{"id":31,"slug":"31-tirzepatide-ala-2-aminoisobutyric-acid-aib-substitution-at-position-2-re","title":"Tirzepatide Aib-2 substitution for DPP-4 resistance and prolonged dual agonism","status":"PROMISING","fold_verdict":"PROMISING","discard_reason":null,"peptide":{"name":"Tirzepatide","class":"METABOLIC","sequence":"YAEGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPS","modified_sequence":"Y-Aib-EGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPS","modification_description":"Ala-2 → α-aminoisobutyric acid (Aib) substitution at position 2, replacing the native Ala with the Cα,α-disubstituted non-canonical residue while retaining the native C20 fatty diacid on Lys-20"},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Replacing Ala-2 in tirzepatide with α-aminoisobutyric acid (Aib) will block DPP-4 cleavage at the Tyr1-Ala2 scissile bond, the canonical incretin proteolysis site, while the Cα-methyl group caps the N-terminal helix and stabilizes the bioactive conformation that engages GLP-1R's transmembrane core. We expect retained dual GLP-1R/GIPR agonism with improved enzymatic stability beyond what the C20 diacid alone provides. Structurally, Aib-2 should not perturb the receptor-bound geometry of the N-terminal pharmacophore (Tyr1, Glu3, Gly4) that drives Gαs activation.","rationale":"DPP-4 cleaves N-terminal Xaa-Ala/Pro dipeptides; Cα,α-disubstituted Aib at position 2 is the textbook protection used in semaglutide and many incretin analogs precisely because it destroys the substrate geometry DPP-4 requires. Aib also enforces helical (φ,ψ) angles, which should pre-organize the N-terminal helix that inserts into the GLP-1R/GIPR seven-transmembrane bundle. Although Fold #3 tested the same change on Retatrutide and was DISCARDED, the structural context here differs: tirzepatide's GIPR-biased pharmacology and distinct N-terminal hydrogen-bonding network with GIPR ECL2 may tolerate the methyl perturbation that the triple-agonist scaffold did not. Diversity-wise, this fold rotates focus to STABILITY (last 3 were DELIVERY/CONFORMATION-leaning) and category to Non-canonical amino acid (last 3 were Stapled, Single substitution, Cyclization).","predicted_outcome":"AlphaFold should predict a near-identical backbone to native tirzepatide (Cα RMSD < 1.5 Å over the central helix), with a slightly more rigid N-terminal turn (residues 1-5) reflected in elevated pLDDT around position 2. The C20 diacid–Lys20 attachment site and the C-terminal GPSSGAPPPS tail should be unchanged. Expected pLDDT 0.70-0.78.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.7063803672790527,"ptm":0.7508806586265564,"iptm":0.12768866121768951,"chai_agreement":null,"chai1_gated_decision":"SKIPPED_HIGH_CONFIDENCE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.195,"stability_score":0.54,"bbb_penetration_score":0.062,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":"Fold №31 introduces an Aib-2 substitution at the canonical DPP-4 scissile bond of tirzepatide, predicting improved enzymatic stability orthogonal to its existing C20 fatty diacid half-life extension. Structural prediction returns a pLDDT of 0.71 and pTM of 0.75, consistent with a well-folded central α-helix and a preserved N-terminal pharmacophore geometry. The ipTM of 0.13 means receptor engagement cannot be confirmed in silico, leaving the dual GLP-1R/GIPR agonism hypothesis supported by literature precedent rather than this run's docking signal. The fold is rated PROMISING: the conformational logic is sound, the stability rationale is well-grounded in incretin chemistry, but the marginal PK benefit over the native molecule's ~5-day half-life and the GIPR pocket tolerance for the Cα-methyl remain genuinely open questions.","detailed_analysis":"Tirzepatide is a 39-residue dual GIP/GLP-1 receptor agonist with an approved once-weekly clinical regimen, achieving HbA1c reductions of up to 2.30 percentage points and ~20% body weight loss in the SURPASS and SURMOUNT trial series. Its pharmacokinetic durability is primarily conferred by a C20 fatty diacid conjugated to Lys-20, which drives albumin binding and extends the plasma half-life to approximately five days. Despite this lipidation-based stability, the N-terminal Tyr1-Ala2 dipeptide remains a canonical substrate for dipeptidyl peptidase-4 (DPP-4), the serine protease responsible for rapid inactivation of native GLP-1 and GIP. Cleavage at this bond removes the N-terminal pharmacophore (Tyr1, Ala2/Aib2, Glu3, Gly4) that is required for transmembrane bundle engagement at both receptors, meaning even a small fractional contribution from DPP-4 proteolysis could reduce the pool of biologically active peptide.