{"id":23,"slug":"23-tirzepatide-cys-24-methyl-cysteine-me-cys-substitution-non-canonical-c-m","title":"Tirzepatide Cys-24 → α-methyl-Cys to lock helix and reduce oxidation","status":"PROMISING","fold_verdict":"PROMISING","discard_reason":null,"peptide":{"name":"Tirzepatide","class":"METABOLIC","sequence":"YAEGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPS","modified_sequence":"YAEGTFTSDYSIYLDKQAAKEFV(αMe-C)WLLAGGPSSGAPPPS","modification_description":"Cys-24 → α-methyl-cysteine (αMe-Cys) substitution; non-canonical Cα-methylated residue replacing the native Cys in the central helix"},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Replacing the free Cys-24 in tirzepatide with α-methyl-cysteine will rigidify the central amphipathic α-helix (residues ~16-30) that docks into the GLP-1R transmembrane bundle, while simultaneously eliminating the reactive free thiol that is prone to oxidation and disulfide scrambling. We are testing whether a Cα-methylated analog of Cys preserves the side-chain chemistry context (no charge or bulk change at the receptor interface) while biasing the backbone toward helical (φ,ψ) angles.","rationale":"Cα-methylated residues like Aib and α-methyl-Cys strongly favor helical Ramachandran space due to Thorpe–Ingold-like steric restriction at Cα, a strategy validated in many GLP-1R/GIPR analogs. Tirzepatide's Cys-24 sits in the middle of the agonist helix that engages the receptor's TMD, where helix fraying weakens potency; locking it without altering side-chain identity tests conformation in isolation. Unlike Fold #13's Gln→Aib (which removed a polar contact and was discarded) and Fold #15's Glu→Hge side-chain extension, this preserves the native side chain and only modifies the backbone propensity. Diverges from the last 3 folds (terminal amidation, K→R, N-methylation) in both focus (CONFORMATION) and category (Non-canonical amino acid).","predicted_outcome":"AlphaFold should show maintained or slightly extended helical content across residues 16-30 with high pLDDT (>0.75) in the central helix, no disruption of the C20 fatty acid attachment at Lys-20, and overall fold consistent with native tirzepatide; we expect tighter helical (φ,ψ) clustering around residue 24 versus wild-type.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.7129797339439392,"ptm":0.6128653287887573,"iptm":0.15642470121383667,"chai_agreement":null,"chai1_gated_decision":"SKIPPED_HIGH_CONFIDENCE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.179,"stability_score":0.445,"bbb_penetration_score":0.051,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":"FOLD №23 explores replacing Cys-24 in tirzepatide with α-methyl-cysteine (αMe-Cys), a non-canonical Cα-methylated residue predicted to rigidify the central amphipathic α-helix while eliminating the reactive free thiol. The isolated peptide folds with moderate confidence (pLDDT 0.71), consistent with maintained helical character near the substitution site, but the docked complex against GLP-1R returns a low interface score (ipTM 0.16), leaving receptor engagement geometry unresolved. The heuristic profile reveals a hydrophobic hotspot spanning residues 22–33, consistent with the expected helix region, and the stability score is modest (0.445). The verdict is PROMISING — the backbone conformation rationale is chemically sound, but better docking tools or ensemble prediction would be needed to assess whether αMe-Cys is tolerated at the receptor interface.","detailed_analysis":"Tirzepatide is a 39-residue dual GIP/GLP-1 receptor agonist that has demonstrated best-in-class glycemic control and weight reduction in the SURPASS and SURMOUNT clinical programs. Its pharmacophore depends critically on an amphipathic α-helix spanning roughly residues 16–30, which docks into the transmembrane bundle of GLP-1R in a manner analogous to native GLP-1. The peptide carries a C18 fatty diacid tether at Lys-20 that drives albumin binding and extends the half-life to approximately five days, but the central helix itself contains a free cysteine at position 24 — an unusual feature for a therapeutic peptide, as free thiols are susceptible to oxidation, disulfide scrambling, and inter-chain crosslinking under oxidative formulation or physiological conditions.\n\nThe modification tested in this DISTILLATION replaces Cys-24 with α-methyl-cysteine (αMe-Cys), a non-canonical amino acid carrying an additional methyl group at the α-carbon. This Cα-methylation strategy is grounded in the Thorpe–Ingold steric effect: the gem-disubstitution at Cα significantly narrows the accessible φ,ψ Ramachandran space and biases the residue toward helical conformations. Aib (α-aminoisobutyric acid) is the prototypical example, studied extensively in GLP-1R analog design and explored in FOLD №3 (Retatrutide Aib-2 substitution). αMe-Cys is a close analog that preserves the thioether side chain — critically, it does not change the steric volume or electrostatic character of the side chain at the receptor interface, isolating the conformational backbone effect from any side-chain perturbation. This distinguishes it sharply from FOLD №15, where Glu-16 → homoglutamate in semaglutide extended the side chain and was discarded (pLDDT 0.71), and from the Lys→Arg substitutions in FOLD №10 and prior tirzepatide folds, which modulated side-chain identity and charge.\n\nThe structural prediction returned a peptide pLDDT of 0.71 — equivalent to the discarded semaglutide homoglutamate fold (FOLD №15) and the Retatrutide Aib-2 fold (FOLD №3), but below the 0.78 seen in FOLD №10's Lys-17→Arg Retatrutide variant. While 0.71 is not a high-confidence score, it is within an interpretable range for a modified peptide without a canonical Cα at one position, and the structural reasoning agent has flagged this as consistent with maintained central helical character. The pTM of 0.61 is reasonable for the isolated peptide. The critical limitation is the ipTM of 0.16 for the GLP-1R complex, which falls well below the threshold for reliable interface geometry — meaning the docked pose cannot be trusted to report whether αMe-Cys is sterically tolerated in the transmembrane binding cleft or whether it disrupts the Cys-24 packing environment.\n\nThe heuristic peptide profile adds texture to the structural result. An aggregation propensity of 0.179 is low, which is pharmacologically favorable — helix-stabilizing modifications that lock amphipathic structure can sometimes expose hydrophobic faces and increase aggregation risk, and this flag is not raised here. The hydrophobic hotspot at residues 22–33 is precisely the region containing αMe-Cys-24 and the downstream Trp-25/Leu-26/Leu-27 cluster, consistent with the amphipathic helix architecture. The stability score of 0.445 is moderate, and the long half-life estimate is expected given the fatty acid tether at Lys-20. The BBB penetration score of 0.051 is irrelevant for a metabolic injectable. No affinity prediction (ΔΔG or binding probability score) was returned from the Boltz-2 affinity module, which is the most significant missing data point for this fold.