{"id":73,"slug":"73-tirzepatide-c-terminal-extension-by-one-residue-append-lys-40-bearing-a-","title":"C-terminal Lys-40 γGlu-C20 diacid extension on Tirzepatide for prolonged albumin tethering","status":"PROMISING","fold_verdict":"PROMISING","discard_reason":null,"peptide":{"name":"Tirzepatide","class":"METABOLIC","sequence":"YAEGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPS","modified_sequence":"YAEGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPSK","modification_description":"C-terminal extension by one residue: append Lys-40 bearing a γGlu spacer and C20 fatty diacid (eicosanedioic acid) on its ε-amine, yielding ...PPPS-K(γGlu-C20-diacid)-OH. Native Lys-20 lipidation (γGlu-γGlu-C20 diacid) and all other residues are preserved."},"target":{"protein":"Glucagon-like peptide 1 receptor","uniprot_id":"P43220","chembl_id":"CHEMBL1784","gene_symbol":"GLP1R"},"rationale":{"hypothesis":"Adding a second albumin-binding anchor — a C-terminal Lys-40 conjugated to a C20 fatty diacid via a γGlu spacer — will further extend Tirzepatide's plasma half-life beyond what native Lys-20 lipidation alone achieves by enabling bivalent albumin engagement. Because the C-terminal PPPS tail is disordered and projects away from both the ECD and TMD interfaces of GLP-1R/GIPR, the second lipid should not interfere with receptor binding while doubling the effective albumin avidity.","rationale":"Sister-peptide Retatrutide fold #45 showed PROMISING (pLDDT 0.70) results with the same C-terminal lipidation strategy on the homologous PPPS tail, validating that the disordered C-terminus tolerates lipid conjugation without disrupting class B GPCR engagement. The C20 diacid (vs. Retatrutide's C18) matches Tirzepatide's existing chemistry for synthetic and PK consistency. This proposal diverges from the last 3 folds: PHARMACOKINETICS focus has not appeared in folds #70-72 (which were AFFINITY, DELIVERY, AFFINITY), and Lipidation as a category has not appeared in the last 3 folds either. It also avoids the failure mode of fold #63 (i,i+4 lactam in the central helix DISCARDED) and the AlphaFold-blind chemistries warned against for class B GPCRs (no Aib, no staple, no α-methyl AAs).","predicted_outcome":"Boltz-2/Chai-1 should predict a well-folded central amphipathic helix engaging GLP-1R's TMD with the canonical N-terminal Tyr-1 insertion, with both Lys-20 and the new Lys-40 lipid chains projecting into solvent away from the receptor interface. Expected pLDDT ≥0.70 at the receptor-binding core; the C-terminal Lys-40 region should remain disordered/flexible (low pLDDT locally is expected and acceptable) without distorting the helical pharmacophore.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.7161431312561035,"ptm":0.6601677536964417,"iptm":0.09623834490776062,"chai_agreement":null,"chai1_gated_decision":"SKIPPED_HIGH_CONFIDENCE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.222,"stability_score":0.627,"bbb_penetration_score":0.037,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":"Fold №73 appends a C-terminal Lys-40 bearing a γGlu-C20 fatty diacid to Tirzepatide's native PPPS tail, hypothesizing that a second albumin anchor will extend plasma half-life beyond the ~5-day native value through bivalent albumin engagement. The structural prediction returns a moderate overall confidence (pLDDT 0.72) consistent with retention of the central amphipathic helix, but the receptor interface is poorly resolved (ipTM 0.096), preventing confirmation of canonical GLP-1R TMD engagement. The heuristic profile suggests low aggregation propensity and a long half-life estimate, lending qualified support to the pharmacokinetic rationale. This fold is scored PROMISING — the signal is real but insufficient to confirm receptor-binding preservation without higher-resolution interface data.","detailed_analysis":"Tirzepatide is a 39-residue dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity, distinguished from earlier incretin mimetics by its balanced dual-agonism and a C20 fatty diacid conjugated via a γGlu-γGlu spacer to Lys-20, which drives tight reversible albumin binding and yields a plasma half-life of approximately five days — sufficient for once-weekly subcutaneous dosing. The PPPS C-terminal tail (residues 36–39) is understood to be disordered in solution and in receptor-bound cryo-EM structures of homologous class B GPCRs, projecting away from both the extracellular domain and transmembrane domain interfaces that mediate GLP-1R and GIPR pharmacology. This structural context motivates the hypothesis that the C-terminus is a pharmacologically permissive site for additional lipid conjugation.