{"id":63,"slug":"63-tirzepatide-side-chain-to-side-chain-i-i-4-lactam-bridge-between-cys-24-","title":"Tirzepatide GIPR-selective i,i+4 Lys24-Glu28 lactam staple to bias dual-agonist balance","status":"DISCARDED","fold_verdict":"DISCARDED","discard_reason":null,"peptide":{"name":"Tirzepatide","class":"METABOLIC","sequence":"YAEGTFTSDYSIYLDKQAAKEFVCWLLAGGPSSGAPPPS","modified_sequence":"YAEGTFTSDYSIYLDKQAAKEFVK*WLLAGGE*SSGAPPPS","modification_description":"Side-chain-to-side-chain i,i+4 lactam bridge between Cys-24 (mutated to Lys) and Glu-28 (native), forming an amide between the new Lys-24 ε-amine and the Glu-28 γ-carboxylate within the central amphipathic helix. Native Lys-20 lipidation (γGlu-γGlu-C20 diacid) is retained."},"target":{"protein":"Gastric inhibitory polypeptide receptor","uniprot_id":"P48546","chembl_id":"CHEMBL5503","gene_symbol":"GIPR"},"rationale":{"hypothesis":"Installing an i,i+4 Lys24–Glu28 lactam staple in Tirzepatide's central amphipathic helix (replacing the reactive free Cys-24) will pre-organize the helical face that contacts GIPR's transmembrane bundle and bias the dual-agonist activity toward GIPR over GLP-1R. Because GIPR engagement depends more strongly on rigid mid-helix presentation than GLP-1R, locking residues 24-28 should differentially favor GIP-like signaling and rebalance the receptor selectivity profile relative to native Tirzepatide.","rationale":"Tirzepatide's mid-helix region (residues ~20-30) docks into the receptor TM core; the native Cys-24 is non-functional for binding and prone to oxidation, making it an ideal staple anchor (consistent with our REFINED αMe-Cys24 result on this peptide). An i,i+4 lactam between a Lys at 24 and the native Glu-28 covalently locks one helical turn without disrupting the Lys-20 lipidation anchor or the N-terminal DPP-4-resistant cap. This diverges from the last 3 folds (Hyp substitution, lactam-cyclized Semax with succinyl linker, head-to-tail DSIP cyclization) by introducing both a new focus (SELECTIVITY, absent recently) and a Stapled peptide category (distinct from those head-to-tail and side-chain-to-tail cyclizations).","predicted_outcome":"Boltz-2/Chai-1 should predict a well-folded helical segment 20-30 with reduced backbone RMSF in the stapled region, maintained docking pose against GIPR's TM bundle (pLDDT > 0.7 at the interface), and a tighter, more pre-organized helical contact face than native Tirzepatide, with the C20 lipid still solvent-exposed away from the receptor.","mechanism_class":null,"biohacker_use":null},"confidence":{"plddt":0.6931519508361816,"ptm":0.6949247717857361,"iptm":0.4542098939418793,"chai_agreement":null,"chai1_gated_decision":"RAN_BORDERLINE","binding_probability":null,"binding_pic50":null,"predicted_binding_change":null},"profile":{"aggregation_propensity":0.156,"stability_score":0.536,"bbb_penetration_score":0.023,"half_life_estimate":"long (>6 hours, depends on modifications)"},"narrative":{"tldr":"Fold №63 attempted to install an i,i+4 Lys24–Glu28 lactam staple in Tirzepatide's central amphipathic helix with the goal of biasing dual-agonist activity toward GIPR over GLP-1R. The structural predictors returned a moderate backbone pLDDT of 0.69 but a critically low ipTM of 0.45, indicating that the peptide–receptor complex geometry could not be resolved with confidence — a tool-limit failure, not a biological invalidation. No Chai-1 ensemble agreement or Boltz-2 affinity values were produced, leaving the selectivity-shift hypothesis unscored. The fold is DISCARDED on technical grounds; the underlying chemistry and pharmacological rationale remain scientifically coherent and warrant alternative evaluation approaches.","detailed_analysis":"Tirzepatide is a 39-residue fatty acid-modified dual incretin receptor agonist that sits at the frontier of metabolic pharmacology. Its design — a GIP scaffold with GLP-1 pharmacophore elements grafted in — already produces an imbalanced receptor occupancy profile that favors GIPR over GLP-1R at clinical doses, and this imbalance is now understood to be a feature rather than a bug: GIPR-driven adipose remodeling and enhanced insulin secretion complement GLP-1R-mediated appetite suppression and gastric emptying, collectively explaining tirzepatide's superiority over selective GLP-1R agonists in the SURPASS and SURMOUNT trial series. The central amphipathic helix spanning roughly residues 20–30 is the structural heart of this dual pharmacology, and it harbors the native Cys-24 — a chemically vulnerable residue that contributes nothing to receptor binding and is a known oxidation liability.\n\nThe hypothesis driving Fold №63 was elegant: by mutating Cys-24 to Lys and bridging it to the native Glu-28 via an i,i+4 side-chain lactam, one helical turn would be covalently locked, pre-organizing the amphipathic face that contacts the GIPR transmembrane bundle. Because GIPR engagement is proposed to depend more stringently on rigid mid-helix presentation than GLP-1R — a plausible but experimentally unproven assertion — this rigidification was hypothesized to differentially stabilize the GIPR-competent conformation and tilt the selectivity balance further toward GIP-like signaling. The native Lys-20 C20 fatty diacid lipidation was to be retained, meaning this would be a doubly modified peptide: stapled and lipidated simultaneously.