\n\nThe literature context is sparse on the specific question. The retrieved abstracts are exclusively clinical — SURPASS and SURMOUNT trial outcomes — and provide no structural or analog chemistry data on Cys-24's role, tirzepatide's oxidative degradation pathways, or precedent for αMe-Cys in incretin-class peptides. The structural rationale must therefore rest on the broader non-canonical amino acid and GLP-1R structural biology literature, where the general principle (Cα-methylation → helical bias) is well established but the specific tolerance of GLP-1R's transmembrane bundle for a quaternary α-carbon at this position is not characterized. The dual GIP receptor engagement also remains unaddressed — GIPR's tolerance for αMe-Cys at position 24 is an open question.\n\nIn aggregate, FOLD №23 earns a PROMISING verdict rather than REFINED because the hypothesis is chemically compelling and the isolated peptide structural signal is interpretable, but the poor ipTM and absent affinity data mean the receptor engagement question — the pharmacologically decisive one — cannot be answered from this run. This is a fold that would benefit substantially from ensemble prediction, a higher-confidence docking tool against the GLP-1R cryo-EM structure, and an explicit ΔΔG estimate. The pharmaceutical rationale for eliminating the free thiol is independently strong and does not depend on binding improvement — even a binding-neutral modification that improves oxidative stability would have formulation value for a molecule dosed weekly at 15 mg.\n\nThe broader lab narrative positions this fold as a deliberate evolution in the METABOLIC peptide series. Where earlier tirzepatide folds explored terminal amidation, Lys→Arg side-chain swaps, and N-methylation, FOLD №23 introduces non-canonical amino acid backbone modification — the same category as FOLD №3's Aib-2 Retatrutide experiment, which was discarded for weak signal, but applied here to a mid-helix position with a stronger mechanistic rationale. The Aib substitution at position 2 in FOLD №3 was targeted at DPP-4 resistance at the N-terminus; αMe-Cys-24 targets amphipathic helix rigidity in the receptor-docking domain, a distinct hypothesis with different success criteria.","executive_summary":"Tirzepatide Cys-24 → αMe-Cys: peptide folds with moderate confidence (pLDDT 0.71) and low aggregation risk, supporting helix-locking rationale. Interface score (ipTM 0.16) is too weak to confirm GLP-1R tolerance. Verdict: PROMISING — strong hypothesis, thin structural evidence.","tweet_draft":"DISTILLATION №23 — promising.\nTirzepatide Cys-24 → α-methyl-Cys: helix lock + thiol elimination.\npLDDT 0.71 (peptide). ipTM 0.16 (GLP-1R complex — unresolved).\nAggregation risk low. Affinity: not returned.\nIn silico only. Full report: alembic.bio","research_brief_markdown":"# FOLD №23 — Tirzepatide Cys-24 → α-Methyl-Cys: Helix Locking and Thiol Elimination\n**Verdict: PROMISING** | Class: METABOLIC | Target: GLP-1R (P43220)\n\n---\n\n## Mechanism of Action\n\nTirzepatide is a 39-residue synthetic dual agonist of the glucagon-like peptide-1 receptor (GLP-1R, UniProt P43220) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). Its central amphipathic α-helix (approximately residues 16–30) inserts into the transmembrane bundle of GLP-1R in a conformation analogous to native GLP-1 and semaglutide, stabilizing the active receptor state and driving downstream cAMP signaling, insulin secretion, glucagon suppression, and satiety signaling. The fatty diacid chain at Lys-20 provides albumin binding for extended half-life (~5 days). Position 24 falls within this helix, occupied natively by a free cysteine whose thiol is not engaged in a disulfide bond — an unusual and potentially reactive feature for a therapeutic peptide administered at weekly doses up to 15 mg.\n\n---\n\n## Performance Applications\n\nTirzepatide is approved for type 2 diabetes (Mounjaro) and obesity (Zepbound), with Phase 3 evidence supporting use in MASH and obstructive sleep apnea. The clinical case for structural optimization of tirzepatide centers on formulation stability and manufacturing robustness rather than potency improvement: the parent molecule already outperforms semaglutide on HbA1c reduction and weight loss in head-to-head SURPASS trials. A more oxidatively stable analog could reduce degradation during long-term storage, simplify formulation without antioxidant excipients, and potentially support higher-concentration presentations for autoinjector delivery. If helical rigidification at position 24 also tightens receptor engagement, a modest potency gain could allow dose reduction with equivalent efficacy — a relevant consideration given dose-dependent GI tolerability profiles.\n\n---\n\n## Modification Rationale\n\nα-Methyl-cysteine (αMe-Cys) introduces a methyl group at the α-carbon of cysteine, creating a quaternary Cα. This Thorpe–Ingold steric effect dramatically restricts the accessible φ,ψ Ramachandran space and enforces helical backbone geometry — the same principle underlying Aib (α-aminoisobutyric acid), the most studied helix-nucleating non-canonical residue in peptide drug design. Critically, αMe-Cys **preserves the thioether side chain** of cysteine, meaning no change in side-chain volume, charge, or electrostatic character at the receptor interface. This isolates the backbone conformational effect from any side-chain perturbation — a design principle distinct from FOLD №15 (Glu-16 → homoglutamate in semaglutide, which extended the side chain and was discarded at pLDDT 0.71) and from FOLD №3 (Aib-2 in Retatrutide, which replaced the side chain entirely with a methyl group at the N-terminal DPP-4 resistance site).\n\nThe elimination of the free thiol is a parallel and independent pharmacological benefit: free cysteines in therapeutic peptides are susceptible to oxidation (sulfenic/sulfinic/sulfonic acid formation), disulfide scrambling with plasma proteins, and crosslinking under oxidative stress. Replacing Cys-24 with αMe-Cys eliminates this liability without introducing a charge, changing the molecular weight significantly, or altering the side-chain contact geometry that may interface with GLP-1R transmembrane residues.\n\nThis fold is also conceptually connected to the lab's ongoing exploration of non-canonical amino acids in the METABOLIC class. FOLD №3's Aib substitution in Retatrutide explored helix stabilization at the N-terminus for DPP-4 resistance — a different position and mechanism, but the same chemical category. FOLD №23 applies the Cα-methylation strategy to a mid-helix receptor-docking position for the first time in this lab series.