\n\nThe modification hypothesis centers on replacing Ala-2 with α-aminoisobutyric acid (Aib), the Cα,α-disubstituted non-canonical amino acid whose gem-dimethyl geometry sterically occludes the DPP-4 active site and eliminates it as a substrate. This is not a novel chemical strategy in the incretin field — semaglutide and several investigational GLP-1/GIP analogues employ this or closely related approaches — but its application to the tirzepatide scaffold specifically is uncharacterized in the published literature. The rationale for this fold is thus an informed extrapolation from validated incretin chemistry rather than tirzepatide-specific SAR data, a distinction the literature agent correctly flags as a knowledge gap.\n\nAlphaFold3 returned a pLDDT of 0.71 and pTM of 0.75 for the modified peptide in isolation, consistent with the researcher's predicted range of 0.70–0.78 and with a well-ordered central amphipathic α-helix. The N-terminal region encompassing Tyr1 through Gly4 is resolved within the helical fold, which is structurally consistent with the hypothesis that the Aib Cα-methyl caps the N-terminal turn without introducing backbone distortion. This mirrors the pLDDT of 0.71 observed in Fold №23 (tirzepatide Cys-24 → αMe-Cys), suggesting the tirzepatide scaffold tolerates Cα-methylation at multiple positions without gross conformational disruption. The disordered C-terminal GPSSGAPPPS tail and Lys-20 lipidation anchor are present but not separately scored; their expected flexibility is consistent with prior tirzepatide structural models.\n\nThe critical caveat is the ipTM of 0.13, which represents the inter-chain confidence score for the peptide-receptor complex. This score is too low to support any claim about preserved GLP-1R or GIPR transmembrane bundle engagement from this run alone. The dual agonism hypothesis — that Aib-2 is accommodated in both receptor binding pockets without potency loss — rests entirely on the mechanistic precedent from GLP-1R and GIP analogue literature, not on the structural output of this prediction. The GIPR binding pocket geometry at position 2 is less characterized than GLP-1R, and the literature agent appropriately identifies this as the higher-risk unknown: GIPR is noted to have a narrower orthosteric cavity, and the added Cα-methyl may impose a steric penalty that differentially reduces GIPR versus GLP-1R potency.\n\nComparing across the lab's running narrative, this fold revisits the Aib-2 concept previously explored in Fold №3 (Retatrutide, DISCARDED, pLDDT 0.71), where the triple-agonist scaffold's more complex N-terminal hydrogen-bonding network may have been less tolerant of the modification. The researcher's argument that tirzepatide's distinct GIPR-biased pharmacology and N-terminal geometry represent a meaningfully different structural context is plausible, but the structural output here does not resolve whether tirzepatide's Aib-2 variant performs better than Retatrutide's at the receptor interface — that question remains open pending a higher-quality complex run or wet-lab SAR data.\n\nHeuristic property estimates (sequence-based, not wet-lab numbers) suggest low aggregation propensity (0.195), moderate stability (0.54), negligible BBB penetration (0.062), and a long half-life consistent with the C20 diacid — none of these values are materially altered by the single Aib-2 point change, as expected. The practical clinical question of whether Aib-2 provides meaningful additional in vivo stability on top of the existing ~5-day half-life is the central pharmacokinetic uncertainty: if DPP-4 proteolysis contributes only marginally to tirzepatide inactivation at weekly steady-state dosing, this modification may offer limited incremental PK benefit, however chemically elegant.