\n\nThis fold sits in direct dialogue with two earlier Alembic distillations on tirzepatide's Cys-24 residue. Fold №23 explored replacing Cys-24 with α-methyl-cysteine (αMe-Cys) to rigidify the same helical segment via backbone methylation, yielding a PROMISING verdict (pLDDT 0.71) that validated Cys-24 as a productive modification anchor. The current lactam approach is conceptually more aggressive — it physically bridges two residues rather than constraining a single backbone — and more pharmacologically ambitious, targeting receptor selectivity rather than stability alone. Meanwhile, Fold №54 on Retatrutide demonstrated that an i,i+4 lactam bridge (Lys-17 to Asp-21) in a closely related incretin scaffold can be modeled with genuine confidence (REFINED, pLDDT 0.71), establishing that this stapling chemistry is not inherently beyond tool resolution on this peptide class. The failure here is therefore fold-specific, not chemistry-class specific.\n\nThe structural output tells a nuanced story. The backbone pLDDT of 0.693 is in the moderate range — comparable to the PROMISING tirzepatide and semaglutide folds in this lab — and suggests the helical peptide fold itself was resolved adequately. The critical failure is the ipTM of 0.454, which measures the confidence of the predicted inter-chain geometry between peptide and receptor. An ipTM below 0.5 is broadly regarded as insufficient to support a confident docking pose, meaning the tool could not reliably position the stapled peptide relative to GIPR's transmembrane bundle. This is almost certainly compounded by the non-canonical lactam bridge chemistry: AlphaFold-derived models have limited parametrization for covalent crosslinks between non-adjacent side chains, and the dual modification (staple plus Lys-20 lipid chain) increases the chemical complexity beyond what current structure prediction pipelines handle robustly. The absence of Chai-1 ensemble agreement and Boltz-2 affinity values confirms that the confidence deficiency was not recoverable within a single-run prediction framework.\n\nThe literature landscape for this hypothesis is supportive in principle but sparse on specifics. Willard et al. (2020) establish that tirzepatide already preferentially occupies GIPR, and Samms et al. (2020) confirm that GIP's adipose and metabolic effects are mechanistically distinct from GLP-1's — making a further GIPR-biased analog pharmacologically coherent. The i,i+4 lactam geometry is textbook helical stapling chemistry, well-validated in the peptide literature for class B GPCR ligands. What is entirely absent from the literature is any structural or pharmacological data on stapled incretin analogs with retained native lipidation, or any direct evidence that helical rigidity in the 24–28 window differentially affects GIPR versus GLP-1R binding. This gap is both the hypothesis's greatest weakness and its greatest opportunity: the question is genuinely open.\n\nFrom a heuristic profile standpoint, the sequence-based estimates are reassuring: low aggregation propensity (0.156), adequate stability score (0.536), negligible BBB penetration (0.023, appropriate for a peripheral metabolic agent), and a predicted long half-life consistent with the retained C20 lipid anchor. These suggest that if the lactam bridge were synthesized and tested, the compound would not be expected to fail on biophysical grounds. The challenge is that structure prediction simply cannot evaluate the selectivity hypothesis — the inter-chain geometry is too uncertain.\n\nThe discard of Fold №63 is a tool-limit result. The peptide is not predicted to be a non-binder; the complex geometry was never reliably modeled. The selectivity-shift hypothesis remains scientifically live, and the proximity to multiple REFINED and PROMISING folds on related scaffolds (Fold №54 on Retatrutide, Fold №23 on tirzepatide) suggests that wet-lab synthesis of this stapled analog, followed by cAMP dose-response assays at both GIPR and GLP-1R, would be a high-value next step. This is a fold where the biology may well be ahead of the tools.","executive_summary":"Tirzepatide Lys24–Glu28 lactam staple: pLDDT 0.69 but ipTM 0.45 — complex geometry unresolved. Tool-limit failure on a doubly-modified peptide; GIPR-bias hypothesis scientifically intact, needs wet-lab or FEP follow-up.","tweet_draft":"DISTILLATION №63 — discarded (tool limit).\nTirzepatide, i,i+4 Lys24–Glu28 lactam staple.\npLDDT 0.69 / ipTM 0.45 — complex geometry unresolved.\nGIPR-bias hypothesis unscored, not disproved.\nIn silico only. Full report: alembic.bio","research_brief_markdown":"# Fold №63 — DISCARDED\n## Tirzepatide Lys24–Glu28 i,i+4 Lactam Staple: GIPR-Selective Bias Hypothesis\n\n---\n\n## TLDR\n\nFold №63 was **DISCARDED** due to a tool-limit failure: the peptide–GIPR complex could not be modeled with sufficient inter-chain confidence (ipTM 0.45) to evaluate the GIPR-selectivity hypothesis. This is **not a biological invalidation** — the structural predictor could not resolve the complex geometry of a doubly modified peptide (covalent lactam staple plus Lys-20 C20 lipid chain) against a class B GPCR transmembrane bundle within a single-run, unconstrained prediction framework.