\n\n---\n\n## Predicted Properties (Where Signal Is Moderate)\n\n| Parameter | Value | Interpretation |\n|---|---|---|\n| pLDDT (isolated peptide) | 0.71 | Moderate confidence — interpretable, not high-confidence |\n| pTM | 0.61 | Acceptable fold topology score |\n| ipTM (GLP-1R complex) | 0.16 | **Poor** — receptor interface geometry unreliable |\n| Affinity prediction (ΔΔG) | Not returned | Cannot quantify binding change |\n| Aggregation propensity | 0.179 | Low — favorable for a helix-stabilized amphipathic peptide |\n| Stability score | 0.445 | Moderate |\n| Half-life estimate | Long (>6 h) | Expected; dominated by fatty acid tether at Lys-20 |\n| BBB penetration | 0.051 | Not relevant for injectable metabolic agent |\n\nThe peptide-level pLDDT of 0.71 is consistent with maintained helical character in the central helix region — the predictor does not signal gross structural disruption from the αMe-Cys substitution. The hydrophobic hotspot at residues 22–33 maps precisely onto the amphipathic helix region containing the modification and the downstream Trp-25/Leu-26/Leu-27 cluster, consistent with the expected hydrophobic face of the receptor-docking helix. The low aggregation propensity (0.179) is reassuring — helix-locking modifications that rigidify amphipathic structure can expose hydrophobic faces and promote aggregation, and this flag is not raised here.\n\nThe critical signal gap is the ipTM of 0.16. This is too low to support any conclusions about whether αMe-Cys-24 is sterically accommodated in the GLP-1R transmembrane cleft or whether the quaternary α-carbon introduces steric clash with receptor residues. At this interface confidence level, the docked pose geometry should not be interpreted as predictive.\n\n---\n\n## What Would Strengthen This Signal\n\n**Additional predictions:**\n- **Ensemble docking** against the published GLP-1R–tirzepatide cryo-EM structure (if available) or GLP-1R–GLP-1 complex (PDB: 6X18 and related) using RosettaFold2 or AF-Multimer with multiple seeds, to assess whether ipTM convergence toward ≥0.4 is achievable with repeated runs\n- **Explicit ΔΔG estimation** using a structural perturbation tool (FoldX, Rosetta ddg_monomer, or ProteinMPNN energy estimation) applied to the cryo-EM template with αMe-Cys modeled in at position 24 — this bypasses the ipTM problem by using an experimental receptor structure as scaffold\n- **GIPR complex docking** — tirzepatide's dual agonism requires that any modification be tolerated at both receptors; a parallel fold against GIPR (UniProt P25092) is needed\n- **Comparative fold against native Cys-24 tirzepatide** in this lab's pipeline, to establish a pLDDT/ipTM baseline under identical prediction conditions\n\n**Experimental validation (wet lab):**\n- Solid-phase peptide synthesis of αMe-Cys-24 tirzepatide analog (αMe-Cys is commercially available from Sigma/Bachem as Fmoc-protected building block)\n- GLP-1R and GIPR radioligand displacement assay (competitive binding vs. native tirzepatide) — the decisive pharmacological experiment\n- cAMP accumulation assay in GLP-1R-overexpressing HEK293 cells — functional potency readout\n- Forced degradation study: H₂O₂ stress (0.1–1% w/v, 24 h) comparing native tirzepatide vs. αMe-Cys-24 analog — quantifies the oxidative stability gain independently of receptor binding\n- CD spectroscopy in aqueous buffer — direct measurement of helical content change vs. native tirzepatide\n\n**What a REFINED verdict would require:** ipTM ≥ 0.4 on a repeated or ensembled docking run, or a positive ΔΔG prediction from a structure-based tool, combined with maintained aggregation propensity and no new steric clash flags in the receptor pocket.","structural_caption":"The αMe-Cys24 tirzepatide analog folds into a coherent peptide structure with reasonable per-residue confidence (pLDDT ~0.71), consistent with maintained central helical character around the substitution site. However, the docked pose against GLP-1R shows poor interface confidence (ipTM 0.16), meaning the predicted peptide-receptor contact geometry is unreliable. The heuristic profile flags a hydrophobic hotspot spanning residues 22-33, consistent with the expected amphipathic helix region containing the modification. No affinity prediction was returned, so binding impact cannot be quantified from this run.","key_findings_summary":"Tirzepatide is a well-established dual GIP/GLP-1 receptor agonist with extensive Phase 3 clinical evidence demonstrating superior glycemic control and weight reduction compared to semaglutide and placebo across multiple indications including type 2 diabetes, obesity, MASH, and obstructive sleep apnea. However, the available literature is almost exclusively focused on clinical pharmacology, efficacy, and safety outcomes — none of the retrieved papers address the molecular structural basis of tirzepatide's interaction with GLP-1R, the role of specific residues in receptor binding, or any analog chemistry. The hypothesis under investigation — substituting Cys-24 with α-methyl-cysteine (αMe-Cys) to rigidify the central amphipathic α-helix and eliminate the reactive free thiol — is not addressed, even tangentially, in any of these papers.\n\nThe structural context of the hypothesis relies on published cryo-EM and crystallographic work (not represented in this abstract set) showing that tirzepatide's central helix (approximately residues 16–30) docks into the transmembrane bundle of GLP-1R in a manner analogous to GLP-1 and other peptide agonists. Tirzepatide's sequence differs from native GLP-1 at multiple positions, including the incorporation of a C18 fatty diacid at Lys-20 for albumin binding, and the peptide is understood to adopt a helical conformation upon receptor engagement. The identity and functional role of Cys-24 specifically — whether it is solvent-exposed, buried at the receptor interface, or contributes to any intramolecular interactions — is not discussed in any retrieved abstract.\n\nThe chemical rationale for Cα-methylation is well-grounded in the broader non-canonical amino acid literature (not retrieved here): α-methyl amino acids constrain backbone φ,ψ dihedral angles toward helical conformations (Aib being the prototypical example), and αMe-Cys specifically would be expected to preserve the thioether side chain while introducing the gem-dimethyl steric effect at Cα that enforces helical bias. The elimination of the free thiol as a reactive liability (oxidation, disulfide scrambling) is a legitimate pharmaceutical chemistry concern for any cysteine-containing therapeutic peptide, and no papers in this set address tirzepatide's known degradation or oxidation pathways.\n\nIn summary, the retrieved literature provides strong clinical context for tirzepatide as a therapeutic agent but offers no mechanistic, structural, or analog chemistry data relevant to the proposed Cys-24 → αMe-Cys substitution. The hypothesis must be evaluated against the broader structural biology literature on GLP-1R peptide agonist complexes and the non-canonical amino acid/helix-stabilization literature, neither of which is represented in these abstracts."},"structured":{"known_activity":null,"known_binders":null,"candidate_variants":null,"domain_annotations":null,"literature_context":{"pubmed":[{"pmid":"38078870","title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.","abstract":"IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.\n\nOBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.\n\nDESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.\n\nINTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.\n\nMAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.\n\nRESULTS: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.\n\nCONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.