\n\nFold №73 extends Tirzepatide by one residue — appending Lys-40 C-terminally — and decorates its ε-amine with a γGlu spacer and C20 fatty diacid (eicosanedioic acid), deliberately matching the chain length of the native Lys-20 lipidation for synthetic and physicochemical consistency. The design intent is bivalent albumin engagement: two fatty acid anchors on the same molecule could in principle increase the effective albumin-binding avidity, slowing renal clearance and proteolytic exposure and pushing the half-life meaningfully beyond five days — potentially enabling bi-weekly or monthly dosing formats that are not achievable with the native molecule. The γGlu (rather than γGlu-γGlu) spacer at Lys-40 is intentionally shorter than the native Lys-20 linker, providing spatial differentiation between the two anchors.\n\nThe structural prediction (Boltz-2) returns a peptide-level pLDDT of 0.716, which falls into the moderate-confidence band and is consistent with a folded amphipathic helix being predicted for the pharmacophore core while the C-terminal extension remains locally disordered — the expected and acceptable outcome given the flexible PPPS-K tail. The pTM of 0.66 suggests that the overall topology of the full peptide is reasonably well-predicted, and the heuristic aggregation propensity of 0.222 is reassuringly low, which matters for a molecule carrying two large lipid-linker conjugates that could in principle drive self-association or peptide bridging of albumin molecules. The critical weakness of this prediction is the ipTM of 0.096, which is very low and reflects the known difficulty of Boltz-2 in resolving the complex interface between a short peptide and a large class B GPCR transmembrane bundle. This does not indicate a predicted failure of receptor engagement — it indicates that the tool cannot adjudicate the interface at this resolution for this target class.\n\nThe laboratory context strongly supports this fold. Retatrutide Fold №45 applied the same conceptual strategy — C-terminal Lys-40 with γGlu-C18 diacid on the PPPS tail — and returned PROMISING (pLDDT 0.70), establishing the template that the disordered C-terminus of PPPS-tail incretins tolerates lipid conjugation without distorting the helical pharmacophore. Fold №73 advances on that precedent by applying the strategy to Tirzepatide with a C20 (rather than C18) chain to match native chemistry, yielding a slightly higher pLDDT (0.716 vs 0.70) and consistent heuristic stability. Fold №63, which attempted an i,i+4 lactam staple in Tirzepatide's central helix, was DISCARDED — a failure mode explicitly avoided here by confining the modification to the disordered C-terminus. Folds №23 and №31 explored non-canonical residue substitutions in Tirzepatide's helix (αMe-Cys-24, Aib-2) and returned PROMISING results, confirming that the Tirzepatide helical core is structurally robust to perturbation; the current fold does not touch that core.\n\nFrom a biological significance standpoint, the bivalent albumin-binding concept is well-motivated but not yet experimentally validated for incretin peptides. The GLP-1 analog precedent (liraglutide C16 ~13 h → semaglutide C18 diacid ~7 days → tirzepatide C20 diacid ~5 days) demonstrates that longer and more polar fatty acid chains correlate with extended half-life, but the mechanism is single-anchor albumin binding with varying affinity and off-rate. Whether a second anchor on the same molecule acts additively, synergistically, or instead drives inter-molecular albumin bridging and aggregation is an open experimental question. The clinical motivation is real but modest: tirzepatide's current half-life is already sufficient for once-weekly dosing with strong clinical outcomes, so further extension would serve niche use cases (adherence, bi-weekly convenience) rather than addressing a critical gap.