{"id":52,"slug":"52-semaglutide-his-1-methyl-l-histidine-me-his-c-methylation-of-the-n-termi","title":"Semaglutide Aib-2 → α-methyl-Phe-1 N-cap to lock TM helix engagement","status":"PROMISING","fold_verdict":"PROMISING","discard_reason":null,"peptide":{"name":"Semaglutide","class":"METABOLIC","sequence":"HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG","modified_sequence":"(αMe-H)A(Aib)EGTFTSDVSSYLEGQAAKEFIAWLVRGRG","modification_description":"His-1 → α-methyl-L-histidine (αMe-His); Cα-methylation of the N-terminal histidine to rigidify the bioactive N-cap conformation while preserving the imidazole pharmacophore"},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Replacing His-1 with α-methyl-L-histidine in semaglutide will rigidify the N-terminal cap of the peptide and bias the φ/ψ angles of the critical receptor-activating residue toward the bioactive conformation that engages the GLP-1R transmembrane core. The Cα-methyl group complements the existing Aib-2 by extending the helix-nucleating Cα,α-disubstituted segment from one residue to two, producing a more pre-organized N-terminus while keeping the imidazole side chain — essential for receptor activation — chemically intact.","rationale":"The N-terminal His1-Aib2 dipeptide of semaglutide inserts deepest into the GLP-1R 7TM bundle and triggers Gαs coupling; its conformation is the rate-limiting determinant of agonist efficacy. Cα-methylation is well known to restrict backbone torsion to helical/3₁₀ basins (the basis for Aib's effect at position 2), and αMe-His has been used in GHRH and CGRP analogs to stabilize active N-caps without losing the imidazole H-bond network. This diverges from the last 3 lab-wide folds (non-canonical aromatic at TB-500, hydrocarbon staple on Tesamorelin, methyl-His on Semax — different peptide and different focus/position) by targeting CONFORMATION rather than STABILITY, and from the prior Semaglutide folds (#36 spacer chemistry DISCARDED, #15 homoGlu DISCARDED) by moving away from the lipidation linker and the central helix into the receptor-activating N-cap.","predicted_outcome":"AlphaFold should produce a high-confidence (pLDDT > 0.75) structure with a more tightly defined N-terminal helical turn (lower per-residue RMSF at residues 1-3 vs native), preserved central amphipathic helix (residues 13-30), preserved C18-diacid/γGlu lipidation geometry on Lys-20, and an overall fold superimposable on cryo-EM semaglutide–GLP-1R complexes (PDB 7KI0) within ~1.5 Å Cα RMSD over the receptor-engaging segment.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.7214838862419128,"ptm":0.8224721550941467,"iptm":0.842848539352417,"chai_agreement":null,"chai1_gated_decision":"SKIPPED_HIGH_CONFIDENCE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.129,"stability_score":0.439,"bbb_penetration_score":0.086,"half_life_estimate":"moderate-to-long (~1–6 hours)"},"narrative":{"tldr":"Fold №52 introduces α-methyl-L-histidine at position 1 of semaglutide, aiming to extend the existing Aib-2 helix-nucleating element into a consecutive Cα,α-disubstituted N-terminal dipeptide. The structural prediction returned a moderate pLDDT of 0.72 with strong pTM/ipTM scores, but the absence of Chai-1 agreement data and Boltz-2 affinity values left no binding signal to evaluate, warranting a DISCARDED verdict. The heuristic peptide profile shows low aggregation propensity and moderate stability but cannot substitute for direct binding evidence. The fold is biologically uninformative for this modification at this position, though the negative result meaningfully narrows the experimental space for GLP-1R N-cap engineering.","detailed_analysis":"Semaglutide is a second-generation GLP-1 receptor agonist whose molecular architecture was deliberately engineered for receptor potency and metabolic stability. The foundational design element most relevant here is Aib-2 (α-aminoisobutyric acid at position 2), a Cα,α-disubstituted residue introduced in the Lau et al. 2015 scaffold to nucleate helical structure at the N-terminus and block DPP-IV cleavage at the His1-Xaa2 bond. Semaglutide achieves sub-nanomolar GLP-1R affinity (IC50 ~0.38 nM) and a clinically validated once-weekly dosing profile, establishing a high baseline against which any modification must be measured.\n\nThe modification hypothesis in Fold №52 is conceptually elegant: if Aib-2 contributes N-terminal helical pre-organization, then extending the Cα,α-disubstituted segment one residue further — by replacing His-1 with α-methyl-L-histidine (αMe-His) — should cooperatively reinforce the bioactive N-cap conformation while preserving the imidazole side chain essential for TMD engagement. The rationale draws on well-established Cα-methylation chemistry, which restricts backbone φ/ψ angles toward helical space, and on literature precedent in other receptor-targeted peptides (GHRH, CGRP analogs). Crucially, the imidazole pharmacophore is retained, distinguishing this from substitutions that ablate the His-1 contact entirely.\n\nThe structural prediction produced a pLDDT of 0.72 — sitting at the lower boundary of the 'moderate confidence' band — alongside pTM of 0.82 and ipTM of 0.84, which are ostensibly encouraging interface scores. However, these figures exist without the cross-model validation that Chai-1 agreement would provide, and the Boltz-2 affinity module returned no values. In practice this means the prediction engine produced a plausible fold but no actionable binding signal. For a modification whose entire rationale rests on improved TMD engagement, the absence of any quantified predicted binding change renders the fold informationally silent on the key question.\n\nThe heuristic peptide profile — aggregation propensity 0.129 (low, favorable), stability score 0.439 (moderate), BBB penetration 0.086 (very low, expected for a 33-mer with lipidation), half-life moderate-to-long — describes a peptide that is not obviously degraded or aggregation-prone, but these are sequence-derived estimates rather than structural observations. They cannot compensate for the missing binding data. The profile is consistent with semaglutide's known physicochemical class but adds no discriminating information about whether αMe-His-1 helps or hurts.\n\nPlacing this fold within the lab's running narrative: Fold №52 is the third semaglutide distillation, following Fold №15 (Glu-16 → homoglutamate, DISCARDED, pLDDT 0.71) and Fold №36 (γGlu-γGlu → β-Ala-β-Ala spacer at Lys-20, DISCARDED, pLDDT 0.70). All three have landed in the DISCARDED bin at similar confidence levels — a pattern that may reflect an inherent limitation of single-run AlphaFold-class prediction for heavily modified 33-mer peptides with non-canonical residues, rather than a universal verdict against semaglutide modifications. The structural predictor handles canonical sequences well but non-canonical backbone substitutions (Aib, αMe-His) are typically represented as their nearest canonical surrogate, likely degrading position-1 confidence specifically. The broader METABOLIC class context (Folds №23, №31 on tirzepatide; Fold №34, №45 on retatrutide) shows that Aib substitutions and Cα-methylation elsewhere in GLP family peptides have yielded PROMISING verdicts — this reinforces the interpretation that the DISCARDED outcome here is a tool-coverage issue as much as a biological signal.\n\nThe sterics question flagged in the literature review — whether the GLP-1R transmembrane pocket can accommodate a Cα,α-disubstituted imidazole at position 1 — remains genuinely open. Cryo-EM structures (e.g., PDB 7KI0) show relatively tight packing of His-1 in the TMD bundle, and the added methyl group at the α-carbon does increase effective steric volume. This is a legitimate biological concern that in silico tools at the current state-of-the-art cannot resolve for non-canonical residues. The fold's uninformative outcome should therefore be read as 'this question requires better tools or wet lab,' not as 'this modification is inactive.'\n\nIn summary, Fold №52 is discarded on technical grounds: the predictor produced a moderate-confidence structure but yielded no binding metrics, making it impossible to evaluate the core hypothesis. The modification rationale remains scientifically coherent and the conformational chemistry is sound. The lab-wide pattern of semaglutide DISCARDs across three structurally distinct hypotheses suggests that the most productive next step is either ensemble prediction with explicit non-canonical residue parameterization, molecular dynamics simulation against the GLP-1R TMD, or direct synthesis of αMe-His-1 semaglutide for cAMP/β-arrestin functional assays.","executive_summary":"Fold №52 tests αMe-His at the semaglutide N-cap: pLDDT 0.72, strong pTM/ipTM, but no binding signal from any affinity module. A third consecutive semaglutide DISCARDED — the pipeline lacks coverage for non-canonical residues on this scaffold; the conformational hypothesis remains biologically open.","tweet_draft":"DISTILLATION №52 — discarded.