\n\nTRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.","authors":["Aronne Louis J","Sattar Naveed","Horn Deborah B","Bays Harold E","Wharton Sean","Lin Wen-Yuan","Ahmad Nadia N","Zhang Shuyu","Liao Ran","Bunck Mathijs C","Jouravskaya Irina","Murphy Madhumita A"],"year":2024,"journal":"JAMA"},{"pmid":"39536238","title":"Tirzepatide for Obesity Treatment and Diabetes Prevention.","abstract":"BACKGROUND: Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes.\n\nMETHODS: We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods.\n\nRESULTS: At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified.\n\nCONCLUSIONS: Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).","authors":["Jastreboff Ania M","le Roux Carel W","Stefanski Adam","Aronne Louis J","Halpern Bruno","Wharton Sean","Wilding John P H","Perreault Leigh","Zhang Shuyu","Battula Ramakrishna","Bunck Mathijs C","Ahmad Nadia N","Jouravskaya Irina"],"year":2025,"journal":"The New England journal of medicine"},{"pmid":"34170647","title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.","abstract":"BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown.\n\nMETHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks.\n\nRESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide.\n\nCONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).","authors":["Frías Juan P","Davies Melanie J","Rosenstock Julio","Pérez Manghi Federico C","Fernández Landó Laura","Bergman Brandon K","Liu Bing","Cui Xuewei","Brown Katelyn"],"year":2021,"journal":"The New England journal of medicine"},{"pmid":"38912654","title":"Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.","abstract":"BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.\n\nMETHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure.\n\nRESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity.\n\nCONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).","authors":["Malhotra Atul","Grunstein Ronald R","Fietze Ingo","Weaver Terri E","Redline Susan","Azarbarzin Ali","Sands Scott A","Schwab Richard J","Dunn Julia P","Chakladar Sujatro","Bunck Mathijs C","Bednarik Josef"],"year":2024,"journal":"The New England journal of medicine"},{"pmid":"37385275","title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.","abstract":"BACKGROUND: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes.\n\nMETHODS: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003.\n\nFINDINGS: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator.\n\nINTERPRETATION: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.\n\nFUNDING: Eli Lilly and Company.","authors":["Garvey W Timothy","Frias Juan P","Jastreboff Ania M","le Roux Carel W","Sattar Naveed","Aizenberg Diego","Mao Huzhang","Zhang Shuyu","Ahmad Nadia N","Bunck Mathijs C","Benabbad Imane","Zhang Xiaotian M"],"year":2023,"journal":"Lancet (London, England)"},{"pmid":"38819983","title":"Tirzepatide for Weight Reduction in Chinese Adults With Obesity: The SURMOUNT-CN Randomized Clinical Trial.","abstract":"IMPORTANCE: Obesity has become a global public health concern and China has the largest number of affected people worldwide.\n\nOBJECTIVE: To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities.\n\nDESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes.\n\nINTERVENTIONS: Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks.\n\nMAIN OUTCOMES AND MEASURES: Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population.\n\nRESULTS: Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%).\n\nCONCLUSIONS AND RELEVANCE: In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile.\n\nTRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05024032.","authors":["Zhao Lin","Cheng Zhifeng","Lu Yibing","Liu Ming","Chen Hong","Zhang Min","Wang Rui","Yuan Yuan","Li Xiaoying"],"year":2024,"journal":"JAMA"},{"pmid":"38856224","title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.","abstract":"BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\n\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\n\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\n\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).","authors":["Loomba Rohit","Hartman Mark L","Lawitz Eric J","Vuppalanchi Raj","Boursier Jérôme","Bugianesi Elisabetta","Yoneda Masato","Behling Cynthia","Cummings Oscar W","Tang Yuanyuan","Brouwers Bram","Robins Deborah A","Nikooie Amir","Bunck Mathijs C","Haupt Axel","Sanyal Arun J"],"year":2024,"journal":"The New England journal of medicine"},{"pmid":"34186022","title":"Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.","abstract":"BACKGROUND: Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone.\n\nMETHODS: We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834.\n\nFINDINGS: From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of -1·91% (-21 mmol/mol) with tirzepatide 5 mg, -1·93% (-21 mmol/mol) with tirzepatide 10 mg, and -2·11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87-92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group.\n\nINTERPRETATION: Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment.\n\nFUNDING: Eli Lilly and Company.","authors":["Rosenstock Julio","Wysham Carol","Frías Juan P","Kaneko Shizuka","Lee Clare J","Fernández Landó Laura","Mao Huzhang","Cui Xuewei","Karanikas Chrisanthi A","Thieu Vivian T"],"year":2021,"journal":"Lancet (London, England)"},{"pmid":"37940101","title":"The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception.","abstract":"BACKGROUND: Tirzepatide is a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA) whose mechanism of action leads to a greater effect of gastric emptying (GE) than typical GLP-1 RAs. After the first dose of tirzepatide, GE is most substantially delayed. The drug then undergoes tachyphylaxis after subsequent doses. Although data on GLP1-RAs have historically demonstrated a lack of impact on bioavailability of oral hormonal contraceptives, manufacturer recommendations for tirzepatide indicate an interaction exists.\n\nOBJECTIVES: The objectives of this literature review were to review trial data on differences in the impact of tirzepatide and GLP-1 RAs on oral hormonal contraceptives and provide an analysis of safety data between oral contraceptives and incretin agents.\n\nMETHODS: PubMed and Google Scholar were searched using the generic name for the GLP-1/GIP agent, the generic names for GLP-1 RAs and hormonal contraceptives, followed by the generic names plus the interacting medication. A total of 6 clinical trials were selected for inclusion in the literature review.\n\nRESULTS: Of the 6 articles included in the review, one investigated the use of tirzepatide and showed a statistically significant reduction in area under the plasma drug concentration-time curve, maximum concentration, and time to maximum plasma concentration when tirzepatide was concomitantly administered with an oral hormonal contraceptive. The remaining 5 studies involving GLP-1 RAs did not show a statistically or clinically significant difference of impact of the agents on oral hormonal contraceptives.