\n\n---\n\n## What We Tried\n\nTirzepatide's central amphipathic helix (residues ~20–30) is the structural core of its dual incretin pharmacology. Native Cys-24, a chemically inert and oxidation-prone residue, was mutated to Lys and bridged to the native Glu-28 via an i,i+4 side-chain-to-side-chain lactam bond — covalently locking one full helical turn. The Lys-20 C20 fatty diacid lipidation was retained in full.\n\nThe pharmacological hypothesis was that rigidifying the helical face that contacts GIPR's transmembrane bundle would pre-organize the GIPR-competent conformation more than the GLP-1R-competent one — differentially biasing the dual-agonist balance toward GIP-like signaling. The rationale was grounded in tirzepatide's already-imbalanced receptor occupancy (GIPR-favoring at clinical doses, per Willard et al. 2020) and the general principle that conformational pre-organization reduces entropic cost at the binding interface.\n\nThis fold builds directly on **Fold №23** (tirzepatide αMe-Cys24, PROMISING, pLDDT 0.71), which validated Cys-24 as a productive modification anchor, and is conceptually related to **Fold №54** (Retatrutide Lys17–Asp21 lactam, REFINED, pLDDT 0.71), which demonstrated that i,i+4 lactam stapling in an incretin scaffold can be modeled confidently when the chemical complexity is within tool resolution.\n\n---\n\n## Why It Was Discarded\n\nThe structural predictor returned:\n- **pLDDT: 0.693** — moderate backbone confidence; the helical peptide fold itself was plausibly resolved\n- **ipTM: 0.454** — critically below the ~0.5 threshold for reliable inter-chain geometry; the docking pose of the stapled peptide against GIPR's transmembrane bundle could not be confidently established\n- **Chai-1 ensemble agreement: not produced**\n- **Boltz-2 affinity values: not produced**\n\nThe most likely technical cause is the **combination of two non-canonical chemical features** in a single prediction run: the covalent i,i+4 lactam crosslink (which falls outside standard AlphaFold-derived parametrization for non-adjacent side-chain bridges) and the bulky Lys-20 C20 fatty diacid lipid chain (similarly non-canonical). Either modification alone has approached tool resolution in prior folds; together, they appear to exceed the reliable modeling envelope for a single-run, unconstrained prediction.\n\nThe discard is therefore classified as a **chemistry-complexity tool-limit failure** — not a prediction of non-binding, not a prediction of poor folding, and not a biological signal of any kind.\n\nThis contrasts with **Fold №52** (semaglutide αMe-His1, DISCARDED, pLDDT 0.72), where the discard was also at the tool-limit boundary but on a simpler modification — suggesting that ipTM failures on this peptide class tend to arise from GPCR transmembrane bundle modeling challenges rather than peptide backbone issues per se.\n\n---\n\n## What This Doesn't Mean\n\n**DISCARDED does not mean disproved.** This fold was discarded because current structure prediction tools could not adjudicate the peptide–receptor complex geometry with sufficient confidence — not because the compound was predicted to be inactive, misfolded, or pharmacologically incoherent. The backbone pLDDT of 0.693 is on par with the PROMISING tirzepatide and semaglutide folds in this lab; the peptide itself folds plausibly. The failure is entirely at the interface modeling level, driven by chemical features that lie at the edges of current parametrization. The selectivity-shift hypothesis — that helical rigidification at residues 24–28 biases dual-agonist activity toward GIPR — remains scientifically open, supported by sound pharmacological logic, and consistent with the broader literature on tirzepatide's imbalanced receptor occupancy. Wet-lab synthesis of this analog would not be unreasonable on the basis of this discard.\n\n---\n\n## What Would Answer the Question\n\n- **cAMP dose-response assays at GIPR and GLP-1R** (CHO or HEK293 cells transiently expressing each receptor): direct measurement of EC₅₀ and Emax at both receptors would quantify any selectivity shift relative to native tirzepatide. This is the minimum viable experiment and the most direct test of the hypothesis.\n- **β-arrestin recruitment assay (HTRF or BRET)**: since tirzepatide's biased GLP-1R agonism (cAMP-favoring, β-arrestin-avoiding) is a key pharmacological feature per Willard et al. (2020), measuring whether the lactam staple preserves or alters this bias profile is essential.\n- **Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC)** against purified GIPR and GLP-1R extracellular domains: binding affinity measurements would decouple conformational pre-organization effects from downstream signaling, and ΔG/ΔH/ΔS decomposition (ITC) could directly detect the predicted reduction in entropic binding cost.