{"id":76,"slug":"76-retatrutide-replace-the-native-lys-20-glu-glu-c20-diacid-lipidation-with","title":"Retatrutide Lys-20 oleoyl swap: shorter C18 monoacid lipid for tuned albumin binding","status":"PENDING","fold_verdict":"DISCARDED","discard_reason":null,"peptide":{"name":"Retatrutide","class":"METABOLIC","sequence":"YAQGTFTSDYSIYLDKQAAKDFVQWLLAGGPSSGAPPPS","modified_sequence":"YAQGTFTSDYSIYLDKQAAK(γGlu-oleoyl)DFVQWLLAGGPSSGAPPPS","modification_description":"Replace the native Lys-20 γGlu-γGlu-C20 diacid lipidation with a single γGlu spacer and a C18 monoacid (oleoyl, cis-Δ9 octadecenoyl) chain on the Lys-20 ε-amine, yielding Lys-20(γGlu-oleoyl). All other residues unchanged."},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Swapping Retatrutide's native γGlu-γGlu-C20 diacid at Lys-20 for a single γGlu-oleoyl (C18 monoacid, mono-unsaturated) anchor will yield a tunable albumin-binding profile: weaker, more reversible albumin engagement than the dual-γGlu C20 diacid, but with a kinked oleoyl tail whose cis-Δ9 unsaturation reduces lipid self-aggregation at injection-site depots. We are testing whether the predicted Retatrutide–GLP-1R complex tolerates this lighter lipid without disrupting the helical docking pose around Lys-20.","rationale":"Native Retatrutide uses a γGlu-γGlu-C20 diacid that binds albumin tightly via two anionic anchors plus a long saturated tail; this gives ~6-day half-life but also slow onset and depot precipitation. Oleoyl (C18:1) on a single γGlu is the lipid chemistry used in liraglutide-class analogs and has well-characterized weaker, faster-equilibrating albumin binding via FA1/FA2 sites; the cis double bond disrupts crystalline packing at the depot. Lys-20 sits on the solvent-exposed face of the central helix in class B GPCR-bound poses, so the lipid mainly projects into bulk solvent — pLDDT around the receptor interface should be preserved. This diverges from the last three folds (truncation/STABILITY on Semaglutide, substitution/CONFORMATION on Semax, extension/PHARMACOKINETICS on Tirzepatide) by combining PK focus with a Lipidation-category swap rather than an addition, and category-wise no Lipidation has appeared in the last 3.","predicted_outcome":"Boltz-2/Chai-1 should produce a Retatrutide-GLP1R ECD+TMD complex with pLDDT ≥0.70 at the peptide core (residues 1–30), with the γGlu-oleoyl chain modeled as disordered/solvent-exposed off Lys-20 and no clash with the receptor ECD. The His-1/Tyr-1 N-terminal pose into the TM bundle should be unchanged versus the native Lys-20(γGlu-γGlu-C20-diacid) reference fold.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.6971041560173035,"ptm":0.6767641305923462,"iptm":0.23291026055812836,"chai_agreement":null,"chai1_gated_decision":"RAN_BORDERLINE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.139,"stability_score":0.563,"bbb_penetration_score":0.056,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":null,"detailed_analysis":null,"executive_summary":null,"tweet_draft":null,"research_brief_markdown":null,"structural_caption":"No reliable 3D structure could be obtained for this peptide.","key_findings_summary":"Retatrutide (LY3437943) is a synthetic triple agonist of GIP, GLP-1, and glucagon receptors that has demonstrated exceptional efficacy in Phase 2 trials, achieving up to 22–24% body weight reduction at 48 weeks with 8–12 mg doses, outperforming all currently approved incretin-based therapies. Its molecular architecture includes a C20 fatty diacid linked via a dual γGlu spacer at Lys-20, which confers extended half-life through albumin binding, enabling once-weekly subcutaneous dosing. The clinical literature is exclusively focused on pharmacodynamic outcomes (weight loss, glycemic control, liver fat, blood pressure, body composition) and safety in Phase 2 RCTs; no published work directly characterizes the structural or biophysical basis of Retatrutide's lipidation chemistry or its GLP-1R docking pose.\n\nThe albumin-binding strategy for half-life extension is well-established across the incretin class. Fatty acid lipidation of lysine residues via γGlu spacers is the foundational technology behind semaglutide (C18 monoacid via two mini-PEG and one γGlu linker) and has been adapted in Retatrutide's more elaborate C20 diacid/dual-γGlu system to achieve tighter, more sustained albumin engagement. The trade-off is that longer, saturated diacid chains increase lipid self-aggregation at subcutaneous injection sites, which can affect absorption kinetics and local tolerability. The proposed modification—replacing the native γGlu-γGlu-C20 diacid with a single γGlu-oleoyl (C18 cis-Δ9) anchor—is conceptually analogous to moving from a semaglutide-like to a slightly simpler monoacid architecture, but with the added feature of cis-unsaturation, which is known from lipid biophysics to disrupt ordered lipid packing and reduce self-aggregation propensity.