\n\nThe most significant biological uncertainty is whether the C-terminal Lys-40 region, despite being distal to the GLP-1R TMD interface, could perturb GIPR engagement. Tirzepatide's C-terminal residues (approximately 30–39) are understood to participate in contacts with GIPR's extracellular loops and ECD in its dual-agonist binding mode, and the addition of a bulky lipid-linker at position 40 — even one residue beyond the native C-terminus — could sterically compete with or alter the orientation of those C-terminal contacts. This is a genuine gap that in silico predictions cannot resolve.\n\nIn summary, Fold №73 presents a chemically logical, precedent-supported pharmacokinetic modification of Tirzepatide with a moderate structural confidence signal and a favorable heuristic property profile. The PROMISING verdict reflects a real but incomplete signal: the helical core appears intact, the C-terminal extension is appropriately disordered, and the heuristic aggregation risk is low — but the interface ipTM is too weak to confirm receptor engagement, and the bivalent albumin hypothesis requires dedicated experimental validation. This fold is a credible candidate for in vitro pharmacokinetic and receptor-binding follow-up, not a confirmed advance.","executive_summary":"Tirzepatide Fold №73 adds a second C20 fatty diacid anchor at a new C-terminal Lys-40, targeting bivalent albumin binding for extended half-life. pLDDT 0.72 supports an intact helical core; ipTM 0.096 leaves the receptor interface unresolved. PROMISING — the PK rationale is sound, but albumin-binding and receptor assays are needed.","tweet_draft":"DISTILLATION №73 — promising.\nTirzepatide + C-terminal Lys-40 γGlu-C20 diacid: bivalent albumin anchor hypothesis.\npLDDT 0.72 | ipTM 0.096 | aggregation risk low.\nBuilds on Retatrutide fold №45 precedent.\nIn silico only. Full report: alembic.bio","research_brief_markdown":"# Fold №73 — Tirzepatide C-terminal Lys-40 γGlu-C20 Diacid Extension\n**Verdict: PROMISING** | Class: METABOLIC | Target: GLP-1R (P43220) / GIPR\n\n---\n\n> **Mandatory disclaimer:** All findings are in silico predictions only. No wet-lab validation has been performed. Predicted properties do not constitute evidence of real-world biological activity. This is research, not medical advice.\n\n---\n\n## Mechanism of Action\n\nTirzepatide is a 39-residue dual GIP/GLP-1 receptor agonist that engages two class B GPCRs: GLP-1R, driving insulin secretion and satiety, and GIPR, which augments the GLP-1R signal and contributes to the superior weight-loss profile observed in clinical trials (SURPASS, SURMOUNT series). The pharmacophore is an amphipathic α-helix spanning roughly residues 1–29, with N-terminal Tyr-1 insertion into the GLP-1R TMD orthosteric pocket as the canonical activation mechanism. The native C20 fatty diacid conjugated via a γGlu-γGlu spacer to Lys-20 binds reversibly to human serum albumin, dramatically reducing renal clearance and proteolytic exposure to yield a plasma half-life of approximately five days and enabling once-weekly subcutaneous dosing.\n\nThe C-terminal PPPS tail (residues 36–39) is structurally disordered in solution and in cryo-EM structures of homologous class B GPCR incretin complexes, projecting away from both the ECD and TMD interfaces. This disorder is well-established for GLP-1 and semaglutide receptor complexes in the broader class B literature and is the structural premise underlying the C-terminal lipidation strategy.\n\n---\n\n## Performance Applications\n\nThis modification targets **pharmacokinetic extension** rather than acute receptor potency. The primary application space is:\n\n- **Extended dosing interval:** A substantially longer half-life (targeting >7–10 days vs. native ~5 days) could enable bi-weekly or potentially monthly subcutaneous injection formats, addressing adherence barriers in chronic metabolic disease management.\n- **Obesity and MASH pharmacotherapy:** The clinical evidence base for tirzepatide in obesity (SURMOUNT) and MASH is strong; longer-acting formats could improve real-world adherence in these chronic indications where treatment discontinuation rates are high.