\n\nCONCLUSION: It could be suggested that tirzepatide had a greater impact on absorption of oral hormonal contraceptives than other GLP-1 RAs. The rapid dose escalation and greater delay on GE enhanced the impact on oral medications such as contraceptives. This differed from other GLP-1 RAs and creates a unique need for enhanced provider and patient education regarding the management of this interaction and future studies to evaluate this interaction further.","authors":["Skelley Jessica W","Swearengin Katelyn","York Adriane L","Glover Lacey H"],"year":2024,"journal":"Journal of the American Pharmacists Association : JAPhA"},{"pmid":"40186344","title":"Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis.","abstract":"Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text, Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m2. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy. PRACTITIONER POINTS: Question: Does discontinuation of Glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment lead to significant weight gain? Findings: In this systematic review and meta-analysis, discontinuing GLP-1RA treatment led to a pooled overall mean weight regain of 2.20 kg in participants taking liraglutide and 9.69 kg in those patients prescribed semaglutide/tirzepatide. The proportion of weight regained was proportional to the amount originally lost. Meaning: Discontinuation of GLP-1RA treatment leads to weight regain, regardless of lifestyle interventions, and should therefore be considered a chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity.","authors":["Berg Sara","Stickle Hannah","Rose Suzanne J","Nemec Eric C"],"year":2025,"journal":"Obesity reviews : an official journal of the International Association for the Study of Obesity"},{"pmid":"39719170","title":"Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis.","abstract":"BACKGROUND AND AIMS: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity.\n\nMETHODS: A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators.\n\nRESULTS: Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [-4.81, -2.29]), fat mass (MD -2.95 kg, 95 %-CI [-4.11, -1.79]), and lean mass (MD -0.86 kg, 95 %-CI [-1.30, -0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass.\n\nCONCLUSIONS: Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.","authors":["Karakasis Paschalis","Patoulias Dimitrios","Fragakis Nikolaos","Mantzoros Christos S"],"year":2025,"journal":"Metabolism: clinical and experimental"},{"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"}],"biorxiv":[{"pmid":"","doi":"10.21203/rs.3.rs-9289959/v1","title":"Starvation ketosis following self-administered tirzepatide obtained via online services in a young woman later diagnosed with anorexia nervosa: a case report","abstract":"<title>Abstract</title>  <p>Background  Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, induces potent appetite suppression and substantial weight loss. Increasing access to incretin-based therapies through online services has raised concerns regarding metabolic and psychiatric complications, particularly in vulnerable individuals. We report a case of starvation ketosis associated with self-administered tirzepatide, followed by the clinical recognition of anorexia nervosa. Case presentation:  A 21-year-old woman with no prior formal psychiatric or metabolic diagnoses had a history of dieting behaviors and intermittent binge-purge episodes. Seeking further weight loss, she obtained tirzepatide through online medical services and self-administered 2.5 mg weekly for approximately four weeks, followed by 5.0 mg weekly for another month, without direct medical supervision. Her body weight decreased from 47 kg to 41 kg (BMI 17.9 to 15.6 kg/m²). Approximately two months after initiation, she developed severe nausea, bilious vomiting, and presyncope, requiring emergency admission. Laboratory evaluation revealed marked ketonemia (serum 3-hydroxybutyrate 2057 µmol/L), normoglycemia (glucose 79 mg/dL), mildly elevated anion gap, normal HbA1c (5.1%), and no clinically significant acidemia. She had no history of SGLT2 inhibitor use or habitual alcohol consumption. She was diagnosed with starvation ketosis and improved with intravenous glucose infusion and nutritional support. Shortly after discharge, psychiatric evaluation led to a diagnosis of anorexia nervosa. At early follow-up, body weight had increased to 42 kg, the Eating Attitudes Test-26 (EAT-26) score decreased to 14, but serum 3-hydroxybutyrate remained elevated at 166 µmol/L. At later outpatient reassessment several months later, body weight remained 42 kg, serum 3-hydroxybutyrate had normalized to 24 µmol/L, and the EAT-26 score was 16; however, her drive for thinness persisted. Conclusions  This case highlights that unsupervised tirzepatide use may be associated with starvation ketosis and the clinical recognition or exacerbation of eating-disorder psychopathology. Metabolic recovery did not parallel full improvement in eating-disorder symptoms, underscoring the need for careful screening, longitudinal psychiatric follow-up, and interdisciplinary management when incretin-based therapies are used.</p>","authors":["Yasui-Furukori N","Tasaki K","Kaiga Y","Aso Y."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-8818962/v1","title":"Case Report: Gastric Retention Induced by Tirzepatide in a Patient Undergoing Gastroscopy","abstract":"<title>Abstract</title>  <p>We report a case of gastric retention induced by tirzepatide in a 42-year-old female patient with a body mass index of 29.3 kg/m² who was scheduled for painless gastroscopy due to back distension and pain. The patient had fasted for 12 hours as required and was assessed with a difficult airway in the pre-anesthesia clinic, with no history of hypertension or diabetes mellitus noted initially. During gastroscopy, undigested semisolid food chyme was found in the gastric body, and gastric peristalsis was weakened, leading to the suspension of the procedure. Further inquiry revealed that the patient had received weekly subcutaneous injections of tirzepatide for weight management for one month. The patient was then instructed to discontinue tirzepatide for one week, adopt a liquid diet preoperatively, and extend the fasting time to 15 hours. A follow-up ultrasonic assessment showed no residual gastric contents, and the painless gastroscopy was completed successfully thereafter. Tirzepatide, a dual GIP/GLP-1 receptor agonist, delays gastric emptying through a central pathway, which is the primary cause of gastric retention in this case. This case highlights that anesthesiologists may overlook the medication history of GLP-1 receptor agonists when focusing on difficult airway assessment, leading to unanticipated gastric retention. Clinicians should conduct a comprehensive pre-anesthetic assessment including detailed medication history for patients using tirzepatide, and consider drug discontinuation, extended fasting and bedside ultrasonography as necessary to reduce the risk of regurgitation and aspiration during anesthesia.</p>","authors":["Zhao Y."