\n\nOverall, Fold №31 represents a scientifically credible and chemically grounded modification with a clear mechanistic rationale, supported by strong incretin field precedent and a structurally consistent prediction. The PROMISING verdict is warranted: the fold demonstrates a preserved helical scaffold and a testable stability hypothesis, but the receptor engagement confidence is insufficient for a REFINED classification, and the marginal PK benefit in the context of an already long-acting molecule tempers the headline claim. The path forward requires either a higher-quality receptor-complex prediction (ensembled or Boltz-2 affinity-enabled) or direct DPP-4 cleavage assay data on the tirzepatide Aib-2 variant.","executive_summary":"Tirzepatide Aib-2: pLDDT 0.71, pTM 0.75 — helical scaffold intact, N-terminal pharmacophore preserved. DPP-4 resistance predicted on chemical first principles; ipTM 0.13 leaves receptor engagement unconfirmed. PROMISING, but marginal PK gain above the C20 diacid baseline remains the key open question.","tweet_draft":"DISTILLATION №31 — promising.\nTirzepatide, Ala-2 → Aib substitution.\nDPP-4 resistance + helix pre-organization predicted.\npLDDT 0.71 | pTM 0.75 | ipTM 0.13 (complex unresolved).\nDual GLP-1R/GIPR agonism hypothesis intact — needs ensemble validation.\nIn silico only. alembic.bio","research_brief_markdown":"# FOLD №31 — Tirzepatide Aib-2 Substitution\n**Verdict: PROMISING** | Class: METABOLIC | Modification: Non-canonical amino acid\n\n---\n\n## Mechanism of action\n\nTirzepatide is a 39-residue synthetic peptide dual agonist of the GIP receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R), approved for type 2 diabetes and obesity management. Its N-terminal sequence (Tyr1-Ala2-Glu3-Gly4-Thr5...) is GIP-derived and engages the orthosteric transmembrane binding pockets of both GIPR and GLP-1R to activate Gαs-coupled cAMP signaling, driving insulin secretion, glucagon suppression, and CNS-mediated appetite reduction. The intact N-terminal pharmacophore — particularly Tyr1, Glu3, and Gly4 — is required for receptor activation at both targets. Metabolic stability is primarily conferred by a C20 fatty diacid conjugated to Lys-20, enabling albumin binding and a ~5-day plasma half-life that supports once-weekly dosing. However, the Tyr1-Ala2 bond remains the canonical DPP-4 scissile bond, and proteolytic removal of the N-terminal dipeptide eliminates receptor agonism regardless of lipidation status.\n\n---\n\n## Performance applications\n\nTirzepatide's clinical efficacy in the SURPASS and SURMOUNT trial series is well established: HbA1c reductions of up to 2.30 percentage points and body weight reductions approaching 20% at 15 mg weekly doses, with emerging data in MASH, sleep apnea, and cardiovascular outcomes. SURMOUNT-4 weight regain data following discontinuation underscore the dependency on continuous dosing and motivate exploration of variants with enhanced pharmacokinetic durability. A tirzepatide analogue with orthogonal DPP-4 resistance at Aib-2 could, in principle, maintain or extend the pharmacological profile while reducing the theoretical contribution of N-terminal proteolysis to dose-to-dose variability — though the marginal PK benefit on top of the existing C20 diacid half-life remains the central unresolved question.\n\n---\n\n## Modification rationale\n\nAib (α-aminoisobutyric acid) is a Cα,α-disubstituted non-proteinogenic amino acid with gem-dimethyl geometry at the α-carbon. This geometry sterically blocks DPP-4's S1 pocket, which requires a planar Cα at the P1' position, rendering Aib-containing peptides non-substrates for DPP-4 cleavage. This is the same chemical logic that underpins the Aib-2 strategy used in semaglutide and validated across numerous GLP-1 and GIP analogue programs. Critically, Aib also constrains backbone dihedral angles to the α-helical region (φ ≈ −60°, ψ ≈ −30°), acting as a helix-capping residue that may pre-organize the N-terminal turn prior to receptor binding — a property structurally consistent with the requirement for an ordered helical N-terminus for incretin receptor engagement.\n\nThe Aib-2 and C20 diacid modifications are structurally orthogonal: the fatty diacid on Lys-20 operates via albumin-mediated half-life extension, while Aib-2 acts directly at the proteolytic cleavage site. They address different inactivation mechanisms and are not expected to sterically interfere with one another.\n\n**Cross-fold context:** This fold revisits the Aib-2 concept previously tested in **Fold №3** (Retatrutide Aib-2, DISCARDED, pLDDT 0.71), where the triple-agonist scaffold's more complex N-terminal hydrogen-bonding network with GCGR appeared less tolerant of the modification, contributing to a weak structural signal. The present fold tests whether tirzepatide's distinct GIPR-biased pharmacology and simpler dual-receptor N-terminal geometry represents a more permissive context for this substitution. Separately, **Fold №23** demonstrated that tirzepatide tolerates Cα-methylation at position 24 (αMe-Cys, pLDDT 0.71, PROMISING), providing precedent that the tirzepatide scaffold is generally compatible with backbone-constraining non-canonical residue insertions without gross conformational disruption.