\n- **Comparator to semaglutide PK:** Semaglutide achieves ~7 days via a C18 fatty diacid/mini-PEG/γGlu linker; a bivalent-anchor tirzepatide analog could, in principle, meet or exceed semaglutide's PK profile while preserving the dual-agonist pharmacology that drives superior weight loss.\n\nNote: Tirzepatide's current once-weekly dosing already satisfies clinical needs in approved indications. The incremental benefit of further half-life extension is real but targets convenience optimization rather than unmet medical need.\n\n---\n\n## Modification Rationale\n\nThe modification appends a single Lys-40 residue C-terminally to the native PPPS tail, conjugating a γGlu spacer and C20 fatty diacid (eicosanedioic acid) to its ε-amine. Key design decisions:\n\n- **C20 chain length:** Matches the native Lys-20 lipidation chemistry (also C20 diacid), minimizing synthetic novelty and maintaining physicochemical consistency. This contrasts with Retatrutide Fold №45, which used a C18 chain on the same conceptual scaffold — the C20 choice here is deliberate for Tirzepatide-specific synthetic integration.\n- **γGlu (single) spacer at Lys-40:** The native Lys-20 uses a γGlu-γGlu (double) spacer; using a single γGlu at Lys-40 provides spatial differentiation between the two anchors, potentially reducing the risk of intramolecular steric conflict between the two lipid chains while still providing sufficient linker flexibility for albumin engagement.\n- **C-terminal positioning:** The PPPS tail is the most chemically permissive region of the peptide. Fold №63 (Tirzepatide, i,i+4 lactam in the central helix) was DISCARDED (pLDDT 0.69) due to tool-limit failure on helix-perturbing chemistry — the C-terminal strategy deliberately avoids that failure mode.\n- **Retatrutide precedent:** Fold №45 applied the same conceptual framework to Retatrutide (C-terminal Lys-40, γGlu-C18 diacid) and returned PROMISING (pLDDT 0.70), validating that the PPPS tail of incretin peptides tolerates lipid conjugation without disrupting the helical pharmacophore in structural prediction.\n\n---\n\n## Predicted Properties — Where the Signal Is Moderate\n\n| Metric | Value | Interpretation |\n|---|---|---|\n| pLDDT (peptide) | 0.716 | Moderate confidence; consistent with intact helical core + disordered C-terminus |\n| pTM | 0.660 | Moderate; overall peptide topology reasonably predicted |\n| ipTM | 0.096 | Very low; GLP-1R interface not resolved by Boltz-2 at this target class |\n| Chai-1 agreement | Not available | Single-model prediction; ensemble uncertainty unquantified |\n| Aggregation propensity (heuristic) | 0.222 | Low; favorable for a dual-lipidated molecule |\n| Stability score (heuristic) | 0.627 | Moderate-to-good |\n| Half-life estimate (heuristic) | Long (>6 h, modification-dependent) | Consistent with extended PK rationale |\n| BBB penetration (heuristic) | 0.037 | Negligible; appropriate for a peripheral metabolic agent |\n\n**Where the PROMISING signal is genuine:**\n- pLDDT of 0.716 is consistent with the helical pharmacophore being well-folded in the model, matching the predictions for Retatrutide Fold №45 (0.70) and Tirzepatide Folds №23 and №31 (both 0.71).\n- Low aggregation propensity (0.222) is encouraging given the dual-lipidation burden — two C20 fatty acid chains on the same 40-residue peptide create real self-association risk that the heuristic does not flag.\n- The heuristic long half-life estimate is consistent with — though not quantitatively predictive of — the bivalent albumin hypothesis.\n\n**Where the signal is weak:**\n- The ipTM of 0.096 means that GLP-1R TMD engagement, including the canonical Tyr-1 insertion, cannot be confirmed from this prediction. This is a known limitation of Boltz-2 for class B GPCR peptide-receptor complexes and reflects tool resolution rather than a predicted binding failure — but it leaves the receptor pharmacology hypothesis unvalidated.\n- Lipid conjugates are not explicitly modeled; both Lys-20 and Lys-40 sidechain positions appear solvent-exposed, which is consistent with the hypothesis, but the albumin-binding geometry of the dual-anchor configuration cannot be assessed in silico.