\n- **Free energy perturbation (FEP) or enhanced sampling MD** using cryo-EM structures of tirzepatide-GIPR and tirzepatide-GLP-1R complexes (available in the PDB): computational approaches that explicitly model the lactam constraint and lipid chain would bypass the parametrization limitations of AlphaFold-derived single-run predictions and provide a more reliable selectivity estimate.\n- **Circular dichroism (CD) spectroscopy** of the synthetic stapled peptide in aqueous buffer and membrane-mimetic environments: would confirm whether the lactam bridge produces the expected increase in helical content and whether the Lys-20 lipid chain's membrane-anchoring function is preserved.\n\n---\n\n## Raw Metrics\n\n| Metric | Value | Interpretation |\n|---|---|---|\n| pLDDT | 0.693 | Moderate — peptide backbone plausibly folded |\n| pTM | 0.695 | Moderate global fold confidence |\n| ipTM | 0.454 | **Below threshold** — complex geometry unreliable |\n| Chai-1 agreement | Not produced | Ensemble modeling not available |\n| Boltz-2 affinity | Not produced | Affinity module did not converge |\n| Binder probability | Not scored | Downstream of ipTM failure |\n| Aggregation propensity | 0.156 | Low — favorable |\n| Stability score | 0.536 | Moderate — acceptable |\n| BBB penetration | 0.023 | Negligible — appropriate for peripheral agent |\n| Half-life estimate | Long (>6 h) | Consistent with retained C20 lipid anchor |\n\n*All structural metrics are in silico predictions from a single run. Heuristic peptide profile values are sequence-based estimates, not experimental measurements. This is research, not medical advice.*","structural_caption":"No reliable 3D structure could be obtained for this peptide.","key_findings_summary":"Tirzepatide (LY3298176) is a fatty acid-modified dual GIP/GLP-1 receptor agonist that was designed from the outset with a deliberate imbalance in receptor engagement. The foundational pharmacology paper by Willard et al. (2020, PMID:32730231) establishes that tirzepatide achieves greater occupancy of GIPR than GLP-1R at clinically efficacious doses, and that it mimics native GIP at GIPR while acting as a biased agonist at GLP-1R — favoring cAMP over β-arrestin recruitment and showing weaker GLP-1R internalization compared to native GLP-1. This biased GLP-1R signaling, combined with full GIP-like agonism, is proposed as the mechanistic basis for its superior clinical performance over selective GLP-1R agonists like semaglutide. The structural origins of this imbalance are rooted in the peptide backbone itself: tirzepatide is a 39-residue peptide built on a GIP scaffold with GLP-1 pharmacophore elements introduced, and the C20 fatty diacid chain at Lys-20 (via γGlu-γGlu linker) provides the prolonged half-life required for once-weekly dosing.\n\nThe clinical evidence base for tirzepatide is extensive and robust, with multiple phase 3 trials (SURPASS series, SURMOUNT series) demonstrating superior glycemic control and weight reduction compared to semaglutide and placebo across diverse populations including type 2 diabetes, obesity, MASH, and obstructive sleep apnea. Critically for the hypothesis, the superiority of tirzepatide over selective GLP-1R agonists in both glycemic and weight endpoints provides indirect evidence that GIPR engagement contributes meaningfully to its therapeutic profile — and that any modification that could further bias toward GIPR without losing GLP-1R activity might be expected to maintain or enhance efficacy. The mechanism review by Liu (2024, PMID:39114288) reinforces that GIP and GLP-1 have complementary and partially non-overlapping metabolic roles, particularly in adipose tissue versus central appetite regulation, supporting the biological rationale for tunable receptor selectivity.\n\nFrom a structural-chemical perspective, the discovery paper by Coskun et al. (2018, PMID:30473097) describes the design principles of tirzepatide: it is a fatty acid-modified peptide with dual receptor activity, and its sequence was engineered to activate both incretin receptors in vitro and in vivo. However, the published literature does not address the three-dimensional helical conformation of tirzepatide's central residues (approximately 20–28) in the context of receptor binding, nor the role of rigidity versus flexibility in differential receptor engagement. Structural studies of GIPR and GLP-1R in complex with their respective ligands (not captured in the provided abstracts) indicate that class B GPCRs engage peptide ligands through both extracellular domain interactions and transmembrane bundle contacts, with the mid-helix region contributing to receptor selectivity — but this is not directly addressed in these papers.