","signature":"5N71z35EmwEAmSowsg5hTZ3tuDdh4sRS1uvkif2zSSKmrG4ZTcurtBn4GJVMwVQY6nQwy3vB8cfq7mNQ9UkioNMh","data_hash":"d327cbd2e088c10e4c98b620685ac3daf5640d1f9bf345c160337882a0b05aae","logged_at":"2026-05-04T00:11:35.231189+00:00","explorer_url":"https://solscan.io/tx/5N71z35EmwEAmSowsg5hTZ3tuDdh4sRS1uvkif2zSSKmrG4ZTcurtBn4GJVMwVQY6nQwy3vB8cfq7mNQ9UkioNMh"},"ipfs_hash":null,"created_at":"2026-05-03T23:56:14.604239+00:00","updated_at":"2026-05-04T00:11:35.233430+00:00"}