\n- No Chai-1 ensemble data are available; single-model predictions carry higher uncertainty.\n\n---\n\n## What Would Strengthen This Signal\n\n**Additional computational work:**\n- **Ensemble prediction (Chai-1 multi-seed):** Run 5+ seeds to assess structural convergence of the helical core and variability of the C-terminal tail disposition. Retatrutide Fold №45 would benefit from the same treatment as a direct comparator.\n- **Explicit albumin co-fold:** Model the dual-lipidated Tirzepatide in complex with human serum albumin (HSA, PDB 1AO6 fatty acid binding sites) using AlphaFold-Multimer or Boltz-2 multimer mode to assess whether both anchors simultaneously engage albumin or compete stereoelectronically.\n- **Free energy perturbation (FEP) or MM-GBSA:** Estimate relative albumin-binding affinity of single-anchor (native) vs. dual-anchor analog — this is the most direct computational test of the bivalent PK hypothesis.\n- **Molecular dynamics simulation:** Assess conformational stability of the PPPS-K(γGlu-C20) tail and its impact on receptor-proximal residues over nanosecond timescales.\n\n**Wet-lab validation experiments:**\n- **SPR or ITC against human serum albumin:** Measure Kd and off-rate for native Tirzepatide vs. Fold №73 analog — direct test of whether dual lipidation increases albumin affinity.\n- **GLP-1R and GIPR cAMP assay (HEK293 or CHO overexpression):** Quantify EC50 for both receptors; critical to confirm that the Lys-40 C-terminal lipid does not perturb GIPR C-terminal engagement.\n- **In vitro DPP-4 stability assay:** Confirm that the C-terminal modification does not indirectly alter proteolytic susceptibility at the N-terminal scissile bond.\n- **Pharmacokinetic study in rodents or NHP:** The definitive test — plasma half-life measurement for dual-anchor vs. native Tirzepatide is the only way to confirm the bivalent albumin hypothesis experimentally.\n- **SEC or DLS aggregation assay:** Assess self-association of the dual-lipidated analog, particularly at concentrations relevant to subcutaneous injection formulation.\n\n**Key comparator experiment:** Synthesize the Retatrutide Fold №45 analog (γGlu-C18 diacid at Lys-40) and the Tirzepatide Fold №73 analog (γGlu-C20 diacid at Lys-40) in parallel and run head-to-head albumin-binding and receptor-activation assays — this would validate the cross-peptide PPPS-tail lipidation strategy as a generalizable platform.\n\n---\n\n## Lab Context & Cross-Fold Connections\n\nThis fold is part of a developing Tirzepatide medicinal chemistry series at Alembic Labs:\n\n- **Fold №45 (Retatrutide)** — the direct structural precedent: C-terminal Lys-40 γGlu-C18 diacid on the homologous PPPS tail, PROMISING (pLDDT 0.70). Fold №73 advances this to Tirzepatide with a C20 chain for chemistry consistency, returning an equivalent PROMISING verdict with slightly higher pLDDT (0.716).\n- **Fold №63 (Tirzepatide, DISCARDED)** — the cautionary precedent: i,i+4 lactam staple in the central helix was DISCARDED (pLDDT 0.69) due to AlphaFold-blind crosslink chemistry. Fold №73 explicitly avoids helix-perturbing modifications.\n- **Folds №23 and №31 (Tirzepatide, both PROMISING, pLDDT 0.71)** — non-canonical substitutions (αMe-Cys-24, Aib-2) in the helical core returned consistent moderate-confidence predictions, establishing the baseline pLDDT range for this peptide scaffold. Fold №73 falls within this established range, suggesting the C-terminal modification does not degrade the global structural prediction.\n- **Fold №54 (Retatrutide, REFINED)** — Lys-17/Asp-21 lactam in the central helix returned REFINED (pLDDT 0.71), confirming that the incretin helix is a productive target for conformational pre-organization; however, this strategy targets potency rather than PK, and Fold №73 occupies the complementary pharmacokinetic space.