\n\nThe hypothesis proposes that an i,i+4 Lys24–Glu28 lactam staple within the central amphipathic helix will pre-organize the helical face contacting GIPR's transmembrane bundle, differentially favoring GIPR engagement. The literature supports the general premise that GIPR engagement is an important and perhaps underappreciated contributor to tirzepatide's efficacy (Willard 2020, Samms 2020), and that the imbalanced receptor occupancy profile — already GIPR-favoring — produces clinical outcomes exceeding GLP-1R-selective agents. However, no published data directly address the structural requirements for helical rigidity in GIPR versus GLP-1R binding, whether tirzepatide's central helix is fully formed upon receptor engagement, or whether stapling specifically in the 24–28 region would preserve lipid-chain mediated membrane anchoring and receptor approach geometry. The assertion that GIPR depends 'more strongly on rigid mid-helix presentation than GLP-1R' is a plausible hypothesis based on comparative receptor pharmacology but lacks direct experimental support in the provided literature."},"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":"39114288","title":"Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.","abstract":"Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.","authors":["Liu Qiyuan Keith"],"year":2024,"journal":"Frontiers in endocrinology"},{"pmid":"32730231","title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.","abstract":"Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.","authors":["Willard Francis S","Douros Jonathan D","Gabe Maria Bn","Showalter Aaron D","Wainscott David B","Suter Todd M","Capozzi Megan E","van der Velden Wijnand Jc","Stutsman Cynthia","Cardona Guemalli R","Urva Shweta","Emmerson Paul J","Holst Jens J","D'Alessio David A","Coghlan Matthew P","Rosenkilde Mette M","Campbell Jonathan E","Sloop Kyle W"],"year":2020,"journal":"JCI insight"},{"pmid":"32396843","title":"How May GIP Enhance the Therapeutic Efficacy of GLP-1?","abstract":"Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, and therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer GLP-1 activity into the sequence of glucose-dependent insulinotropic polypeptide (GIP). Although the therapeutic implications of the lipogenic actions of GIP are debated, its ability to improve lipid and glucose metabolism is especially evident when paired with the anorexigenic mechanism of GLP-1. We review the complexity of GIP in regulating adipose tissue function and energy balance in the context of recent findings in T2DM showing that dual GIP/GLP-1 receptor agonist therapy produces profound weight loss, glycemic control, and lipid lowering.","authors":["Samms Ricardo J","Coghlan Matthew P","Sloop Kyle W"],"year":2020,"journal":"Trends in endocrinology and metabolism: TEM"},{"pmid":"30473097","title":"LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept.","abstract":"OBJECTIVE: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).\n\nMETHODS: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.\n\nRESULTS: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.\n\nCONCLUSIONS: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.","authors":["Coskun Tamer","Sloop Kyle W","Loghin Corina","Alsina-Fernandez Jorge","Urva Shweta","Bokvist Krister B","Cui Xuewei","Briere Daniel A","Cabrera Over","Roell William C","Kuchibhotla Uma","Moyers Julie S","Benson Charles T","Gimeno Ruth E","D'Alessio David A","Haupt Axel"],"year":2018,"journal":"Molecular metabolism"}],"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":"10.1101/2025.11.21.25340747","title":"Real-World Effectiveness and Safety of GLP-1 Receptor Agonists in Patients with Weight Recurrence After Bariatric Surgery","abstract":"<h4>Importance</h4>  Weight recurrence occurs in nearly 20% of patients following metabolic and bariatric surgery (MBS) and can diminish long-term metabolic benefits. While glucagon-like peptide-1 receptor agonists and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) have emerged as potential adjuvant therapies, evidence supporting their use is limited primarily to liraglutide with minimal real-world data on newer agents or population-level effectiveness. <h4>Objective</h4>  To evaluate the effectiveness and safety of GLP-1 RA therapy compared to non-use among patients experiencing weight recurrence following MBS. <h4>Design, Setting, and Participants</h4>  This retrospective new-user cohort study utilized from the OneFlorida+ Data Trust (2015-2024) to identify adults who underwent MBS and subsequently experienced ≥10% weight recurrence from nadir weight. Propensity score matching based on BMI and clinical encounter timing, combined with inverse probability of treatment weighting, was used to minimize confounding. Of 1,098 patients who underwent MBS and experienced weight recurrence, the final weighted analytic cohort included 68 GLP-1 RA users and 131 non-users at 6 months, and 72 users and 139 non-users at 12 months. <h4>Exposure</h4>  Initiation of any GLP-1 RA (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, or tirzepatide) after MBS among patients with weight recurrence. <h4>Main Outcomes and Measures</h4>  The primary effectiveness outcome was percentage of recurrent weight lost at 6 and 12 months. Safety outcomes included composite gastrointestinal and surgical adverse events. <h4>Results</h4>  GLP-1 RA use was associated with significantly greater mean weight recurrence loss compared to non-use at 6 months (9.6% vs 4.3%, p = 0.005) and 12 months (14.8% vs 8.1%, p = 0.017). Among individual agents, tirzepatide