\n\n---\n\n## Predicted properties (where signal is moderate)\n\n| Property | Native tirzepatide (reference) | Tirzepatide Aib-2 (predicted) | Confidence |\n|---|---|---|---|\n| pLDDT (fold quality) | ~0.70–0.72 est. | **0.706** | Moderate |\n| pTM (global topology) | ~0.74 est. | **0.751** | Moderate |\n| ipTM (receptor engagement) | N/A (isolated) | **0.128** | Low — not interpretable |\n| N-terminal helix integrity | Resolved | Resolved (consistent) | Moderate |\n| DPP-4 susceptibility | Yes (Ala-2 substrate) | Predicted abolished (Aib not a substrate) | High (chemical principle) |\n| Half-life profile (heuristic) | Long (>6 hr, C20 diacid) | Long (>6 hr, unchanged) | Moderate |\n| Aggregation propensity (heuristic) | ~0.19 | 0.195 | Low confidence |\n| Stability score (heuristic) | ~0.54 | 0.54 | Low confidence |\n| BBB penetration (heuristic) | ~0.06 | 0.062 | Not applicable |\n\nThe pLDDT of 0.706 and pTM of 0.751 are consistent with a structurally plausible, well-folded helical peptide, matching the researcher's predicted range of 0.70–0.78. The N-terminal Tyr1-Aib2-Glu3-Gly4 pharmacophore is resolved within the helical fold, consistent with backbone geometry preservation. The ipTM of 0.128 is below the threshold for confident receptor engagement inference and should not be interpreted as evidence of reduced binding — it reflects the limitations of the single-run complex prediction, not a predicted potency loss.\n\nThe DPP-4 resistance prediction is made on chemical first principles (Cα,α-disubstitution abolishes DPP-4 substrate geometry) rather than the structural run; this is the highest-confidence claim in the fold. The practical magnitude of in vivo benefit is uncertain given tirzepatide's existing ~5-day half-life.\n\n---\n\n## What would strengthen this signal\n\n**Additional in silico predictions:**\n- **Ensemble prediction (≥5 AlphaFold3 seeds or Boltz-2 affinity module)** on the tirzepatide(Aib2)–GLP-1R and tirzepatide(Aib2)–GIPR complexes with full receptor structure included; ipTM from a single run is insufficient to assess dual agonism preservation.\n- **Chai-1 agreement run** (noted as None in this fold) — inter-model agreement on the complex would materially increase confidence in receptor interface geometry.\n- **Comparative docking** of native tirzepatide vs. Aib-2 variant against available GIPR and GLP-1R cryo-EM structures (PDB: 7DTX, 7MHZ, 7SK8) to assess steric accommodation of the Cα-methyl in both binding pockets.\n- **MD simulation** of the N-terminal turn (residues 1–8) comparing native Ala-2 vs. Aib-2 conformational sampling, to quantify the predicted helix pre-organization effect.\n\n**Wet-lab experiments to validate:**\n- **DPP-4 cleavage assay** (fluorogenic substrate competition or LC-MS peptide stability assay) comparing tirzepatide vs. tirzepatide(Aib2) in human plasma — this is the most direct test of the primary hypothesis.\n- **cAMP accumulation assay** at GLP-1R and GIPR (HEK293 overexpression or primary cells) with full dose-response curves for tirzepatide vs. Aib-2 variant — essential to confirm that dual agonist potency is retained and to quantify any GIPR/GLP-1R selectivity shift introduced by the Cα-methyl.\n- **SPR or ITC binding affinity** measurements at purified GIPR and GLP-1R extracellular domains to isolate affinity effects from functional assay confounds.\n- **In vivo PK comparison** (rodent, sc dosing) of native tirzepatide vs. tirzepatide(Aib2) — specifically, plasma half-life and intact N-terminal peptide quantification by mass spectrometry to determine whether Aib-2 provides measurable additional stability above the C20 diacid baseline.\n\n**Key unknowns to resolve:**\n1. What fraction of tirzepatide inactivation in vivo is attributable to DPP-4 vs. renal/hepatic clearance? If DPP-4 contributes <10% to total clearance, the Aib-2 modification may be pharmacokinetically inert in practice.\n2. Does the GIPR binding pocket at position 2 accommodate the Cα-methyl without potency loss? This is the highest-risk structural unknown and the primary differentiator from the GLP-1R precedent.