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9180565/v1","title":"Use of Tirzepatide in the Management of Obesity and Overweight: Feasibility Analysis for Incorporation into the Public Health System of Mato Grosso, Brazil","abstract":"<title>Abstract</title>  <p>  <bold>Background/Objectives:</bold>  Obesity is a chronic disease with high prevalence in Brazil. Tirzepatide (a dual GIP/GLP-1 agonist) has emerged as a highly effective alternative, albeit with substantial costs. This study assessed the feasibility of offering tirzepatide within the public health system of Mato Grosso, Brazil.  <bold>Methods:</bold>  A systematic review was conducted to evaluate the efficacy and safety of tirzepatide in head-to-head comparisons with other anti-obesity medications. Additionally, a 5-year budget impact analysis (from the payer perspective, State Health Secretariat) and a short-term cost-effectiveness analysis (72 weeks) were performed for weight loss targets of ≥10%, ≥15%, ≥20%, and ≥25%. Two population scenarios were considered: a broad scenario (overweight with comorbidities and obesity) and a restricted scenario (BMI ≥35 with multiple comorbidities), with progressive uptake rates (10–50%).  <bold>Results:</bold>  A single randomized controlled trial (SURMOUNT-5, n=751) directly compared tirzepatide versus semaglutide. Tirzepatide was superior in percentage weight reduction (difference -6.5%; 95% CI -8.1 to -4.9; p<0.001), waist circumference (-5.4 cm; 95% CI -7.1 to -3.6), and BMI (-2.7 points; 95% CI -3.3 to -2.0) after 72 weeks. The annual cost per patient was US$ 5,445.96 for tirzepatide and ranged from US$ 2,855.29 (first year) to US$ 3,274.83 (subsequent years) for semaglutide. In the broad scenario, the 5-year cumulative budget impact was US$ 9.38 billion for tirzepatide and US$ 5.59 billion for semaglutide. In the cost-effectiveness analysis, semaglutide had a lower cost per responder for ≥10% and ≥15% targets; costs were similar for the ≥20% target, and tirzepatide was more efficient for the ≥25% target.  <bold>Conclusions:</bold>  Despite tirzepatide's superior efficacy, particularly for more aggressive weight loss targets, both technologies impose a substantial financial burden. These findings support the recommendation against state-level incorporation, especially in the broad population scenario.  </p>","authors":["Pereira P","Nakata K","Nakata G","Oliveira L","Oliveira H","Guenkka T","Barreto Z","Teixeira E","Pizzaro C","Cosme A."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.1715.v1","title":"Metformin and Tirzepatide in Lipedema: Targeting Fibrosis and Inflammation Through Complementary Pathways. A Mechanistic, Translational and Therapeutic Perspective","abstract":"Lipedema is a chronic and progressive adipose tissue disorder characterized by disproportionate fat accumulation, microvascular dysfunction, chronic inflammation, and progressive fibrosis. Despite its prevalence and significant impact on quality of life, current therapeutic approaches remain largely symptomatic and fail to address the underlying biological mechanisms of the disease. Emerging evidence suggests that lipedema should be understood as a multifactorial condition involving genetic susceptibility, endothelial alterations, immune dysregulation, and extracellular matrix remodeling. In this context, pharmacological strategies targeting these pathways have gained increasing attention. Metformin, through activation of AMP-activated protein kinase (AMPK), exerts antifibrotic and immunometabolic effects, including inhibition of TGF-β signaling, reduction of extracellular matrix deposition, and modulation of adipose tissue inflammation. In parallel, incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP agonists such as tirzepatide, have demonstrated pleiotropic effects that extend beyond weight reduction, including improvements in metabolic homeostasis, reduction of systemic inflammation, and enhancement of endothelial function. These therapies appear to act through complementary mechanisms, with metformin primarily targeting tissue remodeling and fibrosis, and incretin-based therapies exerting broader systemic effects on metabolism, inflammation, and vascular integrity. This review proposes a hypothesis-generating mechanistic framework, supporting a shift from weight-centric and symptomatic approaches toward disease-modifying strategies. Although current evidence in lipedema is largely indirect, the convergence of experimental and clinical data provides a strong rationale for further investigation. Future studies should focus on evaluating combined therapeutic approaches and identifying biomarkers that reflect fibrosis, inflammation, and microvascular dysfunction, with the aim of developing targeted and personalized treatments for this complex disorder.","authors":["Fernandes Lima M","Pinheiro Rios Lima M."],"year":2026,"journal":"PPR","source":"PPR","preprint":true}],"preprints":[{"pmid":"","doi":"10.21203/rs.3.rs-9289959/v1","title":"Starvation ketosis following self-administered tirzepatide obtained via online services in a young woman later diagnosed with anorexia nervosa: a case report","abstract":"<title>Abstract</title>  <p>Background  Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, induces potent appetite suppression and substantial weight loss. Increasing access to incretin-based therapies through online services has raised concerns regarding metabolic and psychiatric complications, particularly in vulnerable individuals. We report a case of starvation ketosis associated with self-administered tirzepatide, followed by the clinical recognition of anorexia nervosa. Case presentation:  A 21-year-old woman with no prior formal psychiatric or metabolic diagnoses had a history of dieting behaviors and intermittent binge-purge episodes. Seeking further weight loss, she obtained tirzepatide through online medical services and self-administered 2.5 mg weekly for approximately four weeks, followed by 5.0 mg weekly for another month, without direct medical supervision. Her body weight decreased from 47 kg to 41 kg (BMI 17.9 to 15.6 kg/m²). Approximately two months after initiation, she developed severe nausea, bilious vomiting, and presyncope, requiring emergency admission. Laboratory evaluation revealed marked ketonemia (serum 3-hydroxybutyrate 2057 µmol/L), normoglycemia (glucose 79 mg/dL), mildly elevated anion gap, normal HbA1c (5.1%), and no clinically significant acidemia. She had no history of SGLT2 inhibitor use or habitual alcohol consumption. She was diagnosed with starvation ketosis and improved with intravenous glucose infusion and nutritional support. Shortly after discharge, psychiatric evaluation led to a diagnosis of anorexia nervosa. At early follow-up, body weight had increased to 42 kg, the Eating Attitudes Test-26 (EAT-26) score decreased to 14, but serum 3-hydroxybutyrate remained elevated at 166 µmol/L. At later outpatient reassessment several months later, body weight remained 42 kg, serum 3-hydroxybutyrate had normalized to 24 µmol/L, and the EAT-26 score was 16; however, her drive for thinness persisted. Conclusions  This case highlights that unsupervised tirzepatide use may be associated with starvation ketosis and the clinical recognition or exacerbation of eating-disorder psychopathology. Metabolic recovery did not parallel full improvement in eating-disorder symptoms, underscoring the need for careful screening, longitudinal psychiatric follow-up, and interdisciplinary management when incretin-based therapies are used.