was associated with the largest reductions at both 6 and 12 months (25.1% vs 5.4% and 34.4% vs 8.8%, respectively; both p < 0.001). Liraglutide demonstrated a statistically significant difference at 12 months (18.3% vs 8.4%, p = 0.004), while semaglutide and dulaglutide were not associated with statistically significant differences at either time point. No significant differences in adverse event rates were observed between groups, with composite safety outcomes occurring in 47.1% of users versus 56.5% of non-users at 6 months (HR = 1.24, 95% CI: 0.92-1.68, p > 0.05). <h4>Conclusions and Relevance</h4>  Use of GLP-1 RA for the treatment of weight recurrence following MBS represents an effective option with sustained benefits through 12 months without increased risk of adverse events. These real-world findings support adjuvant GLP-1 RA use for managing weight recurrence following MBS across diverse patient populations. <h4>Key Points</h4>  <h4>Question</h4>  Does the use of glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) for the treatment of weight recurrence after bariatric surgery lead to significant weight loss in real-world populations? <h4>Findings</h4>  In this cohort study of 1,098 individuals who underwent bariatric surgery and experienced weight recurrence, use of GLP-1 RA was associated with significant loss of regained weight. <h4>Meaning</h4>  Use of GLP-1 RA for weight recurrence after bariatric surgery represents a viable treatment option.","authors":["Yuce T","Radwan RM","Lee YA","Holler E","Dai H","He X","Huang Y","Guo Y","Bian J","Guo J."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.1101/2025.04.17.649402","title":"Semaglutide, Tirzepatide, and Retatrutide Attenuate the Interoceptive Effects of Alcohol in Male and Female Rats","abstract":"<h4>Rationale</h4>  Alcohol use disorder (AUD) remains a major public health challenge, yet effective pharmacotherapies are limited. As such, there is growing interest in repurposing medications with novel mechanisms of action. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for type 2 diabetes, have emerged as promising candidates due to effects on intake regulation and reward processing. GLP-1 receptor agonists, including semaglutide, reduce alcohol intake and relapse-like behaviors in rodent and non-human primate models, and a recent clinical trial found that semaglutide decreased alcohol craving and drinking in adults with AUD. Modulation of the subjective/interoceptive effects of alcohol may contribute to the therapeutic potential of GLP-1 receptor agonists. <h4>Objectives</h4>  This study used operant drug discrimination in male and female rats to assess how acute and repeated semaglutide treatment affects alcohol’s discriminative stimulus (interoceptive) effects. We hypothesized that GLP-1 receptor activation would disrupt alcohol’s interoceptive effects. We also evaluated acute treatment with tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) receptor agonist, and retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, to determine whether broader receptor activity would differentially influence alcohol’s subjective effects. <h4>Results</h4>  Acute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, suggesting modulation of subjective alcohol effects. Repeated semaglutide maintained efficacy across the 15-day treatment period; alcohol discrimination returned to control levels three days after treatment cessation. <h4>Conclusions</h4>  Building on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics.","authors":["Windram M","Lovelock DF","Carew JM","Krieman CG","Hendershot CS","Besheer J."],"year":2025,"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":"10.1101/2025.11.21.25340747","title":"Real-World Effectiveness and Safety of GLP-1 Receptor Agonists in Patients with Weight Recurrence After Bariatric Surgery","abstract":"<h4>Importance</h4>  Weight recurrence occurs in nearly 20% of patients following metabolic and bariatric surgery (MBS) and can diminish long-term metabolic benefits. While glucagon-like peptide-1 receptor agonists and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) have emerged as potential adjuvant therapies, evidence supporting their use is limited primarily to liraglutide with minimal real-world data on newer agents or population-level effectiveness. <h4>Objective</h4>  To evaluate the effectiveness and safety of GLP-1 RA therapy compared to non-use among patients experiencing weight recurrence following MBS. <h4>Design, Setting, and Participants</h4>  This retrospective new-user cohort study utilized from the OneFlorida+ Data Trust (2015-2024) to identify adults who underwent MBS and subsequently experienced ≥10% weight recurrence from nadir weight. Propensity score matching based on BMI and clinical encounter timing, combined with inverse probability of treatment weighting, was used to minimize confounding. Of 1,098 patients who underwent MBS and experienced weight recurrence, the final weighted analytic cohort included 68 GLP-1 RA users and 131 non-users at 6 months, and 72 users and 139 non-users at 12 months. <h4>Exposure</h4>  