\n3. Does combining Aib-2 with the C20 diacid alter the balance of GLP-1R vs. GIPR agonism, and if so, in which direction?","structural_caption":"The predicted tirzepatide(Aib2) structure shows a well-folded central α-helix consistent with native tirzepatide topology, with pLDDT and pTM in the expected 0.70–0.75 range matching the predicted outcome. The N-terminal pharmacophore region (Tyr1, Aib2, Glu3, Gly4) is resolved within the helical fold, consistent with the hypothesis that Aib-2 caps the N-terminal turn without distorting backbone geometry. However, the receptor-peptide interface is poorly scored (ipTM 0.13), so any claim about preserved GLP-1R/GIPR engagement is not supported by this run. The C-terminal GPSSGAPPPS tail and Lys20 lipidation site are present but their disorder is not separately quantified here.","key_findings_summary":"Tirzepatide is a well-characterized dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity, demonstrating superior glycemic control and weight reduction compared to selective GLP-1 receptor agonists such as semaglutide across multiple large phase 3 trials (SURPASS, SURMOUNT series). Its clinical efficacy is firmly established, with HbA1c reductions of up to 2.30 percentage points and body weight reductions of up to ~20% at 15 mg weekly doses. However, none of the retrieved literature directly addresses the molecular pharmacology of tirzepatide's N-terminal sequence, DPP-4 susceptibility, or structure-activity relationships relevant to the proposed Ala-2 → Aib substitution.\n\nThe structural basis of tirzepatide's dual agonism is known from prior work in the incretin field (not directly represented in these abstracts): tirzepatide's sequence is GIP-derived at the N-terminus with GLP-1-like elements, and position 2 (Ala-2) sits at the canonical DPP-4 scissile bond (after Tyr-1). DPP-4 cleaves the Xaa-Pro or Xaa-Ala dipeptide at the N-terminus of incretin peptides, and the introduction of Aib (α-aminoisobutyric acid, Cα,α-disubstituted) at position 2 is a well-established strategy in the broader incretin literature to block this cleavage, as Aib is not a DPP-4 substrate. This approach has been validated for GLP-1 analogues and GIP analogues in preclinical contexts, though direct evidence for tirzepatide specifically is absent from the retrieved abstracts.\n\nThe pharmacokinetic profile of tirzepatide already includes a C20 fatty diacid on Lys-20, which confers albumin binding and substantially extends half-life (~5 days), reducing dependence on DPP-4 resistance for in vivo stability. The clinical once-weekly dosing regimen reflects this. Nevertheless, DPP-4 cleavage at the N-terminus can still reduce biological activity by eliminating the critical N-terminal pharmacophore (Tyr-1, Ala-2/Aib-2, Glu-3), which is required for receptor activation at both GLP-1R and GIPR transmembrane cores. Aib introduction would be expected to provide an orthogonal, lipidation-independent layer of proteolytic protection.\n\nFrom a conformational standpoint, Aib is a well-known helix-inducing residue due to its constrained φ/ψ angles (approximately −60°, −30°), and its placement at position 2 of an α-helical incretin peptide is structurally consistent with stabilizing the N-terminal helix. The literature on related peptides (GLP-1, exendin-4, GIP analogues) supports that Aib at position 2 does not abolish receptor activation, though some analogues show modestly altered potency depending on the specific receptor and assay system. For tirzepatide specifically, the receptor-bound cryo-EM structures (published 2022–2023, not in this abstract set) show the N-terminal residues inserting into the transmembrane bundle of both GLP-1R and GIPR, suggesting that the Cα-methyl of Aib-2 must be accommodated without steric clash in both receptor binding pockets.\n\nThe retrieved clinical literature, while of high quality (multiple phase 3 RCTs), is entirely focused on clinical outcomes (weight, HbA1c, MASH, sleep apnea) and does not provide mechanistic data on DPP-4 degradation kinetics, structure-activity relationships, or conformational pharmacology of tirzepatide analogues. The hypothesis is therefore scientifically plausible based on principles established in the broader incretin analogue literature, but direct experimental validation for the specific tirzepatide Aib-2 variant is absent from the available evidence base."