\n\nFrom the GLP-1R structural biology perspective (not directly covered in these abstracts, but inferred from the incretin class literature), the receptor's extracellular domain and transmembrane bundle engage the N-terminal activation domain of GLP-1-class peptides, while Lys-20 (in the mid-helical region) is a solvent-exposed position primarily important for lipidation and albumin tethering rather than direct receptor contact. Helical docking poses for GLP-1R agonists are generally tolerant of lipid chain modifications at mid-helix positions, provided the helical amphipathicity is maintained. A lighter, shorter lipid anchor at Lys-20 is unlikely to sterically disrupt GLP-1R engagement, but could alter the conformational ensemble and receptor residence time indirectly through effects on albumin dissociation kinetics.\n\nThe clinical data demonstrate that Retatrutide's efficacy is robustly dose-dependent across a wide range, with the 12 mg dose achieving ~22% weight loss and superior glycemic, hepatic, and cardiovascular metabolic outcomes. Phase 3 TRIUMPH trials are ongoing. Adverse effects are predominantly gastrointestinal (nausea, vomiting, constipation) and dose-related. Notably, a gray-market peptide quality survey found retatrutide among the most common self-administered peptides, with 41–71% of gray-market samples failing quality criteria—a context that underscores the importance of precise structural characterization of lipidation modifications. No published study directly investigates the pharmacokinetic consequences of varying the lipid anchor structure on Retatrutide specifically."},"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":"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":"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":"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 is that Retatrutide's once-weekly efficacy is enabled by its lipidation-mediated albumin binding, which extends its half-life to approximately 6 days. The native γGlu-γGlu-C20 diacid architecture was selected over simpler monoacid designs (as used in semaglutide's C18 monoacid system) specifically to achieve tighter albumin association and potentially more sustained exposure at higher doses. The GLP-1R component of Retatrutide's activity is well-established clinically, and the class-wide consensus holds that lipidation at mid-helix lysine residues does not directly impair receptor binding when the residue is solvent-exposed and the helical structure is maintained. However, there is no published literature specifically examining structure-activity relationships for Retatrutide's lipid anchor, nor any biophysical characterization of its albumin-binding affinity or injection-site depot behavior. The hypothesis that a C18 cis-Δ9 oleoyl anchor would yield weaker, more reversible albumin binding is mechanistically plausible by analogy to the semaglutide/tirzepatide literature, but remains entirely untested for this molecule.","knowledge_gaps":"No published study has characterized the albumin-binding affinity (Kd) of Retatrutide's native γGlu-γGlu-C20 diacid anchor, nor compared it to alternative lipid anchors. The injection-site depot pharmacokinetics and self-aggregation behavior of the C20 diacid versus a C18 monoacid for this specific peptide sequence are completely unstudied. The GLP-1R structural docking pose of Retatrutide specifically (as opposed to GLP-1 or semaglutide) has not been published—particularly the role of Lys-20 lipidation in modulating receptor affinity or helical stability in the receptor-bound conformation. The effect of cis-Δ9 unsaturation (oleoyl vs. saturated stearoyl) on self-aggregation at subcutaneous injection depots for GLP-1 class peptides is also not directly studied; this is inferred from lipid biophysics rather than peptide pharmacology literature. Whether a 'lighter' lipid would shorten half-life enough to compromise once-weekly dosing for Retatrutide's specific dose-response curve is unknown.","supporting_evidence":"1) Semaglutide uses a C18 monoacid (with different but analogous spacer chemistry) and achieves sufficient albumin binding for once-weekly dosing, establishing that a single C18 fatty acid chain is pharmacologically viable for this drug class. 2) The incretin class literature confirms that mid-helix lysine lipidation is a PK/albumin-binding handle rather than a receptor-contact residue, supporting the hypothesis that GLP-1R docking would tolerate the lighter anchor. 3) The cis-Δ9 kink in oleic acid is well-established in lipid biophysics to reduce ordered packing—this would mechanistically reduce self-aggregation at injection sites relative to straight-chain saturated C20 diacids. 4) Retatrutide's dose-response curve shows substantial efficacy even at lower doses (4 mg), suggesting there may be a therapeutic window that a slightly shorter-acting formulation could still address. 5) The gray-market quality paper confirms that lipidation integrity is critical for peptide identity, implicitly validating the importance of characterizing alternative lipidation designs.","challenging_evidence":"1) The native C20 diacid/dual-γGlu design was almost certainly chosen by Eli Lilly over simpler alternatives through medicinal chemistry optimization; reverting to a monoacid/single-γGlu risks reduced albumin affinity and shorter effective half-life, potentially requiring dose-frequency adjustment. 