</p>","authors":["Yasui-Furukori N","Tasaki K","Kaiga Y","Aso Y."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-8818962/v1","title":"Case Report: Gastric Retention Induced by Tirzepatide in a Patient Undergoing Gastroscopy","abstract":"<title>Abstract</title>  <p>We report a case of gastric retention induced by tirzepatide in a 42-year-old female patient with a body mass index of 29.3 kg/m² who was scheduled for painless gastroscopy due to back distension and pain. The patient had fasted for 12 hours as required and was assessed with a difficult airway in the pre-anesthesia clinic, with no history of hypertension or diabetes mellitus noted initially. During gastroscopy, undigested semisolid food chyme was found in the gastric body, and gastric peristalsis was weakened, leading to the suspension of the procedure. Further inquiry revealed that the patient had received weekly subcutaneous injections of tirzepatide for weight management for one month. The patient was then instructed to discontinue tirzepatide for one week, adopt a liquid diet preoperatively, and extend the fasting time to 15 hours. A follow-up ultrasonic assessment showed no residual gastric contents, and the painless gastroscopy was completed successfully thereafter. Tirzepatide, a dual GIP/GLP-1 receptor agonist, delays gastric emptying through a central pathway, which is the primary cause of gastric retention in this case. This case highlights that anesthesiologists may overlook the medication history of GLP-1 receptor agonists when focusing on difficult airway assessment, leading to unanticipated gastric retention. Clinicians should conduct a comprehensive pre-anesthetic assessment including detailed medication history for patients using tirzepatide, and consider drug discontinuation, extended fasting and bedside ultrasonography as necessary to reduce the risk of regurgitation and aspiration during anesthesia.</p>","authors":["Zhao Y."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.21203/rs.3.rs-9180565/v1","title":"Use of Tirzepatide in the Management of Obesity and Overweight: Feasibility Analysis for Incorporation into the Public Health System of Mato Grosso, Brazil","abstract":"<title>Abstract</title>  <p>  <bold>Background/Objectives:</bold>  Obesity is a chronic disease with high prevalence in Brazil. Tirzepatide (a dual GIP/GLP-1 agonist) has emerged as a highly effective alternative, albeit with substantial costs. This study assessed the feasibility of offering tirzepatide within the public health system of Mato Grosso, Brazil.  <bold>Methods:</bold>  A systematic review was conducted to evaluate the efficacy and safety of tirzepatide in head-to-head comparisons with other anti-obesity medications. Additionally, a 5-year budget impact analysis (from the payer perspective, State Health Secretariat) and a short-term cost-effectiveness analysis (72 weeks) were performed for weight loss targets of ≥10%, ≥15%, ≥20%, and ≥25%. Two population scenarios were considered: a broad scenario (overweight with comorbidities and obesity) and a restricted scenario (BMI ≥35 with multiple comorbidities), with progressive uptake rates (10–50%).  <bold>Results:</bold>  A single randomized controlled trial (SURMOUNT-5, n=751) directly compared tirzepatide versus semaglutide. Tirzepatide was superior in percentage weight reduction (difference -6.5%; 95% CI -8.1 to -4.9; p<0.001), waist circumference (-5.4 cm; 95% CI -7.1 to -3.6), and BMI (-2.7 points; 95% CI -3.3 to -2.0) after 72 weeks. The annual cost per patient was US$ 5,445.96 for tirzepatide and ranged from US$ 2,855.29 (first year) to US$ 3,274.83 (subsequent years) for semaglutide. In the broad scenario, the 5-year cumulative budget impact was US$ 9.38 billion for tirzepatide and US$ 5.59 billion for semaglutide. In the cost-effectiveness analysis, semaglutide had a lower cost per responder for ≥10% and ≥15% targets; costs were similar for the ≥20% target, and tirzepatide was more efficient for the ≥25% target.  <bold>Conclusions:</bold>  Despite tirzepatide's superior efficacy, particularly for more aggressive weight loss targets, both technologies impose a substantial financial burden. These findings support the recommendation against state-level incorporation, especially in the broad population scenario.  </p>","authors":["Pereira P","Nakata K","Nakata G","Oliveira L","Oliveira H","Guenkka T","Barreto Z","Teixeira E","Pizzaro C","Cosme A."],"year":2026,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.20944/preprints202604.1715.v1","title":"Metformin and Tirzepatide in Lipedema: Targeting Fibrosis and Inflammation Through Complementary Pathways. A Mechanistic, Translational and Therapeutic Perspective","abstract":"Lipedema is a chronic and progressive adipose tissue disorder characterized by disproportionate fat accumulation, microvascular dysfunction, chronic inflammation, and progressive fibrosis. Despite its prevalence and significant impact on quality of life, current therapeutic approaches remain largely symptomatic and fail to address the underlying biological mechanisms of the disease. Emerging evidence suggests that lipedema should be understood as a multifactorial condition involving genetic susceptibility, endothelial alterations, immune dysregulation, and extracellular matrix remodeling. In this context, pharmacological strategies targeting these pathways have gained increasing attention. Metformin, through activation of AMP-activated protein kinase (AMPK), exerts antifibrotic and immunometabolic effects, including inhibition of TGF-β signaling, reduction of extracellular matrix deposition, and modulation of adipose tissue inflammation. In parallel, incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP agonists such as tirzepatide, have demonstrated pleiotropic effects that extend beyond weight reduction, including improvements in metabolic homeostasis, reduction of systemic inflammation, and enhancement of endothelial function. These therapies appear to act through complementary mechanisms, with metformin primarily targeting tissue remodeling and fibrosis, and incretin-based therapies exerting broader systemic effects on metabolism, inflammation, and vascular integrity. This review proposes a hypothesis-generating mechanistic framework, supporting a shift from weight-centric and symptomatic approaches toward disease-modifying strategies. Although current evidence in lipedema is largely indirect, the convergence of experimental and clinical data provides a strong rationale for further investigation. Future studies should focus on evaluating combined therapeutic approaches and identifying biomarkers that reflect fibrosis, inflammation, and microvascular dysfunction, with the aim of developing targeted and personalized treatments for this complex disorder.","authors":["Fernandes Lima M","Pinheiro Rios Lima M."],"year":2026,"journal":"PPR","source":"PPR","preprint":true}],"consensus_view":"The literature consensus on tirzepatide is exclusively clinical: it is a potent, well-tolerated