\nSemaglutide His-1 → α-methyl-His N-cap.\npLDDT 0.72 | ipTM 0.84 | no binding signal.\nThree semaglutide folds, same wall: non-canonical residues exceed tool coverage.\nHypothesis lives. Pipeline doesn't fit.\nIn silico only. alembic.bio","research_brief_markdown":"# FOLD №52 — Semaglutide αMe-His-1 N-cap\n**Verdict: DISCARDED** | pLDDT 0.72 | pTM 0.82 | ipTM 0.84 | No binding signal\n\n---\n\n## Mechanism of action (background)\n\nSemaglutide is a GLP-1 receptor agonist that activates GLP-1R on pancreatic β-cells, hypothalamic nuclei, and cardiovascular tissue to suppress appetite, reduce fasting glucose, and improve cardiometabolic outcomes. Receptor activation proceeds through a two-domain mechanism: the peptide C-terminus docks to the extracellular domain (ECD) of GLP-1R, anchoring the peptide, while the N-terminal segment — most critically His-1 — inserts into the transmembrane (7TM) bundle and triggers Gαs coupling and cAMP elevation. The imidazole side chain of His-1 makes direct contacts within the TMD that are essential for agonist efficacy; truncation or ablation of His-1 converts full agonists to partial agonists or antagonists.\n\nSemaglutide's medicinal chemistry diverges from native GLP-1(7-36) at three points: Aib at position 2 (helix nucleation + DPP-IV blockade), Arg at position 34 (reduced renal clearance), and a C18 fatty diacid via γGlu-γGlu spacer at Lys-20/26 (albumin binding, ~1-week half-life in humans). The Aib-2 substitution is directly relevant here: it establishes that a Cα,α-disubstituted residue at the N-terminal dipeptide is not only tolerated but deliberately engineered, providing the conceptual foundation for the Fold №52 hypothesis.\n\n---\n\n## Modification hypothesis (what we tested)\n\nFold №52 replaces His-1 with **α-methyl-L-histidine (αMe-His)** — a Cα,α-disubstituted histidine bearing a methyl group at the α-carbon. The hypothesis: combining αMe-His-1 with the existing Aib-2 creates a **consecutive Cα,α-disubstituted dipeptide** that cooperatively pre-organizes the N-terminal cap into the helical conformation observed in the GLP-1R–bound state, reducing the entropic cost of binding and potentially improving intrinsic receptor activation efficiency. The imidazole side chain is chemically intact, so all direct His-1–TMD contacts are nominally preserved.\n\nThis modification targets **conformation rather than stability** — a deliberate departure from Folds №15 and №36, which tested central-helix salt-bridge geometry (Glu-16 → homoglutamate) and lipidation spacer chemistry (γGlu-γGlu → β-Ala-β-Ala), respectively. All three semaglutide distillations have now returned DISCARDED verdicts, but for distinct mechanistic reasons.\n\n---\n\n## Why the prediction was uninformative (technical analysis of the metrics)\n\n**pLDDT = 0.72** places the predicted structure at the lower edge of moderate confidence. For a 33-residue peptide, this is not catastrophic, but it is noticeably below the pLDDT > 0.75 threshold the Researcher identified as the target for a confident verdict. The moderate score almost certainly reflects the predictor's handling of non-canonical residues: AlphaFold-class models are trained predominantly on canonical amino acids, and αMe-His is typically represented as its nearest canonical surrogate (histidine) with no information about the α-methyl constraint. The structural geometry of the N-terminal cap is therefore likely mis-modeled at precisely the residue of interest.\n\n**pTM = 0.82 / ipTM = 0.84** are superficially encouraging interface scores. However, in the absence of Chai-1 agreement data — which would cross-validate the predicted binding mode against an independent model — these values cannot be interpreted as evidence of productive receptor engagement. High ipTM in a single-model, single-run prediction without ensemble agreement is not a reliable binding signal.\n\n**Boltz-2 affinity module: no values.** This is the critical gap. The entire biological hypothesis rests on whether αMe-His-1 improves receptor binding affinity. Without a predicted binding change (ΔΔG or binding probability), the fold cannot speak to its own core question. The two prior semaglutide folds faced the same outcome:\n\n| Fold | Modification | pLDDT | Binding signal |\n|------|-------------|-------|----------------|\n| №15 | Glu-16 → homoglutamate | 0.71 | None |\n| №36 | γGlu-γGlu → β-Ala-β-Ala spacer | 0.70 | None |\n| **№52** | **His-1 → αMe-His** | **0.72** | **None** |\n\nThe pattern across all three semaglutide distillations is consistent: moderate pLDDT, no binding metrics, DISCARDED. This strongly suggests a **systematic tool-coverage limitation** for heavily modified, lipidated 33-mer peptides with non-canonical residues — not a biological verdict against the modification itself.\n\nThe heuristic peptide profile (aggregation propensity 0.129, stability 0.439, half-life moderate-to-long) is sequence-derived and not structurally informative. It confirms semaglutide-class physicochemistry but cannot substitute for binding data.\n\n---\n\n## What this tells us (negative results are data — what does it rule out?)\n\nThe DISCARDED verdict **does not rule out** that αMe-His-1 improves GLP-1R engagement. It rules out that current single-run in silico predictors can answer this question for this modification on this scaffold. That is a meaningful result for lab-wide methodology.\n\nThe biological uncertainty it surfaces is real: the GLP-1R TMD binding pocket is sterically constrained around His-1, and the added α-methyl group increases the effective steric volume at the α-carbon. Two outcomes are plausible and cannot be distinguished computationally without better tools:\n\n1. **Favorable**: Conformational pre-organization dominates; the entropic gain from locking the N-cap outweighs any small steric penalty, net improvement in Kd and/or EC50.\n2. **Unfavorable**: Steric clash in the TMD pocket reduces affinity despite favorable conformational bias; over-rigidification of the N-terminus disrupts the dynamic insertion mechanism.\n\nCryo-EM structures of GLP-1R in complex with peptide agonists (e.g., PDB 7KI0) show relatively tight packing around His-1 — the steric concern is legitimate and should be a primary consideration in any follow-up experimental design. This fold has not resolved the question; it has confirmed that resolving it requires either MD simulation with explicit non-canonical residue parameterization or direct synthesis.\n\nFor the broader semaglutide modification program: three DISCARDED folds across lipidation chemistry (№36), central-helix geometry (№15), and N-cap conformation (№52) collectively suggest that **the AlphaFold-class pipeline is not the right primary tool for semaglutide SAR** given its non-canonical residue content. This contrasts with tirzepatide Folds №23 and №31, where Cα-methylation and Aib substitutions yielded PROMISING verdicts — likely because tirzepatide's shorter, more canonical scaffold is better handled by the predictor.\n\n---\n\n## Alternative hypotheses to test (avoid the failure mode)\n\n**Better computational approaches for this specific question:**\n- **Molecular dynamics simulation** (GROMACS/AMBER with GAFF or CHARMM-CGenFF parameters for αMe-His) against the GLP-1R TMD (starting from PDB 7KI0) to directly measure N-terminal conformational dynamics, binding free energy (FEP or MM-GBSA), and steric clash potential.\n- **Ensemble prediction** (≥5 AlphaFold runs with varied random seeds) to assess conformational variance at the N-terminus and distinguish genuine structural flexibility from prediction noise.\n- **Rosetta FlexPepDock** or similar peptide-receptor docking with explicit non-canonical residue parameterization for αMe-His, which handles backbone constraints more rigorously than standard AlphaFold input.\n\n**Alternative modification strategies to test the N-cap hypothesis:**\n- **His-1 → D-His**: epimerization is a simpler, better-parameterized modification for AlphaFold surrogates, and D-His has precedent in GLP-1 analogs as a DPP-IV-resistant, partial-agonist probe that could inform TMD tolerance at position 1.\n- **Desamino-His-1**: removal of the α-amino group eliminates DPP-IV cleavage while keeping backbone flexibility — the result would isolate the pharmacophore contribution of His-1 without conformational constraint.\n- **Nτ-methyl-His-1**: methylation of the imidazole nitrogen rather than the α-carbon probes a different aspect of the His-1–TMD interaction (H-bond donor capacity) without introducing steric bulk at the backbone.\n- **Single-point cAMP assay on synthetic αMe-His-1 semaglutide**: given that this fold cannot be resolved computationally, direct synthesis and functional testing against HEK293-GLP1R is the definitive experiment. The modification is chemically feasible via solid-phase peptide synthesis with Fmoc-αMe-His(Trt)-OH building blocks.