2) No clinical or preclinical PK data exist for any Retatrutide lipid variant—all efficacy data in the literature are for the native molecule, making it impossible to infer what PK reduction is tolerable. 3) The phase 2 data show that Retatrutide's superior efficacy over semaglutide and tirzepatide may depend on sustained high receptor occupancy at all three targets; if albumin Kd increases substantially with the C18 monoacid, trough concentrations could fall below the threshold for meaningful glucagon receptor engagement (which requires higher agonist concentrations than GLP-1R). 4) The preprint meta-analysis and all RCTs use fixed doses; there is no dose-titration PK data that would allow extrapolation of how a PK-shifted analog would behave clinically. 5) The oleoyl chain's cis-Δ9 unsaturation, while reducing self-aggregation, also increases susceptibility to oxidative degradation, which could compromise shelf-life and introduce formulation chemistry challenges not present with the saturated C20 diacid."},"caveats":null,"works_cited":[{"pmid_or_doi":"37366315","title":"Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial","year":2023,"relevance":"Primary Phase 2 dose-ranging RCT establishing Retatrutide's clinical efficacy and dose-response profile; confirms once-weekly subcutaneous dosing enabled by the native C20 diacid lipidation strategy."},{"pmid_or_doi":"40563436","title":"Retatrutide-A Game Changer in Obesity Pharmacotherapy","year":2025,"relevance":"Reviews Retatrutide's molecular structure and mechanism; highlights the role of the triple-receptor agonist design and contextualizes the lipidation as central to its pharmacokinetic profile."},{"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 RCT in T2D establishing efficacy and safety; confirms dose-dependent outcomes consistent with a stable, albumin-bound pharmacokinetic profile conferred by the native lipidation."},{"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 complex mechanism of action and structure-activity context, relevant as background for understanding how lipidation supports its pharmacological profile."},{"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 once-weekly efficacy, implying that the native lipidation provides sufficient albumin binding for the desired PK; a benchmark against which modified lipidation PK could be compared."},{"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 the breadth of Retatrutide's therapeutic effects; efficacy at 48 weeks is predicated on stable weekly exposure, which depends on intact albumin-binding lipidation."},{"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":"Phase 3 design paper; the subcutaneous once-weekly dosing paradigm it describes is entirely dependent on the lipidation-mediated PK of the native molecule, providing context for what a modified anchor must replicate."},{"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":"Body composition data from T2D trial; sustained fat mass reduction over 36 weeks confirms stable weekly PK exposure from native lipidation, setting the bar for the proposed modification."},{"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":"Comparative network context showing Retatrutide 12 mg achieves the highest weight loss of all agents reviewed; benchmarks the PK adequacy of native lipidation that any modification must not substantially compromise."},{"pmid_or_doi":"39305981","title":"Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss: an updated systematic review and network meta-analysis","year":2024,"relevance":"Network meta-analysis ranking Retatrutide highest for weight loss efficacy, contextualizing the importance of PK integrity (enabled by lipidation) for maintaining therapeutic exposure."},{"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 comparing incretin lipidation strategies across the class (liraglutide C16, semaglutide C18 monoacid, tirzepatide C20 diacid, retatrutide C20 diacid), providing direct structural analogy to the proposed C18 monoacid modification."},{"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 robust clinical outcomes; as a preprint, evidence quality is preliminary, but it reinforces that native Retatrutide's lipidation supports consistent once-weekly exposure."},{"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":2026,"relevance":"Identifies Retatrutide as a gray-market peptide with high quality variability; underscores the importance of precise lipidation chemistry in defining authentic peptide identity, directly relevant to any proposed structural modification."},{"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 has the greatest systolic BP reduction of all GLP-1 class agents; BP effects depend on adequate receptor engagement, which is contingent on PK profile maintained by lipidation."}]},"onchain":{"hash":null,"signature":null,"data_hash":null,"logged_at":null,"explorer_url":null},"ipfs_hash":null,"created_at":"2026-05-04T23:59:07.550547+00:00","updated_at":"2026-05-05T00:16:34.442986+00:00"}