dual GIP/GLP-1 receptor agonist with best-in-class weight reduction and glycemic efficacy. There is no published consensus — or indeed any retrieved literature — on the structural role of individual residues in tirzepatide's receptor interactions, the reactivity of Cys-24 as a pharmaceutical liability, or the use of non-canonical Cα-methylated residues to stabilize its helical conformation. The analog chemistry and structural biology relevant to this hypothesis exist in the broader peptide drug design literature (Aib substitution, α-methyl amino acid helix stabilization, GLP-1R cryo-EM structures) but are entirely absent from the retrieved abstract set. No consensus can be reported from this literature on the proposed modification.","knowledge_gaps":"The retrieved literature leaves the following critical gaps entirely unaddressed: (1) The structural role of Cys-24 in tirzepatide's receptor-bound conformation — whether it is helical, solvent-exposed, or makes contact with GLP-1R transmembrane residues — is unknown from these papers. (2) Whether the free thiol of Cys-24 represents a documented degradation or oxidation liability in tirzepatide formulations is not discussed. (3) No data exist in these abstracts on how backbone rigidification at position 24 (or anywhere in the central helix) affects GLP-1R binding affinity, GIP receptor binding, or downstream signaling bias. (4) The tolerance of GLP-1R's transmembrane binding cleft for Cα-methylated residues (increased steric volume at Cα relative to standard amino acids) is not characterized. (5) Whether αMe-Cys specifically (as opposed to the well-studied Aib) has been incorporated into any incretin-class peptide is not addressed. These are precisely the gaps that the proposed in silico and/or experimental study could illuminate.","supporting_evidence":"No direct supporting evidence for the specific hypothesis (Cys-24 → αMe-Cys improving helical stability and eliminating thiol reactivity while preserving GLP-1R activity) is present in the retrieved literature. Indirect support comes from: (1) tirzepatide's established GLP-1R agonism being central to its efficacy (multiple SURPASS/SURMOUNT trials), meaning that helix-stabilizing modifications that preserve receptor engagement would be pharmacologically meaningful; (2) the general principle that GLP-1R peptide agonists require helical structure in their central region for potent receptor activation, as established in the broader structural literature (not retrieved here); (3) the pharmaceutical importance of eliminating reactive liabilities in therapeutic peptides is an accepted principle in drug development, and the clinical use of tirzepatide at doses up to 15 mg weekly makes oxidative degradation a legitimate formulation concern.","challenging_evidence":"No directly challenging evidence is present in the retrieved abstracts. However, several indirect concerns can be noted: (1) Cα-methylation introduces a quaternary carbon that increases steric bulk at the backbone — if Cys-24 packs into a sterically constrained region of the GLP-1R transmembrane bundle, αMe-Cys could clash with receptor residues and reduce binding affinity. (2) Tirzepatide also agonizes the GIP receptor, and any helix-rigidifying modification must preserve dual-receptor engagement; the GIP receptor's tolerance for αMe-Cys at position 24 is unknown. (3) The SURMOUNT/SURPASS trials collectively show that tirzepatide's existing structure is already highly efficacious across diverse populations, raising the question of whether any structural modification would offer meaningful improvement over the already-optimized parent molecule. (4) Preprint case reports (starvation ketosis, gastric retention) suggest that tirzepatide's potent appetite suppression is itself a clinical risk in some patients, and a more potent or more stable analog could amplify these risks. None of these concerns are quantified by the retrieved literature."},"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","ipTM of 0.16 on the GLP-1R complex is below reliable interpretation threshold — receptor interface geometry should not be treated as predictive","αMe-Cys introduces a quaternary α-carbon not natively present in AlphaFold2/Chai-1 training data; the backbone geometry at position 24 may be imperfectly modeled","no affinity prediction (ΔΔG or binding probability) was returned — binding change versus native tirzepatide is entirely unquantified","heuristic stability, aggregation propensity, and half-life estimates are sequence-based approximations, not experimental measurements","GIPR receptor engagement (required for tirzepatide's dual agonism) was not assessed in this fold — GIP receptor tolerance for αMe-Cys-24 is unknown","the oxidative stability benefit (thiol elimination) is pharmacologically independent of receptor binding but is not directly predicted by structural tools used here"],"works_cited":[{"pmid_or_doi":"34170647","title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","year":2021,"relevance":"Establishes tirzepatide's clinical profile as a dual GIP/GLP-1 receptor agonist and confirms its superior GLP-1R-mediated efficacy relative to semaglutide, providing pharmacological context for why preserving GLP-1R engagement in any analog is critical."},{"pmid_or_doi":"34186022","title":"Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1)","year":2021,"relevance":"Phase 3 monotherapy trial confirming tirzepatide's mechanism as a dual receptor agonist; relevant as baseline pharmacological reference for any structural analog intended to maintain the same receptor engagement profile."},{"pmid_or_doi":"38856224","title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","year":2024,"relevance":"Demonstrates pleiotropic GLP-1R-mediated effects of tirzepatide beyond glycemic control, underscoring the breadth of receptor-dependent signaling that any structural modification must preserve."},{"pmid_or_doi":"37940101","title":"The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception","year":2024,"relevance":"Discusses tirzepatide's pharmacokinetic properties including gastric emptying effects, tangentially relevant to understanding how structural modifications affecting plasma half-life or albumin binding could alter drug behavior."},{"pmid_or_doi":"39719170","title":"Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis","year":2025,"relevance":"Confirms tirzepatide's potent GLP-1R agonism relative to other agents in the class, providing a comparative efficacy benchmark against which any αMe-Cys analog's retained potency would need to be measured."}]},"onchain":{"hash":"E8Pp7RwE3xydwPrAsjx959Y6nKABzk4iuJbXi1MK1eBW2sTPTmxGYAC6V7vP73FniBXidHmDdwgTdf8Qwv3xQNo","signature":"E8Pp7RwE3xydwPrAsjx959Y6nKABzk4iuJbXi1MK1eBW2sTPTmxGYAC6V7vP73FniBXidHmDdwgTdf8Qwv3xQNo","data_hash":"1ebcbfac353e54d6ab7b8fe12aca90152189a2bd9735a19da6028469dd0fc8e4","logged_at":"2026-05-03T04:27:49.315189+00:00","explorer_url":"https://solscan.io/tx/E8Pp7RwE3xydwPrAsjx959Y6nKABzk4iuJbXi1MK1eBW2sTPTmxGYAC6V7vP73FniBXidHmDdwgTdf8Qwv3xQNo"},"ipfs_hash":null,"created_at":"2026-05-03T04:23:28.323596+00:00","updated_at":"2026-05-03T04:27:49.320541+00:00"}