\n\nThe emerging Alembic Labs narrative for Tirzepatide modifications is: the helical core is structurally robust to non-canonical substitutions at positions 2 and 24 (Folds №23, 31), the helix is not tolerant of crosslinking chemistry visible to AlphaFold (Fold №63), and the PPPS C-terminus is a permissive site for lipid conjugation (Fold №73, consistent with Fold №45 for Retatrutide). The next logical step in this series is a triple-combination analog combining Aib-2 (DPP-4 resistance, Fold №31) with C-terminal lipidation (Fold №73) to address both enzymatic stability and PK extension simultaneously.","structural_caption":"The predicted structure shows tirzepatide with the C-terminal Lys-40 extension folding with moderate overall confidence (pLDDT 0.72), consistent with retention of the central amphipathic helix. However, the receptor interface is poorly resolved (ipTM 0.096), meaning the canonical GLP-1R TMD engagement with N-terminal Tyr-1 insertion cannot be confirmed from this prediction. The C-terminal PPPS-K(lipid) tail is expected to be disordered, which is consistent with the hypothesis but also contributes to uncertainty in the interface placement. Both Lys-20 and Lys-40 sidechain positions appear solvent-exposed in the model, but lipid conjugates are not explicitly modeled.","key_findings_summary":"Tirzepatide is a well-characterized dual GIP/GLP-1 receptor agonist that achieves once-weekly dosing through a C20 fatty diacid conjugated via a γGlu-γGlu spacer to Lys-20, enabling tight albumin binding and a reported plasma half-life of approximately 5 days. The clinical literature is dominated by large Phase 3 trials (SURPASS, SURMOUNT series) demonstrating robust glycemic and weight-loss efficacy, but none of the retrieved abstracts address the molecular pharmacology of tirzepatide's lipidation chemistry, albumin-binding mechanism, or the structural biology of its receptor-bound conformations. The hypothesis under evaluation — that appending a second albumin-binding moiety (C20 fatty diacid via γGlu on a C-terminal Lys-40) could extend half-life beyond the ~5-day native value through bivalent albumin engagement — is therefore not directly testable from this literature set.\n\nThe structural rationale invoked in the hypothesis (the C-terminal PPPS tail being disordered and projecting away from both GLP-1R ECD and TMD interfaces) is consistent with published cryo-EM and HDX-MS data for class B GPCR incretin complexes in the broader GLP-1R/GIPR field, though none of the retrieved papers provide this structural evidence directly for tirzepatide. The clinical data do confirm that tirzepatide's current half-life is sufficient for once-weekly dosing and that the drug is highly efficacious across multiple indications (T2D, obesity, MASH, OSA), suggesting there is no obvious clinical unmet need for further half-life extension in the approved molecule — though bi-weekly or monthly dosing formats could be enabled by a genuinely extended half-life analog.\n\nThe mechanism by which fatty acid–albumin association prolongs peptide half-life is well-established in the GLP-1 agonist class: semaglutide uses a C18 fatty diacid/mini-PEG/γGlu linker to achieve ~7-day half-life, while tirzepatide's C20 diacid linker at Lys-20 achieves ~5 days. Bivalent albumin engagement as a strategy for further half-life extension has been explored in the antibody and small-molecule albumin-binding domain literature, but this concept has not been demonstrated or refuted for incretin peptides in the retrieved literature. The relevant pharmacokinetic and structural work needed to evaluate this hypothesis exists in the primary medicinal chemistry and structural biology literature for GLP-1 analogs, which is not represented in these abstracts.\n\nFrom a safety and tolerability standpoint, the clinical literature shows that tirzepatide's dominant adverse effects are GI (nausea, vomiting, gastric retention, delayed gastric emptying), weight-loss related (lean mass loss, starvation ketosis in misuse contexts), and drug interaction related (reduced oral contraceptive bioavailability). A C-terminal lipid extension would not be expected to alter the receptor pharmacology that drives these effects, but could conceivably alter the GI absorption kinetics or local injection-site depot formation. None of the retrieved papers address these questions for any modified tirzepatide."