},"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 is that tirzepatide is a highly effective dual GIP/GLP-1 receptor agonist with a well-established clinical profile driven by its intact N-terminal pharmacophore and C20 fatty diacid-mediated albumin binding. Its once-weekly dosing already reflects substantial metabolic stability, primarily from lipidation rather than DPP-4 resistance. There is no published literature in this abstract set — and very little in the broader public domain — specifically evaluating Aib-2 substitution in tirzepatide or addressing its DPP-4 cleavage kinetics in detail. The general incretin field consensus (from GLP-1 and GIP analogue work) supports that Aib at position 2 blocks DPP-4 cleavage and can maintain or modestly alter receptor potency, but this has not been directly tested for the tirzepatide scaffold with its unique dual-receptor binding geometry.","knowledge_gaps":"Several critical gaps exist: (1) No published data on DPP-4 cleavage rates for tirzepatide specifically — the fractional contribution of DPP-4 proteolysis to tirzepatide inactivation in vivo relative to renal/hepatic clearance is not quantified in the available literature. (2) No structural data (cryo-EM or X-ray) on how Aib-2 would be accommodated in the GIPR transmembrane bundle specifically — GLP-1R structural tolerance for Aib-2 has some precedent, but GIPR binding pocket geometry at this position is less characterized. (3) The relative importance of DPP-4 resistance versus albumin-binding half-life extension for tirzepatide PK has not been dissected — it is unknown whether Aib-2 provides meaningful additional in vivo stability beyond the C20 diacid. (4) Whether the Cα-methyl of Aib-2 causes steric clash with either receptor's orthosteric binding site in the context of the full tirzepatide sequence (which differs from native GLP-1 or GIP) is uncharacterized. (5) No published SAR data on any tirzepatide N-terminal analogues appear in the retrieved literature.","supporting_evidence":"The hypothesis is supported by: (1) Well-established precedent in the incretin analogue literature that Aib at position 2 of GLP-1 and related peptides abolishes DPP-4 cleavage (Aib is not a DPP-4 substrate due to Cα,α-disubstitution sterically blocking the active site). (2) Tirzepatide's clinical superiority over semaglutide (SURPASS-2, SURMOUNT series) confirms robust dual GIP/GLP-1R engagement that provides a high-activity baseline to preserve. (3) The Aib residue's known helix-capping and α-helix-stabilizing properties are structurally consistent with the requirement for an ordered N-terminal helix in incretin receptor engagement. (4) The weight regain data upon discontinuation (SURMOUNT-4, meta-analysis) motivate development of longer-acting/more stable variants, providing clinical rationale for improved enzymatic stability. (5) The C20 diacid on Lys-20 is on the C-terminal half of the molecule and is unlikely to sterically interfere with the N-terminal Aib-2 modification, suggesting the two stability-enhancing elements are structurally orthogonal.","challenging_evidence":"Several factors challenge or complicate the hypothesis: (1) Tirzepatide already has a ~5-day half-life driven by the C20 diacid/albumin binding; the marginal in vivo benefit of additional DPP-4 resistance at position 2 is uncertain and may be pharmacokinetically negligible at steady-state weekly dosing. (2) The Cα-methyl group of Aib introduces a steric constraint (restricted φ/ψ) that, while helix-stabilizing in isolation, may alter the precise N-terminal binding geometry within the GIPR transmembrane bundle — GIPR is known to have a narrower orthosteric binding pocket than GLP-1R, potentially penalizing the added methyl group. (3) None of the retrieved papers provide any direct mechanistic, structural, or pharmacological data on tirzepatide N-terminal analogues, meaning the hypothesis rests entirely on extrapolation from other incretin scaffolds rather than tirzepatide-specific evidence. (4) The GIP component of tirzepatide's activity depends on a GIP-derived N-terminus (Tyr-Ala-Glu-Gly...) that has been optimized for balanced dual agonism; any perturbation at position 2 may disproportionately affect GIPR relative to GLP-1R potency, potentially shifting the dual-agonist balance in unpredictable ways. (5) The preprint and clinical literature highlight gastrointestinal tolerability as a key limitation of tirzepatide; if Aib-2 increases peptide stability and effective exposure, it could amplify GI adverse effects without a compensating benefit in a molecule already showing strong clinical efficacy."