\n\n**For the broader semaglutide program**, the lab should consider whether future distillations on this scaffold are better served by switching to the MD/FEP computational track rather than the AlphaFold-binding-predictor pipeline, given the consistent tool-coverage limitation observed across Folds №15, №36, and №52.","structural_caption":"No reliable 3D structure could be obtained for this peptide.","key_findings_summary":"Semaglutide is a well-characterized GLP-1 receptor agonist whose molecular design is documented in the foundational discovery paper (Lau et al., 2015, PMID:26308095). Relative to native GLP-1(7-36), semaglutide carries two amino acid substitutions — Aib at position 8 (equivalent to position 2 of the GLP-1 peptide numbering used in the analogue) and Arg at position 34 — plus a C18 fatty diacid chain at Lys26. The Aib-8 substitution was deliberately introduced to block DPP-IV cleavage at the His7-Aib8 bond and to confer local helical rigidity near the N-terminus, giving semaglutide its extended half-life (~46 h in minipigs i.v.; ~1 week in humans s.c.). This structural rationale is directly relevant to the hypothesis: semaglutide already exploits Cα,α-disubstitution (Aib = α-methyl-alanine) at position 2 as a helix-nucleating element, establishing a clear precedent that N-terminal backbone rigidification is both tolerated and beneficial for this scaffold.\n\nThe GLP-1R activation mechanism places particular functional weight on the N-terminal residues of the peptide ligand. Structural and mutagenesis studies of the GLP-1R (not directly represented in the retrieved abstracts but well established in the broader literature) show that His1 of GLP-1 inserts into the transmembrane bundle and makes key contacts required for receptor activation; the imidazole side chain participates in a hydrogen-bond network with TM residues. The hypothesis proposes that adding a Cα-methyl group to His-1 (yielding α-methyl-L-histidine, αMe-His) would extend the Cα,α-disubstituted segment from one residue (Aib-2) to two consecutive residues (αMe-His-1 + Aib-2), potentially pre-organizing the N-terminal cap into the bioactive helical conformation without altering the imidazole pharmacophore. Precedent for this strategy exists broadly in peptide medicinal chemistry: consecutive Aib or other Cα,α-disubstituted residues are well-known helix nucleators that restrict φ/ψ space near (φ ≈ −57°, ψ ≈ −47°) and have been used to stabilize bioactive helical conformations in numerous receptor-targeted peptides.\n\nThe clinical and pharmacological literature retrieved here confirms the pharmacological importance of receptor engagement potency and duration for semaglutide's therapeutic effects. Semaglutide produces ~15% body-weight reduction at 2.4 mg/week (STEP trials, PMID:33667417; PMID:36578889; PMID:34706925; PMID:34942372), a 42% reduction in atrial fibrillation incidence (PMID:39058274), and favorable cardiovascular outcomes (PMID:39181497; preprint DOI:10.21203/rs.3.rs-9161583/v1). These effects are mediated through distributed GLP-1R populations in the brain, gut, and cardiovascular system (PMID:32213703). The pharmacokinetic profile — predictable exposure, once-weekly dosing, largely albumin-binding–driven half-life extension — is well understood (PMID:38952487). These data collectively reinforce that GLP-1R agonism potency and duration of engagement are therapeutically important, supporting the rationale for exploring conformationally constrained analogues that might improve intrinsic receptor activation efficiency.\n\nHowever, none of the retrieved papers directly addresses α-methyl-histidine substitution in GLP-1 analogues, N-terminal conformational pre-organization in semaglutide beyond Aib-8, or structure-activity relationships (SAR) at His-1 of semaglutide specifically. The literature base for the proposed modification is therefore inferential, drawing on (a) the known Aib-8 precedent from Lau et al. 2015, (b) general Cα,α-disubstitution chemistry, and (c) structural biology of GLP-1R that is not directly represented in these abstracts. The retrieved corpus is primarily clinical and pharmacological, not structural-chemical, limiting direct evidential support."},"structured":{"known_activity":null,"known_binders":null,"candidate_variants":null,"domain_annotations":null,"literature_context":{"pubmed":[{"pmid":"34305810","title":"Safety of Semaglutide.","abstract":"The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.","authors":["Smits Mark M","Van Raalte Daniël H"],"year":2021,"journal":"Frontiers in endocrinology"},{"pmid":"34942372","title":"Semaglutide for the treatment of obesity.","abstract":"Semaglutide is a glucagon-like peptide-1 receptor agonist that was recently approved by the US Food and Drug Administration for chronic weight management. This paper reviews data on the mechanism of action, weight-loss and cardiometabolic efficacy, and safety of semaglutide 2.4 mg/week for obesity. Semaglutide has demonstrated the largest weight loss of any obesity medication to date with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risks factors and physical functioning. The approval of this medication provides patients with greater options for weight management.","authors":["Chao Ariana M","Tronieri Jena S","Amaro Anastassia","Wadden Thomas A"],"year":2023,"journal":"Trends in cardiovascular medicine"},{"pmid":"33667417","title":"Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.","abstract":"BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes.\n\nMETHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants.\n\nFINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo.\n\nINTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo.\n\nFUNDING: Novo Nordisk.","authors":["Davies Melanie","Færch Louise","Jeppesen Ole K","Pakseresht Arash","Pedersen Sue D","Perreault Leigh","Rosenstock Julio","Shimomura Iichiro","Viljoen Adie","Wadden Thomas A","Lingvay Ildiko"],"year":2021,"journal":"Lancet (London, England)"},{"pmid":"36578889","title":"Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.","abstract":"BACKGROUND: The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\n\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\n\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\n\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. However, risk of gastrointestinal adverse events, discontinuation of treatment and serious adverse events were higher in the semaglutide group versus placebo.","authors":["Tan Hanna Clementine","Dampil Oliver Allan","Marquez Maricar Mae"],"year":2022,"journal":"Journal of the ASEAN Federation of Endocrine Societies"},{"pmid":"34706925","title":"Wegovy (semaglutide): a new weight loss drug for chronic weight management.","abstract":"Obesity is a growing epidemic within the USA. Because weight gain is associated with an increased risk of developing life-threatening comorbidities, such as hypertension or type 2 diabetes, there is great interest in developing non-invasive pharmacotherapeutics to help combat obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic medications that have shown promise in encouraging glycemic control and promoting weight loss in patients with or without type 2 diabetes. This literature review summarizes and discusses the weight loss results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial programs. The SUSTAIN and PIONEER clinical trials studied the use of 1.0 mg, once-weekly, subcutaneous and oral semaglutide (a new GLP-1 homolog), respectively, on participants with type 2 diabetes. The STEP trial examined the effects of 2.4 mg, once-weekly, subcutaneous semaglutide on patients with obesity. Trial data and other pertinent articles were obtained via database search through the US National Library of Medicine Clinical Trials and the National Center for Biotechnology Information. All three clinical trials demonstrated that semaglutide (injected or oral) has superior efficacy compared with placebo and other antidiabetic medications in weight reduction, which led to Food and Drug Administration approval of Wegovy (semaglutide) for weight loss.","authors":["Singh Gurdeep","Krauthamer Matthew","Bjalme-Evans Meghan"],"year":2022,"journal":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research"},{"pmid":"32213703","title":"Semaglutide lowers body weight in rodents via distributed neural pathways.","abstract":"Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.","authors":["Gabery Sanaz","Salinas Casper G","Paulsen Sarah J","Ahnfelt-Rønne Jonas","Alanentalo Tomas","Baquero Arian F","Buckley Stephen T","Farkas Erzsébet","Fekete Csaba","Frederiksen Klaus S","Helms Hans Christian C","Jeppesen Jacob F","John Linu M","Pyke Charles","Nøhr Jane","Lu Tess T","Polex-Wolf Joseph","Prevot Vincent","Raun Kirsten","Simonsen Lotte","Sun Gao","Szilvásy-Szabó Anett","Willenbrock Hanni","Secher Anna","Knudsen Lotte Bjerre","Hogendorf Wouter Frederik Johan"],"year":2020,"journal":"JCI insight"},{"pmid":"38952487","title":"Clinical Pharmacokinetics of Semaglutide: A Systematic Review.","abstract":"PURPOSE: The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use.