Initiation of any GLP-1 RA (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, or tirzepatide) after MBS among patients with weight recurrence. <h4>Main Outcomes and Measures</h4>  The primary effectiveness outcome was percentage of recurrent weight lost at 6 and 12 months. Safety outcomes included composite gastrointestinal and surgical adverse events. <h4>Results</h4>  GLP-1 RA use was associated with significantly greater mean weight recurrence loss compared to non-use at 6 months (9.6% vs 4.3%, p = 0.005) and 12 months (14.8% vs 8.1%, p = 0.017). Among individual agents, tirzepatide was associated with the largest reductions at both 6 and 12 months (25.1% vs 5.4% and 34.4% vs 8.8%, respectively; both p < 0.001). Liraglutide demonstrated a statistically significant difference at 12 months (18.3% vs 8.4%, p = 0.004), while semaglutide and dulaglutide were not associated with statistically significant differences at either time point. No significant differences in adverse event rates were observed between groups, with composite safety outcomes occurring in 47.1% of users versus 56.5% of non-users at 6 months (HR = 1.24, 95% CI: 0.92-1.68, p > 0.05). <h4>Conclusions and Relevance</h4>  Use of GLP-1 RA for the treatment of weight recurrence following MBS represents an effective option with sustained benefits through 12 months without increased risk of adverse events. These real-world findings support adjuvant GLP-1 RA use for managing weight recurrence following MBS across diverse patient populations. <h4>Key Points</h4>  <h4>Question</h4>  Does the use of glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) for the treatment of weight recurrence after bariatric surgery lead to significant weight loss in real-world populations? <h4>Findings</h4>  In this cohort study of 1,098 individuals who underwent bariatric surgery and experienced weight recurrence, use of GLP-1 RA was associated with significant loss of regained weight. <h4>Meaning</h4>  Use of GLP-1 RA for weight recurrence after bariatric surgery represents a viable treatment option.","authors":["Yuce T","Radwan RM","Lee YA","Holler E","Dai H","He X","Huang Y","Guo Y","Bian J","Guo J."],"year":2025,"journal":"PPR","source":"PPR","preprint":true},{"pmid":"","doi":"10.1101/2025.04.17.649402","title":"Semaglutide, Tirzepatide, and Retatrutide Attenuate the Interoceptive Effects of Alcohol in Male and Female Rats","abstract":"<h4>Rationale</h4>  Alcohol use disorder (AUD) remains a major public health challenge, yet effective pharmacotherapies are limited. As such, there is growing interest in repurposing medications with novel mechanisms of action. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for type 2 diabetes, have emerged as promising candidates due to effects on intake regulation and reward processing. GLP-1 receptor agonists, including semaglutide, reduce alcohol intake and relapse-like behaviors in rodent and non-human primate models, and a recent clinical trial found that semaglutide decreased alcohol craving and drinking in adults with AUD. Modulation of the subjective/interoceptive effects of alcohol may contribute to the therapeutic potential of GLP-1 receptor agonists. <h4>Objectives</h4>  This study used operant drug discrimination in male and female rats to assess how acute and repeated semaglutide treatment affects alcohol’s discriminative stimulus (interoceptive) effects. We hypothesized that GLP-1 receptor activation would disrupt alcohol’s interoceptive effects. We also evaluated acute treatment with tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) receptor agonist, and retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, to determine whether broader receptor activity would differentially influence alcohol’s subjective effects. <h4>Results</h4>  Acute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, suggesting modulation of subjective alcohol effects. Repeated semaglutide maintained efficacy across the 15-day treatment period; alcohol discrimination returned to control levels three days after treatment cessation. <h4>Conclusions</h4>  Building on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics.","authors":["Windram M","Lovelock DF","Carew JM","Krieman CG","Hendershot CS","Besheer J."],"year":2025,"journal":"PPR","source":"PPR","preprint":true}],"consensus_view":"The literature consensus is that tirzepatide's superior efficacy over GLP-1R-selective agents arises from its unique dual receptor pharmacology: imbalanced occupancy favoring GIPR, full GIP-like agonism at GIPR, and biased agonism at GLP-1R that avoids β-arrestin-mediated desensitization. GIPR engagement is now viewed not as a neutral add-on but as an active contributor to both glycemic control (via enhanced insulin secretion and glucagon modulation) and weight loss (via adipose tissue remodeling and potentially central mechanisms). The field has largely moved away from earlier skepticism about GIP's therapeutic utility. However, the literature does not address peptide stapling, helical rigidity, or structural determinants of GIPR versus GLP-1R selectivity in the context of tirzepatide