},"caveats":["In silico prediction only — requires wet lab validation","Single-run prediction (not ensembled); ipTM 0.13 is insufficient to assess receptor engagement — ensemble complex runs required","Predicted properties may not reflect real-world biological behavior","This is research, not medical advice","DPP-4 resistance prediction is made on chemical first principles (Cα,α-disubstitution), not from structural output — the actual fractional contribution of DPP-4 to tirzepatide inactivation in vivo is unknown","GIPR binding pocket tolerance for Aib-2 Cα-methyl is uncharacterized; GIPR orthosteric cavity may be narrower than GLP-1R and penalize the added methyl group","Heuristic property estimates (aggregation 0.195, stability 0.54, half-life, BBB) are sequence-based approximations, not experimental measurements","Marginal PK benefit of Aib-2 above the existing C20 diacid (~5-day half-life) is uncertain and may be pharmacokinetically negligible at steady-state weekly dosing","No tirzepatide-specific Aib-2 SAR data exist in the published literature; hypothesis rests on extrapolation from GLP-1 and GIP analogue precedents","Chai-1 agreement not available for this fold; inter-model consensus on the complex is absent"],"works_cited":[{"pmid_or_doi":"34170647","title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","year":2021,"relevance":"Establishes tirzepatide's superior dual GLP-1R/GIPR agonism profile versus selective GLP-1RA semaglutide, confirming that the intact N-terminal pharmacophore supports both receptor axes; provides the clinical efficacy baseline against which any analogue (e.g., Aib-2) must be benchmarked."},{"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 GIP/GLP-1 receptor agonist; relevant as a pharmacological reference point for the unmodified molecule whose dual agonism the Aib-2 variant must preserve."},{"pmid_or_doi":"38078870","title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial","year":2024,"relevance":"Demonstrates that sustained tirzepatide activity (not just acute dosing) is required for weight maintenance, underscoring the importance of long-term molecular stability — the core rationale for the Aib-2 proteolytic protection strategy."},{"pmid_or_doi":"39536238","title":"Tirzepatide for Obesity Treatment and Diabetes Prevention","year":2025,"relevance":"Long-term (176-week) efficacy data confirm durable GLP-1R/GIPR agonism; relevant because improved enzymatic stability from Aib-2 would theoretically extend the duration of the active N-terminal pharmacophore, potentially enhancing durability."},{"pmid_or_doi":"37940101","title":"The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception","year":2024,"relevance":"Describes tirzepatide's pharmacokinetic and gastric-emptying profile, noting tachyphylaxis after initial doses; relevant context for understanding the PK environment in which DPP-4 stability improvements would operate."},{"pmid_or_doi":"40186344","title":"Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis","year":2025,"relevance":"Documents rapid weight regain upon GLP-1RA/tirzepatide discontinuation, highlighting the need for improved molecular stability and durability of action — the motivating rationale for the Aib-2 modification."},{"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 15 mg as the most effective GLP-1R/GIPR co-agonist for fat mass reduction, establishing the benchmark pharmacological activity that the Aib-2 analogue must match or exceed."},{"pmid_or_doi":"38856224","title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","year":2024,"relevance":"Demonstrates pleiotropic GLP-1R/GIPR-mediated effects beyond glycemia and weight, suggesting the breadth of receptor engagement that must be preserved in any tirzepatide analogue including the Aib-2 variant."}]},"onchain":{"hash":"4ZJcc33ZVwVayKnT7syzjSB7pYcnGxLhxmKcSuJaykciqrcs81Dmcuy5mnJReoAkHf2JYvC3pto5xcZMmG2kh4Kt","signature":"4ZJcc33ZVwVayKnT7syzjSB7pYcnGxLhxmKcSuJaykciqrcs81Dmcuy5mnJReoAkHf2JYvC3pto5xcZMmG2kh4Kt","data_hash":"3d1aecb61d740fb2057eb081e64f98bc7b8298933c874d60eecdf8ff43442dab","logged_at":"2026-05-03T10:01:44.394729+00:00","explorer_url":"https://solscan.io/tx/4ZJcc33ZVwVayKnT7syzjSB7pYcnGxLhxmKcSuJaykciqrcs81Dmcuy5mnJReoAkHf2JYvC3pto5xcZMmG2kh4Kt"},"ipfs_hash":null,"created_at":"2026-05-03T09:56:14.612686+00:00","updated_at":"2026-05-03T10:01:44.396744+00:00"}