\n\nMETHODOLOGY: The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies.\n\nRESULTS: Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this.\n\nCONCLUSION: This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.","authors":["Yang Xi-Ding","Yang Yong-Yu"],"year":2024,"journal":"Drug design, development and therapy"},{"pmid":"38958939","title":"Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide.","abstract":"IMPORTANCE: Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION).\n\nOBJECTIVE: To investigate whether there is an association between semaglutide and risk of NAION.\n\nDESIGN, SETTING, AND PARTICIPANTS: In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023.\n\nEXPOSURES: Prescriptions for semaglutide vs non-GLP-1 RA medications to manage either T2D or weight.\n\nMAIN OUTCOMES AND MEASURES: Cumulative incidence and hazard ratio of NAION.\n\nRESULTS: Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non-GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non-GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female). In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non-GLP-1 RA antidiabetes cohort. The cumulative incidence of NAION for the semaglutide and non-GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively. A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001). In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non-GLP-1 RA cohort. The cumulative incidence of NAION for the semaglutide vs non-GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively. A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001).\n\nCONCLUSIONS AND RELEVANCE: This study's findings suggest an association between semaglutide and NAION. As this was an observational study, future study is required to assess causality.","authors":["Hathaway Jimena Tatiana","Shah Madhura P","Hathaway David B","Zekavat Seyedeh Maryam","Krasniqi Drenushe","Gittinger John W","Cestari Dean","Mallery Robert","Abbasi Bardia","Bouffard Marc","Chwalisz Bart K","Estrela Tais","Rizzo Joseph F"],"year":2024,"journal":"JAMA ophthalmology"},{"pmid":"26308095","title":"Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.","abstract":"Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.","authors":["Lau Jesper","Bloch Paw","Schäffer Lauge","Pettersson Ingrid","Spetzler Jane","Kofoed Jacob","Madsen Kjeld","Knudsen Lotte Bjerre","McGuire James","Steensgaard Dorte Bjerre","Strauss Holger Martin","Gram Dorte X","Knudsen Sanne Møller","Nielsen Flemming Seier","Thygesen Peter","Reedtz-Runge Steffen","Kruse Thomas"],"year":2015,"journal":"Journal of medicinal chemistry"},{"pmid":"39181497","title":"Glucagon-like peptide-1 receptor agonist use in pregnancy: a review.","abstract":"Glucagon-like peptide-1 receptor agonists are peptide analogues that are used to treat type 2 diabetes mellitus and obesity. The first medication in this class, exenatide, was approved in 2005, and these medications, specifically semaglutide, have become more popular in recent years due to their pronounced effects on glycemic control, weight reduction, and cardiovascular health. Due to successful weight loss from these medications, many women previously diagnosed with oligomenorrhea and unable to conceive have experienced unplanned pregnancies while taking the medications. However, there are currently little data for clinicians to use in counseling patients in cases of accidental periconceptional exposure. In some studies examining small animals exposed to glucagon-like peptide-1 receptor agonists in pregnancy, there has been evidence of adverse outcomes in the offspring, including decreased fetal growth, skeletal and visceral anomalies, and embryonic death. Although there are no prospective studies in humans, case reports, cohort studies, and population-based studies have not shown a pattern of congenital anomalies in infants. A recent large, observational, population-based cohort study examined 938 pregnancies affected by type 2 diabetes mellitus and compared outcomes from periconceptional exposure to glucagon-like peptide-1 receptor agonists and insulin. The authors concluded there was not a significantly increased risk of major congenital malformations in patients taking glucagon-like peptide-1 receptor agonists, although there was no information on maternal glycemic control or diabetic fetopathy. As diabetic embryopathy is directly related to the degree of maternal hyperglycemia and not the diagnosis of diabetes itself, it is not possible to make this conclusion without this information. Furthermore, there is little evidence available regarding fetal growth restriction, embryonic or fetal death, or other potential complications. At this time, patients should be counseled there is not enough evidence to predict any adverse effects, or the lack thereof, of periconceptional exposure of glucagon-like peptide-1 receptor agonists during pregnancy. We recommend that all patients use contraception to prevent unintended pregnancy while taking glucagon-like peptide-1 receptor agonists.","authors":["Drummond Rosa F","Seif Karl E","Reece E Albert"],"year":2025,"journal":"American journal of obstetrics and gynecology"},{"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":"39058274","title":"Glucagon-like peptide-1 receptor agonist semaglutide reduces atrial fibrillation incidence: A systematic review and meta-analysis.","abstract":"BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are new anti-hyperglycaemic drugs with proven cardiovascular (CV) benefit in diabetic and non-diabetic patients at high CV risk. Despite a neutral class effect on arrhythmia risk, data on semaglutide suggest a possible drug-specific benefit in reducing atrial fibrillation (AF) occurrence.\n\nOBJECTIVE: To perform a meta-analysis of randomized clinical trials (RCTs) to assess the risk of incident AF in patients treated with semaglutide compared to placebo.\n\nMETHODS AND RESULTS: Ten RCTs were included in the analysis. Study population encompassed 12,651 patients (7285 in semaglutide and 5366 in placebo arms), with median follow-up of 68 months. A random effect meta-analytic model was adopted to pool relative risk (RR) of incident AF. Semaglutide reduces the risk of AF by 42% (RR .58, 95% CI .40-.85), with low heterogeneity across the studies (I2 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR .53, 95% CI .23-1.24, I2 0%; subcutaneous: RR .59, 95% CI .39-.91, I2 0%; p-value .83). In addition, meta-regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p-value .14) and body mass index (BMI) (p-value .60).\n\nCONCLUSIONS: Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI.","authors":["Saglietto Andrea","Falasconi Giulio","Penela Diego","Francia Pietro","Sau Arunashis","Ng Fu Siong","Dusi Veronica","Castagno Davide","Gaita Fiorenzo","Berruezo Antonio","De Ferrari Gaetano Maria","Anselmino Matteo"],"year":2024,"journal":"European journal of clinical investigation"}],"biorxiv":[{"pmid":"","doi":"10.20944/preprints202604.1796.v1","title":"Semaglutide is Associated with Improved Breast Cancer Survival, Lower Metastatic Burden, and a Dose–Survival Relationship Uncoupled from Weight-Loss Magnitude","abstract":"Metabolic dysfunction is increasingly recognized as a risk factor for poor outcomes in breast cancer, but whether incretin-based therapies confer survival benefit beyond weight loss remains unresolved. Using a federated electronic health record platform spanning nearly 29 million patients, we evaluated breast cancer survival after semaglutide and tirzepatide initiation in routine care. In 1:1 propensity-matched pooled-comparator analyses, semaglutide was associated with improved overall survival versus metformin, sodium–glucose cotransporter 2 (SGLT2) inhibitor, and dipeptidyl peptidase 4 (DPP4) inhibitor users, with 54 deaths among 2,433 semaglutide users (2.2%) versus 395 deaths among 2,433 comparators (16.2%) over 24 months (log-rank P &lt; 0.001). Tirzepatide showed a favorable survival association relative to pooled anti-diabetic comparators that did not meet statistical significance (P = 0.24), with 3 deaths among 220 users (1.4%) versus 64 deaths among 220 comparators (29.1%). In a head-to-head propensity-score–matched comparison, overall survival did not differ significantly between semaglutide- and tirzepatide-treated patients with pre-existing breast cancer (2,117 per arm; P = 0.12). In semaglutide-treated patients alive and observable at the 1-year landmark, higher maximum dose achieved was significantly associated with lower post-landmark mortality (P = 0.034), with an event rate of approximately 1.0% in the high-dose group (≥1.7 mg) versus approximately 4.5% in the low-dose group (0.25–1.0 mg). Despite a linear dose–weight loss relationship for semaglutide, however, weight-loss strata did not separate survival outcomes (global P = 0.22). In tirzepatide-treated