},"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":"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":"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":"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, in its native form with a single C20 fatty diacid lipidation at Lys-20, is a highly effective dual GIP/GLP-1 receptor agonist with a ~5-day half-life enabling once-weekly subcutaneous dosing. The clinical evidence base is extensive and robust. However, the literature retrieved here contains no studies on the structural pharmacology of tirzepatide's albumin-binding mechanism, no bivalent albumin-binding peptide studies, and no medicinal chemistry work on C-terminal modifications of tirzepatide. The consensus on extending half-life of fatty-acid–conjugated peptides in the GLP-1 class is that this is achievable through longer or branched fatty acid chains and optimized linkers (as exemplified by semaglutide vs. liraglutide), but the concept of dual/bivalent albumin anchoring within a single peptide has not been validated or refuted in the incretin field by the available literature.","knowledge_gaps":"The retrieved literature does not address: (1) the structural basis for tirzepatide's albumin interaction and how Lys-20 lipidation positions relative to the receptor-bound conformation; (2) whether bivalent or multivalent albumin binding is achievable with two lipid anchors on the same peptide and whether this translates to additive or synergistic half-life extension versus simple avidity effects; (3) the conformational behavior of the native C-terminal PPPS tail in solution and in receptor-bound states for tirzepatide specifically — the hypothesis assumes disorder, but no tirzepatide-specific cryo-EM data are cited; (4) how a C-terminal lipid anchor would affect subcutaneous depot pharmacokinetics, local tolerability, and injection-site absorption; (5) whether the C-terminal Lys-40 addition would alter GIPR engagement, which has a distinct ECD-binding mode from GLP-1R; and (6) the impact of a second bulky lipid-linker on peptide aggregation, solubility, and formulation stability.","supporting_evidence":"Indirect support for the hypothesis comes from: (1) the precedent that longer/more hydrophobic fatty acid chains on GLP-1 analogs (C16 liraglutide ~13 h → C18 semaglutide ~7 days) correlate with extended half-life, suggesting that increasing albumin-binding avidity via a second anchor could further extend half-life beyond the ~5 days of tirzepatide's C20 lipidation; (2) the clinical data showing weight regain upon tirzepatide discontinuation, which motivates interest in longer-acting or bi-weekly/monthly formats achievable only with substantially extended half-lives; (3) the structural logic that the C-terminal tail of incretin peptides is generally disordered in cryo-EM structures of GLP-1R complexes (established for GLP-1 and semaglutide analogs in the broader class B GPCR literature, though not directly cited here), which would be consistent with the C-terminus being a tolerable site for lipid conjugation without steric clash at receptor interfaces.","challenging_evidence":"Several considerations challenge or complicate the hypothesis: (1) No retrieved paper demonstrates bivalent albumin engagement by any peptide with two fatty acid anchors, and there is a theoretical risk that two anchors on the same molecule could drive peptide dimerization or aggregation via bridging albumin molecules rather than increasing single-molecule half-life; (2) The GIPR ECD binding mode for tirzepatide's N-terminal GIP pharmacophore is structurally distinct from GLP-1R, and the C-terminal region of the peptide (residues 30–39 in native tirzepatide) makes contacts with GIPR's extracellular loops and ECD — a Lys-40 extension bearing a bulky C20 diacid could potentially perturb these C-terminal GIPR contacts even if GLP-1R binding is spared; (3) Tirzepatide already achieves once-weekly clinical dosing with favorable efficacy, so the marginal benefit of further half-life extension must be weighed against additional synthetic complexity, potential immunogenicity of a more lipidated molecule, and risk of narrowed therapeutic index (as illustrated by the starvation ketosis case report); (4) The gastric emptying delay that underlies tirzepatide's drug interactions and GI side effects is receptor-mediated and would not be altered by a pharmacokinetic modification, but a longer half-life could extend the duration of these adverse effects and worsen drug interaction risks (oral contraceptive absorption); (5) All retrieved clinical evidence pertains to the native molecule — there are no analog comparison or PK modeling data in this set to validate the bivalent albumin hypothesis quantitatively."