patients alive and observable at the same landmark, neither maximum dose achieved nor weight-loss strata separated post-landmark survival (P = 0.98 and P = 0.50, respectively). Structured EHR and AI-based clinical-note analyses further showed significantly lower frequency of documented metastatic disease in semaglutide-treated patients relative to pooled anti-diabetic comparators, including any metastasis (7.0% versus 15.0%, rate ratio 0.5, P &lt; 0.001), bone metastasis (1.0% versus 5.2%, rate ratio 0.2, P &lt; 0.001), and liver, lung, or brain metastases (all P &lt; 0.001). LLM-derived cause-of-death extraction further showed a 60% lower relative proportion of cancer-associated deaths in semaglutide-treated patients (19% of ascertainable deaths) than in matched pooled anti-diabetic comparators (47% of ascertainable deaths), with comparator deaths more often attributed to cancer progression involving metastatic breast cancer, leptomeningeal carcinomatosis, and cancer-driven organ failure. Overall, this study demonstrates that semaglutide use in patients with pre-existing breast cancer is associated with a dose-correlated but weight-loss independent improvement in overall survival. These findings motivate prospective trials of GLP-1 receptor agonists in breast cancer across various stages and treatment settings.","authors":["Murugadoss K","Venkatakrishnan AJ","Soundararajan V."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.0987.v1","title":"A Retrospective Study Evaluating the Efficacy and Safety of Oral Semaglutide Compared to Injectables in Controlling Diabetes and Weight Reduction","abstract":"<h4>Objective: </h4> To compare the efficacy, safety, weight reduction and treatment adherence of oral versus subcutaneous semaglutide in adults with uncontrolled T2DM and obesity. <h4>Methods:</h4> A multicenter retrospective cohort study was conducted between January 2023 and January 2024. Adult patients (≥18 years) with T2DM (HbA1c ≥ 7%) and obesity (BMI ≥ 30) who received either oral or subcutaneous semaglutide were included. Demographic, clinical, and biochemical variables including body weight, BMI, HbA1c, side effects, and adherence were extracted from electronic medical records. Adverse effects were categorized by severity. Comparative analyses between groups used Chi-square and Mann Whitney U tests, with p&lt;0.05 considered statistically significant. <h4>Results:</h4> A total of 208 patients were included: 89 on oral semaglutide and 119 on subcutaneous semaglutide. Baseline demographics, including gender, age, and physical activity, were comparable between groups (all p&gt;0.05). The severity of adverse effects predominantly gastrointestinal symptoms such as nausea, vomiting, constipation, and diarrhea did not differ significantly between groups (p=0.994). However, dizziness was significantly more frequent in the subcutaneous group (p = 0.04). Adherence was markedly higher with oral semaglutide (p&lt;0.05), with cost identified as the primary barrier among oral users, while subcutaneous users more frequently cited side effects, forgetfulness, and limited weight loss. Weight reduction was comparable at 3 months (p=0.23), but significantly greater with oral semaglutide at 6, 9, and 12 months (all p&lt;0.01). Conversely, HbA1c reduction favored subcutaneous semaglutide at 3 and 6 months (p=0.03 and 0.02), although baseline glycemic control was similar. <h4>Conclusions:</h4> This study demonstrates that while subcutaneous semaglutide may provide a faster early HbA1c decline, oral semaglutide offers superior long-term weight reduction and significantly better adherence, likely attributable to easier administration. Both formulations exhibited comparable safety profiles.","authors":["Ullah Z","Goresh HK","Almarwani SH","Alrashidi M","Almarwani AHD","Hassan M","Alharbi G","Alharbi AMS","Alsohaim SI","Alharbi JS."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9161583/v1","title":"Semaglutide in Non-diabetic Obese East Asian Patients with Acute Coronary Syndrome: A Multicenter Retrospective Study","abstract":"<title>Abstract</title>  <p>  Objective  This study aimed to assess clinical benefits of semaglutide for East Asian non-diabetic obese patients with ACS who have undergone percutaneous coronary intervention (PCI) . Method  This was a multicenter retrospective cohort study. A total of 344 non-diabetic obese patients with ACS who underwent PCI at three hospitals from May 2020 to December 2024 were enrolled (semaglutide group:112 patients, control group: 232 patients). Propensity score matching (PSM) was performed to balance the baseline data between the two groups. The primary endpoint was 6-month major adverse cardiovascular events (MACE), and secondary endpoints included dynamic changes in cardiac troponin I (cTnI) and alterations in metabolic and left ventricular ejection fraction (LVEF) at 6-month follow-up. Results  After PSM, the 6-month MACE (11.6% vs. 23.2%,  <italic>p</italic>   = 0.034) and unplanned revascularization (4.7% vs. 13.4%,  <italic>p</italic>   = 0.033) in the semaglutide group were significantly lower than those in the control group, and the improvement in cTnI levels was faster in the semaglutide group. Both groups showed improvements in blood lipid profiles and LVEF post-PCI. Additionally, the semaglutide group achieved further reductions in fasting blood glucose (FBG) (5.74 ± 0.60mmol/L vs. 5.25 ± 0.43mmol/L,  <italic>p</italic>   < 0.0001), glycated hemoglobin (HbA1c) (5.43 ± 0.59% vs. 5.18 ± 0.50%,  <italic>p</italic>   = 0.016) and body mass index (BMI) (30.94 ± 1.69 kg/m²vs. 28.45 ± 2.82 kg/m²,  <italic>p</italic>   < 0.0001). Particularly, the magnitudes of improvements in BMI (2.49 ± 3.27 kg/m²vs. 0.78 ± 2.76 kg/m², p = 0.002), FBG (0.49 ± 0.75mmol/L vs. 0.03 ± 0.83mmol/L, p < 0.0001), LDL-c(1.78 ± 1.22mmol/L vs. 0.83 ± 0.94mmol/L, p < 0.0001), TG(0.98 ± 1.02mmol/L vs. 0.63 ± 0.70mmol/L, p = 0.003) and LVEF (5.73 ± 8.07% vs. 2.66 ± 8.09%, p = 0.005) in the semaglutide group were significantly superior to those in the control group. Conclusions  Semaglutide can reduce 6-month MACE risk and improve metabolic and cardiac function in non-diabetic obese ACS patients post-PCI, providing real-world evidence for clinical intervention. Clinical trial registration  This was a retrospective study, so clinical trial registration was not applicable.  </p>","authors":["Jin C","Huang L","Wei Y","Xu Y","Zhang B","Wu J","Fan L."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9317100/v1","title":"Comparative Effectiveness of Metformin versus GLP-1 Receptor Agonists in Treating Antipsychotic-Induced Metabolic Disturbances: A Systematic Review and Network Meta-Analysis","abstract":"<title>Abstract</title>  <p>  <bold>Objective:</bold>  The management of antipsychotic-induced metabolic disturbances (AIMD) represents a significant challenge in psychiatric clinical practice. Although metformin is widely used to improve AIMD, the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in metabolic regulation has gained increasing attention. This study aims to compare the efficacy of metformin and different GLP-1 RAs in improving multidimensional metabolic indicators and psychiatric symptoms in AIMD patients through a systematic review and network meta-analysis.  <bold>Methods:</bold>  Randomized controlled trials (RCTs) published up until December 1, 2025, were identified by searching PubMed, Embase, Cochrane Library, and Web of Science databases. Studies that included patients receiving metformin or GLP-1 RAs treatment for at least 12 weeks, while continuously using antipsychotic medications, were included. The Cochrane Risk of Bias 2.0 tool was used to assess the quality of the studies. A random-effects network meta-analysis was performed using Stata 17.0 MP within the frequentist framework. Intervention rankings were determined by calculating the surface under the cumulative ranking curve (SUCRA). Univariate network meta-regression was applied to explore the impact of study-level covariates on treatment efficacy. Evidence quality was rated based on the CINeMA framework.  <bold>Results:</bold>  A total of 29 RCTs (1,761 patients) were included. Semaglutide demonstrated the most significant effect in reducing body mass index (BMI) (MD = -3.55, 95% CI: -4.27 to -2.84). It also showed the best results in reducing waist circumference (WC) (MD = -6.34, 95% CI: -8.17 to -4.51). Moreover, semaglutide was significantly superior to other interventions in controlling glycated hemoglobin A1c (HbA1c) (MD = -0.44, 95% CI: -0.53 to -0.35) and fasting blood glucose (FBG) (MD = -0.53, 95% CI: -0.88 to -0.18). Additionally, metformin demonstrated a significant advantage over placebo in improving psychiatric symptom scores (SMD = -0.35, 95% CI: -0.61 to -0.09), and showed unique benefits in regulating lipid metabolism markers such as total cholesterol and triglycerides.  <bold>Conclusion:</bold>  Different medications exhibit distinct advantages in managing AIMD across various metabolic indicators. GLP-1 RAs, particularly semaglutide, demonstrate remarkable efficacy in weight loss and glycemic control, while metformin excels in lipid regulation and psychiatric symptom improvement. Clinical decisions should be individualized based on the patient's specific metabolic abnormalities, with a comprehensive consideration of the dual impact of medications on both metabolic and psychiatric symptoms to achieve optimal overall health.  </p>","authors":["Chen Y","Yang Q","Lin M","Sun M","Dong Y","Yu R","Mao D","Zhao Y","Zhang L","Zhao J","Zhang Y","Xu J."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9192889/v1","title":"Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis","abstract":"<title>Abstract</title>  <p>  <bold>Background:</bold>  Biliary adverse events (AEs) have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs), but within-class differences remain unclear.  <bold>Methods:</bold>  We conducted a disproportionality analysis of FAERS comparing biliary outcomes (cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis) across semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide; semaglutide was used as the reference agent. Proportional reporting ratios (PRR), reporting odds ratios (ROR), 95% confidence intervals, and Fisher exact tests were calculated. Subgroup analyses and sensitivity analyses were performed.  <bold>Results:</bold>  After deduplication, 3,460 reports were analyzed: semaglutide 1,797, tirzepatide 1,363, liraglutide 1,033, exenatide 999, and dulaglutide 574. Compared with semaglutide, exenatide (PRR 0.39 (0.23–0.65) p<0.001) and tirzepatide (PRR 0.58 (0.39–0.84), p= 0.004) showed lower reporting for  <bold>bile duct stone,</bold>  while dulaglutide (PRR 0.50 (0.30–0.82), p=0.003) and exenatide (PRR 0.30 (0.19–0.47), p<0.001) showed lower reporting for  <bold>biliary colic</bold>  (PRR 0.30 and 0.50). Dulaglutide showed higher reporting for  <bold>cholangitis</bold>  (PRR 1.65 (1.05–2.60), p=0.045). Exenatide (PRR 1.12 (1.08–1.16), p<0.001), liraglutide (PRR 1.07 (1.03–1.12), p<0.001), and tirzepatide (PRR 1.05 (1.01–1.09), p=0.018) showed higher reporting for  <bold>cholecystitis</bold>  . Exenatide (PRR 1.33 (1.23–1.44), p<0.001), liraglutide (PRR 1.21 (1.11–1.31), p<0.001) and tirzepatide (PRR 1.15 (1.06–1.25), p<0.001) also showed higher reporting for  <bold>cholelithiasis</bold>  . Subgroup findings were consistent with heterogeneity mainly observed for bile duct stone and biliary colic. Sensitivity analyses were largely concordant, although rarer outcomes lost significance.  <bold>Conclusions:</bold>  Biliary AE reporting varies across GLP-1RAs, highlighting agent-specific differences within class and the need for individualized prescribing and counseling.  </p>","authors":["FNU A","Jaffar H","Onwuzo CN","Chaar A","Eisa M."],"year":2026,"journal":"PPR","source":"PPR","preprint":true}],"preprints":[{"pmid":"","doi":"10.20944/preprints202604.1796.v1","title":"Semaglutide is Associated with Improved Breast Cancer Survival, Lower Metastatic Burden, and a Dose–Survival Relationship Uncoupled from Weight-Loss Magnitude","abstract":"Metabolic dysfunction is increasingly recognized as a risk factor for poor outcomes in breast cancer, but whether incretin-based therapies confer survival benefit beyond weight loss remains unresolved. Using a federated electronic health record platform spanning nearly 29 million patients, we evaluated breast cancer survival after semaglutide and tirzepatide initiation in routine care. In 1:1 propensity-matched pooled-comparator analyses, semaglutide was associated with improved overall survival versus metformin, sodium–glucose cotransporter 2 (SGLT2) inhibitor, and dipeptidyl peptidase 4 (DPP4) inhibitor users, with 54 deaths among 2,433 semaglutide users (2.2%) versus 395 deaths among 2,433 comparators (16.2%) over 24 months (log-rank P &lt; 0.001). Tirzepatide showed a favorable survival association relative to pooled anti-diabetic comparators that did not meet statistical significance (P = 0.24), with 3 deaths among 220 users (1.4%) versus 64 deaths among 220 comparators (29.1%). In a head-to-head propensity-score–matched comparison, overall survival did not differ significantly between semaglutide- and tirzepatide-treated patients with pre-existing breast cancer (2,117 per arm; P = 0.12). In semaglutide-treated patients alive and observable at the 1-year landmark, higher maximum dose achieved was significantly associated with lower post-landmark mortality (P = 0.034), with an event rate of approximately 1.0% in the high-dose group (≥1.7 mg) versus approximately 4.5% in the low-dose group (0.25–1.0 mg). Despite a linear dose–weight loss relationship for semaglutide, however, weight-loss strata did not separate survival outcomes (global P = 0.22). In tirzepatide-treated patients alive and observable at the same landmark, neither maximum dose achieved nor weight-loss strata separated post-landmark survival (P = 0.98 and P = 0.50, respectively). Structured EHR and AI-based clinical-note analyses further showed significantly lower frequency of documented metastatic disease in semaglutide-treated patients relative to pooled anti-diabetic comparators, including any metastasis (7.0% versus 15.0%, rate ratio 0.5, P &lt; 0.001), bone metastasis (1.0% versus 5.2%, rate ratio 0.2, P &lt; 0.001), and liver, lung, or brain metastases (all P &lt; 0.001). LLM-derived cause-of-death extraction further showed a 60% lower relative proportion of cancer-associated deaths in semaglutide-treated patients (19% of ascertainable deaths) than in matched pooled anti-diabetic comparators (47% of ascertainable deaths), with comparator deaths more often attributed to cancer progression involving metastatic breast cancer, leptomeningeal carcinomatosis, and cancer-driven organ failure. Overall, this study demonstrates that semaglutide use in patients with pre-existing breast cancer is associated with a dose-correlated but weight-loss independent improvement in overall survival. These findings motivate prospective trials of GLP-1 receptor agonists in breast cancer across various stages and treatment settings.","authors":["Murugadoss K","Venkatakrishnan AJ","Soundararajan V."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.0987.v1","title":"A Retrospective Study Evaluating the Efficacy and Safety of Oral Semaglutide Compared to Injectables in Controlling Diabetes and Weight Reduction","abstract":"<h4>Objective: </h4> To compare the efficacy, safety, weight reduction and treatment adherence of oral versus subcutaneous semaglutide in adults with uncontrolled T2DM and obesity. <h4>Methods:</h4> A multicenter retrospective cohort study was conducted between January 2023 and January 2024. Adult patients (≥18 years) with T2DM (HbA1c ≥ 7%) and obesity (BMI ≥ 30) who received either oral or subcutaneous semaglutide were included. Demographic, clinical, and biochemical variables including body weight, BMI, HbA1c, side effects, and adherence were extracted from electronic medical records. Adverse effects were categorized by severity. Comparative analyses between groups used Chi-square and Mann Whitney U tests, with p&lt;0.05 considered statistically significant. <h4>Results:</h4> A total of 208 patients were included: 89 on oral semaglutide and 119 on subcutaneous semaglutide. Baseline demographics, including gender, age, and physical activity, were comparable between groups (all p&gt;0.05). The severity of adverse effects predominantly gastrointestinal symptoms such as nausea, vomiting, constipation, and diarrhea did not differ significantly between groups (p=0.994). However, dizziness was significantly more frequent in the subcutaneous group (p = 0.04). Adherence was markedly higher with oral semaglutide (p&lt;0.05), with cost identified as the primary barrier among oral users, while subcutaneous users more frequently cited side effects, forgetfulness, and limited weight loss. Weight reduction was comparable at 3 months (p=0.23), but significantly greater with oral semaglutide at 6, 9, and 12 months (all p&lt;0.01). Conversely, HbA1c reduction favored subcutaneous semaglutide at 3 and 6 months (p=0.03 and 0.02), although baseline glycemic control was similar. <h4>Conclusions:</h4> This study demonstrates that while subcutaneous semaglutide may provide a faster early HbA1c decline, oral semaglutide offers superior long-term weight reduction and significantly better adherence, likely attributable to easier administration. Both formulations exhibited comparable safety profiles.","authors":["Ullah Z","Goresh HK","Almarwani SH","Alrashidi M","Almarwani AHD","Hassan M","Alharbi G","Alharbi AMS","Alsohaim SI","Alharbi JS."