},"caveats":["in silico prediction only — requires wet-lab validation","single-run prediction (not ensembled); Chai-1 multi-seed data unavailable for this fold","predicted properties may not reflect real-world biological behavior","this is research, not medical advice","ipTM of 0.096 means GLP-1R and GIPR interface geometry cannot be confirmed — receptor pharmacology is inferred from structural analogy, not predicted binding mode","lipid conjugates (γGlu-C20 diacid on Lys-20 and Lys-40) are not explicitly modeled in the structural prediction; sidechain solvent exposure is inferred, not computed","bivalent albumin engagement hypothesis has not been demonstrated experimentally for any incretin peptide; dual-anchor configuration could alternatively drive inter-molecular albumin bridging or peptide aggregation","heuristic half-life estimate (>6 h) is sequence-based and does not model albumin binding kinetics, subcutaneous depot pharmacokinetics, or the specific contribution of the second lipid anchor","potential perturbation of GIPR C-terminal ECD contacts by Lys-40 extension cannot be assessed from this prediction","aggregation propensity score (0.222) is a heuristic estimate — empirical DLS/SEC validation is required for a dual-lipidated molecule at formulation-relevant concentrations"],"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 agonist with once-weekly dosing, providing the baseline pharmacological context against which any half-life–extending modification would 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 the efficacy and tolerability of native tirzepatide, relevant as a comparator for any modified analog."},{"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 tirzepatide's effects require continuous treatment and reverse upon discontinuation, motivating interest in longer-acting formulations."},{"pmid_or_doi":"39536238","title":"Tirzepatide for Obesity Treatment and Diabetes Prevention","year":2025,"relevance":"Long-term (176-week) data confirm sustained efficacy of native tirzepatide, providing context for the clinical value of any half-life–extending modification."},{"pmid_or_doi":"40186344","title":"Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis","year":2025,"relevance":"Meta-analysis showing substantial weight regain after GLP-1RA discontinuation (~9.69 kg for semaglutide/tirzepatide), highlighting the therapeutic rationale for longer-acting or depot-forming analogs."},{"pmid_or_doi":"37940101","title":"The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception","year":2024,"relevance":"Documents tirzepatide's PK interactions via gastric emptying delay, illustrating that modifications affecting systemic exposure duration could have downstream drug-interaction implications."},{"pmid_or_doi":"38856224","title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","year":2024,"relevance":"Expanding therapeutic indications for tirzepatide underscore the clinical interest in optimizing its formulation, including half-life, for chronic disease management."},{"pmid_or_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","year":2026,"relevance":"Preprint case report illustrating risks of prolonged appetite suppression; a longer half-life analog could amplify such risks if the dose-response window narrows."}]},"onchain":{"hash":"EFr8mgd2PseuejUuWwrkUccKhFscmADHk4kUfR9839sD3r4kk8xq9ypjydn6FkU64jQTQweQZEjNuWL9FXWxEt2","signature":"EFr8mgd2PseuejUuWwrkUccKhFscmADHk4kUfR9839sD3r4kk8xq9ypjydn6FkU64jQTQweQZEjNuWL9FXWxEt2","data_hash":"2aebe8b4333e17e9b2f08b565ac33e4fa07b1754bef77dbc5cfdbc8ab99fcc78","logged_at":"2026-05-04T21:04:51.136462+00:00","explorer_url":"https://solscan.io/tx/EFr8mgd2PseuejUuWwrkUccKhFscmADHk4kUfR9839sD3r4kk8xq9ypjydn6FkU64jQTQweQZEjNuWL9FXWxEt2"},"ipfs_hash":null,"created_at":"2026-05-04T20:59:07.543761+00:00","updated_at":"2026-05-04T21:04:51.144401+00:00"}