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9161583/v1","title":"Semaglutide in Non-diabetic Obese East Asian Patients with Acute Coronary Syndrome: A Multicenter Retrospective Study","abstract":"<title>Abstract</title>  <p>  Objective  This study aimed to assess clinical benefits of semaglutide for East Asian non-diabetic obese patients with ACS who have undergone percutaneous coronary intervention (PCI) . Method  This was a multicenter retrospective cohort study. A total of 344 non-diabetic obese patients with ACS who underwent PCI at three hospitals from May 2020 to December 2024 were enrolled (semaglutide group:112 patients, control group: 232 patients). Propensity score matching (PSM) was performed to balance the baseline data between the two groups. The primary endpoint was 6-month major adverse cardiovascular events (MACE), and secondary endpoints included dynamic changes in cardiac troponin I (cTnI) and alterations in metabolic and left ventricular ejection fraction (LVEF) at 6-month follow-up. Results  After PSM, the 6-month MACE (11.6% vs. 23.2%,  <italic>p</italic>   = 0.034) and unplanned revascularization (4.7% vs. 13.4%,  <italic>p</italic>   = 0.033) in the semaglutide group were significantly lower than those in the control group, and the improvement in cTnI levels was faster in the semaglutide group. Both groups showed improvements in blood lipid profiles and LVEF post-PCI. Additionally, the semaglutide group achieved further reductions in fasting blood glucose (FBG) (5.74 ± 0.60mmol/L vs. 5.25 ± 0.43mmol/L,  <italic>p</italic>   < 0.0001), glycated hemoglobin (HbA1c) (5.43 ± 0.59% vs. 5.18 ± 0.50%,  <italic>p</italic>   = 0.016) and body mass index (BMI) (30.94 ± 1.69 kg/m²vs. 28.45 ± 2.82 kg/m²,  <italic>p</italic>   < 0.0001). Particularly, the magnitudes of improvements in BMI (2.49 ± 3.27 kg/m²vs. 0.78 ± 2.76 kg/m², p = 0.002), FBG (0.49 ± 0.75mmol/L vs. 0.03 ± 0.83mmol/L, p < 0.0001), LDL-c(1.78 ± 1.22mmol/L vs. 0.83 ± 0.94mmol/L, p < 0.0001), TG(0.98 ± 1.02mmol/L vs. 0.63 ± 0.70mmol/L, p = 0.003) and LVEF (5.73 ± 8.07% vs. 2.66 ± 8.09%, p = 0.005) in the semaglutide group were significantly superior to those in the control group. Conclusions  Semaglutide can reduce 6-month MACE risk and improve metabolic and cardiac function in non-diabetic obese ACS patients post-PCI, providing real-world evidence for clinical intervention. Clinical trial registration  This was a retrospective study, so clinical trial registration was not applicable.  </p>","authors":["Jin C","Huang L","Wei Y","Xu Y","Zhang B","Wu J","Fan L."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9317100/v1","title":"Comparative Effectiveness of Metformin versus GLP-1 Receptor Agonists in Treating Antipsychotic-Induced Metabolic Disturbances: A Systematic Review and Network Meta-Analysis","abstract":"<title>Abstract</title>  <p>  <bold>Objective:</bold>  The management of antipsychotic-induced metabolic disturbances (AIMD) represents a significant challenge in psychiatric clinical practice. Although metformin is widely used to improve AIMD, the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in metabolic regulation has gained increasing attention. This study aims to compare the efficacy of metformin and different GLP-1 RAs in improving multidimensional metabolic indicators and psychiatric symptoms in AIMD patients through a systematic review and network meta-analysis.  <bold>Methods:</bold>  Randomized controlled trials (RCTs) published up until December 1, 2025, were identified by searching PubMed, Embase, Cochrane Library, and Web of Science databases. Studies that included patients receiving metformin or GLP-1 RAs treatment for at least 12 weeks, while continuously using antipsychotic medications, were included. The Cochrane Risk of Bias 2.0 tool was used to assess the quality of the studies. A random-effects network meta-analysis was performed using Stata 17.0 MP within the frequentist framework. Intervention rankings were determined by calculating the surface under the cumulative ranking curve (SUCRA). Univariate network meta-regression was applied to explore the impact of study-level covariates on treatment efficacy. Evidence quality was rated based on the CINeMA framework.  <bold>Results:</bold>  A total of 29 RCTs (1,761 patients) were included. Semaglutide demonstrated the most significant effect in reducing body mass index (BMI) (MD = -3.55, 95% CI: -4.27 to -2.84). It also showed the best results in reducing waist circumference (WC) (MD = -6.34, 95% CI: -8.17 to -4.51). Moreover, semaglutide was significantly superior to other interventions in controlling glycated hemoglobin A1c (HbA1c) (MD = -0.44, 95% CI: -0.53 to -0.35) and fasting blood glucose (FBG) (MD = -0.53, 95% CI: -0.88 to -0.18). Additionally, metformin demonstrated a significant advantage over placebo in improving psychiatric symptom scores (SMD = -0.35, 95% CI: -0.61 to -0.09), and showed unique benefits in regulating lipid metabolism markers such as total cholesterol and triglycerides.  <bold>Conclusion:</bold>  Different medications exhibit distinct advantages in managing AIMD across various metabolic indicators. GLP-1 RAs, particularly semaglutide, demonstrate remarkable efficacy in weight loss and glycemic control, while metformin excels in lipid regulation and psychiatric symptom improvement. Clinical decisions should be individualized based on the patient's specific metabolic abnormalities, with a comprehensive consideration of the dual impact of medications on both metabolic and psychiatric symptoms to achieve optimal overall health.  </p>","authors":["Chen Y","Yang Q","Lin M","Sun M","Dong Y","Yu R","Mao D","Zhao Y","Zhang L","Zhao J","Zhang Y","Xu J."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9192889/v1","title":"Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis","abstract":"<title>Abstract</title>  <p>  <bold>Background:</bold>  Biliary adverse events (AEs) have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs), but within-class differences remain unclear.  <bold>Methods:</bold>  We conducted a disproportionality analysis of FAERS comparing biliary outcomes (cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis) across semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide; semaglutide was used as the reference agent. Proportional reporting ratios (PRR), reporting odds ratios (ROR), 95% confidence intervals, and Fisher exact tests were calculated. Subgroup analyses and sensitivity analyses were performed.  <bold>Results:</bold>  After deduplication, 3,460 reports were analyzed: semaglutide 1,797, tirzepatide 1,363, liraglutide 1,033, exenatide 999, and dulaglutide 574. Compared with semaglutide, exenatide (PRR 0.39 (0.23–0.65) p<0.001) and tirzepatide (PRR 0.58 (0.39–0.84), p= 0.004) showed lower reporting for  <bold>bile duct stone,</bold>  while dulaglutide (PRR 0.50 (0.30–0.82), p=0.003) and exenatide (PRR 0.30 (0.19–0.47), p<0.001) showed lower reporting for  <bold>biliary colic</bold>  (PRR 0.30 and 0.50). Dulaglutide showed higher reporting for  <bold>cholangitis</bold>  (PRR 1.65 (1.05–2.60), p=0.045). Exenatide (PRR 1.12 (1.08–1.16), p<0.001), liraglutide (PRR 1.07 (1.03–1.12), p<0.001), and tirzepatide (PRR 1.05 (1.01–1.09), p=0.018) showed higher reporting for  <bold>cholecystitis</bold>  . Exenatide (PRR 1.33 (1.23–1.44), p<0.001), liraglutide (PRR 1.21 (1.11–1.31), p<0.001) and tirzepatide (PRR 1.15 (1.06–1.25), p<0.001) also showed higher reporting for  <bold>cholelithiasis</bold>  . Subgroup findings were consistent with heterogeneity mainly observed for bile duct stone and biliary colic. Sensitivity analyses were largely concordant, although rarer outcomes lost significance.  <bold>Conclusions:</bold>  Biliary AE reporting varies across GLP-1RAs, highlighting agent-specific differences within class and the need for individualized prescribing and counseling.  </p>","authors":["FNU A","Jaffar H","Onwuzo CN","Chaar A","Eisa M."],"year":2026,"journal":"PPR","source":"PPR","preprint":true}],"consensus_view":"The literature consensus strongly supports semaglutide as an effective GLP-1RA with a well-characterized clinical profile. The foundational medicinal chemistry consensus (Lau et al., 2015) establishes that N-terminal backbone modification — specifically Aib-8 — is a validated, deliberate design element in semaglutide intended to nucleate helical structure and block proteolysis, directly supporting the conceptual basis of extending this strategy to position 1. However, there is no published literature specifically addressing Cα-methylation of His-1 in GLP-1 analogues, and the retrieved corpus contains no structural, biophysical, or SAR studies at the His-1 position of semaglutide. The consensus on GLP-1R pharmacology recognizes His-1 as essential for receptor activation (imidazole contacts in the TMD), but whether a bulkier Cα,α-disubstituted His-1 is tolerated sterically within the GLP-1R binding pocket is not addressed by the available literature. The predominant literature focus is clinical outcomes, not molecular design.","knowledge_gaps":"1) No published SAR data exist for αMe-His or any Cα-methylated histidine at position 1 of GLP-1 or semaglutide, leaving the steric tolerance of the GLP-1R transmembrane core for a Cα,α-disubstituted imidazole-bearing residue at this position entirely uncharacterized. 2) The degree to which introducing a second consecutive Cα,α-disubstituted residue (αMe-His-1 + Aib-2) further pre-organizes the N-terminal cap — versus the already-constrained Aib-8 semaglutide backbone — has not been studied biophysically (CD, NMR, MD simulation). 3) Whether the enhanced N-terminal rigidity translates to increased GLP-1R binding affinity (Kd), functional potency (EC50 in cAMP assays), or biased agonism (β-arrestin vs. Gs pathway selectivity) is completely unexplored. 4) The impact of Cα-methylation of His-1 on DPP-IV resistance (already addressed by Aib-8 in semaglutide) and on any remaining N-terminal proteolytic vulnerability is not documented. 5) Whether αMe-His-1 alters the conformational ensemble at the receptor-bound state — potentially locking the peptide into a conformation that is productive or non-productive for TMD engagement — cannot be predicted from the available literature.","supporting_evidence":"1) Lau et al. (2015, PMID:26308095) explicitly validates Aib substitution at position 8 (the residue adjacent to His-1 in the GLP-1 numbering) as a helix-nucleating and DPP-IV-blocking strategy, establishing direct precedent that Cα,α-disubstitution is tolerated and beneficial near the N-terminus of semaglutide. 2) The Aib-8 design principle demonstrates that the GLP-1R accommodates conformationally constrained residues near position 1-2 without loss of sub-nanomolar receptor potency (GLP-1R IC50 = 0.38 nM for semaglutide vs. liraglutide). 3) The clinical dose-response relationship (1.0 mg vs. 2.4 mg semaglutide; PMID:33667417) implies that receptor activation level is a key determinant of efficacy, motivating efforts to improve intrinsic potency via conformational optimization. 4) General Cα,α-disubstitution chemistry (Aib, αMe-amino acids) is well-established in medicinal chemistry as a route to helix nucleation and φ/ψ restriction toward helical space; consecutive disubstituted residues are known to cooperatively stabilize helical conformations. 5) The GLP-1R structural biology literature (not in these abstracts but well-established) confirms that the N-terminal histidine inserts into the TMD and makes contacts requiring specific geometry, suggesting that pre-organizing this residue toward the bioactive conformation could reduce the entropic cost of binding and improve potency.","challenging_evidence":"1) The GLP-1R transmembrane binding pocket for His-1 is sterically constrained; introducing a Cα-methyl group adds a β-branch equivalent at the α-carbon and increases the effective steric demand at position 1. Structural models of the GLP-1R-peptide complex (from cryo-EM/crystal structures not retrieved here) show relatively tight packing around this residue, raising the possibility that αMe-His-1 could reduce binding affinity despite favorable conformational pre-organization, net negative effect on potency. 2) The GLP-1R IC50 for semaglutide (0.38 nM) is already three-fold lower than liraglutide (Lau et al., 2015), potentially indicating that the receptor affinity is not the primary limiting factor for clinical efficacy, and that further conformational optimization at position 1 may yield diminishing returns in vivo. 3) Semaglutide's clinical ceiling effect — approximately 15% weight loss at 2.4 mg/week with dose-limiting GI adverse events — may reflect saturation of GLP-1R-mediated pathways rather than insufficient intrinsic potency, suggesting that a more potent analogue would face the same ceiling and tolerability constraints. 4) The existing Aib-8 substitution already provides substantial N-terminal conformational restriction and DPP-IV resistance; whether an additional constraint at His-1 provides additive conformational benefit or instead over-rigidifies the N-terminus in a way that disrupts the dynamic engagement required for receptor activation is unknown. 5) No challenging preclinical or clinical data on αMe-His GLP-1 analogues exist in the retrieved literature — the absence of any published attempts at this specific modification could reflect implicit knowledge in the field that steric tolerance at His-1 is limited, though it could equally reflect a genuine unexplored opportunity."},"caveats":["in silico prediction only — requires wet lab validation","single-run prediction (not ensembled)","predicted properties may not reflect real-world biological behavior","this is research, not medical advice","α-methyl-histidine is not natively parameterized in AlphaFold-class models; the predictor likely treated it as canonical histidine, degrading structural accuracy at the residue of interest","Chai-1 agreement data unavailable — pTM/ipTM scores cannot be cross-validated and should not be interpreted as reliable binding signals","Boltz-2 affinity module returned no values; the core binding hypothesis (improved TMD engagement) cannot be evaluated from this prediction","heuristic peptide profile (aggregation, stability, half-life) is sequence-derived, not structurally derived, and does not account for the lipidation chain or non-canonical residue content","steric tolerance of the GLP-1R TMD pocket for αMe-His at position 1 is a genuine unresolved biological concern not addressed by this fold","Verdict reclassified: DISCARDED → PROMISING. Raw metrics (pLDDT/pTM/ipTM) permit at least the higher tier; the original LLM discard reflected modification chemistry the predictor cannot represent (D-AA, lipid moiety, non-canonical residue). Per the metric-floor rule this is a caveat, not a verdict downgrade. Report text below pre-dates the rule and may still describe the fold as DISCARDED — the structural verdict shown is the authoritative one."],"works_cited":[{"pmid_or_doi":"26308095","title":"Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide","year":2015,"relevance":"Primary discovery paper explicitly documenting the Aib-8 substitution in semaglutide as a DPP-IV resistance and helix-nucleating strategy — the direct structural precedent for extending Cα,α-disubstitution to His-1 as proposed in the hypothesis."},{"pmid_or_doi":"34942372","title":"Semaglutide for the treatment of obesity","year":2023,"relevance":"Describes mechanism of action and ~15% weight loss efficacy of semaglutide, contextualizing the therapeutic value of optimizing GLP-1R engagement potency."},{"pmid_or_doi":"32213703","title":"Semaglutide lowers body weight in rodents via distributed neural pathways","year":2020,"relevance":"Demonstrates that semaglutide's weight-reducing effects are mediated through direct GLP-1R interactions across multiple brain regions, underscoring the importance of receptor-activating efficacy of the N-terminal pharmacophore."},{"pmid_or_doi":"38952487","title":"Clinical Pharmacokinetics of Semaglutide: A Systematic Review","year":2024,"relevance":"Documents semaglutide's PK profile (t½ ~1 week, dose-proportional AUC/Cmax), providing baseline pharmacokinetic context against which a conformationally modified analogue would need to be benchmarked."},{"pmid_or_doi":"34305810","title":"Safety of Semaglutide","year":2021,"relevance":"Comprehensive safety review establishing the known adverse event profile of semaglutide, relevant for assessing whether N-terminal rigidification might alter tolerability or off-target engagement."},{"pmid_or_doi":"39058274","title":"Glucagon-like peptide-1 receptor agonist semaglutide reduces atrial fibrillation incidence: A systematic review and meta-analysis","year":2024,"relevance":"Illustrates pleiotropic GLP-1R-mediated cardiovascular benefits of semaglutide, highlighting that receptor activation quality (not just duration) may contribute to pharmacological outcomes."},{"pmid_or_doi":"34706925","title":"Wegovy (semaglutide): a new weight loss drug for chronic weight management","year":2022,"relevance":"Summarizes SUSTAIN, PIONEER, and STEP trial data, confirming dose-dependent efficacy and supporting the premise that improving GLP-1R activation potency would have measurable therapeutic relevance."},{"pmid_or_doi":"33667417","title":"Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)","year":2021,"relevance":"Phase 3 RCT demonstrating dose-dependent weight loss, providing the clinical benchmark for what an optimized semaglutide analogue would need to meet or exceed."}]},"onchain":{"hash":"QG18KkCC8hfkEhyPYpfiYtt7YHvhDdWvjU2yBbnN6czv9EzKnDdtErUh3aQUeMim36gcLzJawWxwDBFWCEv2Wmc","signature":"QG18KkCC8hfkEhyPYpfiYtt7YHvhDdWvjU2yBbnN6czv9EzKnDdtErUh3aQUeMim36gcLzJawWxwDBFWCEv2Wmc","data_hash":"18c7081ac90d4e4cd619730a1dd01e9dade0a3edb02aec4e5a8a44aba19b7563","logged_at":"2026-05-04T05:34:28.317944+00:00","explorer_url":"https://solscan.io/tx/QG18KkCC8hfkEhyPYpfiYtt7YHvhDdWvjU2yBbnN6czv9EzKnDdtErUh3aQUeMim36gcLzJawWxwDBFWCEv2Wmc"},"ipfs_hash":null,"created_at":"2026-05-04T05:29:41.384297+00:00","updated_at":"2026-05-05T04:34:22.576791+00:00"}