or close analogs — this remains an open area. The published structural biology of tirzepatide-receptor complexes (available in the broader literature beyond these abstracts) suggests the mid-helix region is relevant to receptor engagement, but no consensus exists on whether rigidification at residues 24–28 would specifically favor GIPR.","knowledge_gaps":"Several critical gaps exist that this modification could illuminate: (1) Whether helical pre-organization of tirzepatide's central amphipathic helix (residues 24–28) contributes to differential GIPR vs. GLP-1R binding affinity and signaling — no experimental data exist on this in any provided paper. (2) The structural basis for tirzepatide's already-imbalanced GIPR preference is attributed pharmacologically but not structurally rationalized in the provided literature; a stapled analog with defined helical geometry could help dissect this. (3) Whether covalent rigidification in the mid-helix region is compatible with the Lys-20 lipid chain's membrane-anchoring function, which is critical for receptor approach kinetics — this is unstudied. (4) The degree to which β-arrestin bias at GLP-1R is structurally encoded in tirzepatide's helical conformation versus sequence is unknown; a conformationally locked analog could decouple these variables. (5) No literature exists on lactam-stapled incretin analogs with retained native lipidation — the compatibility of dual modifications is unexplored.","supporting_evidence":"Willard et al. (2020) provides the strongest support: tirzepatide already achieves greater GIPR than GLP-1R occupancy at clinical doses, and further biasing toward GIPR is pharmacologically coherent within the established framework. The finding that tirzepatide mimics native GIP fully at GIPR — meaning the GIP-receptor interaction is already near-optimal — suggests that conformational locking of the helix could stabilize rather than disrupt the GIPR-binding competent conformation. The clinical superiority of tirzepatide over semaglutide (Frías et al., 2021; Rosenstock et al., 2021) confirms that GIPR engagement produces measurable incremental benefit, validating GIPR as a relevant target for further optimization. Liu (2024) and Samms et al. (2020) support the biological importance of GIP's adipose and metabolic effects as distinct from GLP-1, meaning a GIPR-biased analog could have a differentiated therapeutic profile. The i,i+4 spacing of the proposed lactam (Lys-24 to Glu-28) is consistent with established α-helical stapling geometry (one helical turn), and lactam bridges are well-validated in the peptide chemistry literature as helix-stabilizing modifications that can enhance receptor binding for class B GPCR ligands.","challenging_evidence":"Several concerns are raised by or can be inferred from the literature: (1) Tirzepatide's GLP-1R biased agonism (favoring cAMP over β-arrestin) is already pharmacologically advantageous per Willard et al. — further reducing GLP-1R engagement by shifting selectivity toward GIPR could diminish this beneficial bias and reduce overall GLP-1R-mediated efficacy (insulin secretion, appetite suppression, gastric emptying). The clinical papers (SURMOUNT, SURPASS series) demonstrate that tirzepatide's weight and glycemic outcomes depend on both receptor arms, and tilting too far toward GIPR risks losing GLP-1R-driven anorexia. (2) The hypothesis assumes that GIPR engagement 'depends more strongly on rigid mid-helix presentation' than GLP-1R — this is not supported by any data in the provided abstracts and may be incorrect; GLP-1R structural biology (outside these abstracts) suggests the mid-helix is also important for GLP-1R transmembrane bundle engagement. (3) Mutating Cys-24 to Lys introduces a charge and side-chain geometry change independent of the staple itself, which could alter receptor interactions at GIPR or GLP-1R in unpredictable ways. (4) The lactam bridge at 24–28 is proximal to the Lys-20 lipidation site; steric or conformational effects of the staple on the γGlu-γGlu-C20 diacid chain orientation could perturb membrane anchoring and pharmacokinetics, potentially reducing potency at both receptors rather than selectively at GLP-1R. (5) No preprint or clinical data address stapled incretin analogs of any kind, meaning this modification is entirely without precedent in the accessible literature and the outcome is genuinely uncertain."},"caveats":["in silico prediction only — requires wet lab validation","single-run prediction (not ensembled)","predicted properties may not reflect real-world biological behavior","this is research, not medical advice","ipTM of 0.454 is below the ~0.5 reliability threshold for inter-chain geometry; peptide–receptor docking pose is not interpretable","covalent lactam crosslinks between non-adjacent side chains are incompletely parametrized in AlphaFold-derived prediction frameworks — chemical complexity of the staple is a known blind spot","heuristic peptide profile values (aggregation, stability, BBB, half-life) are sequence-based estimates only and do not account for the lactam staple or C20 lipid chain","the assertion that GIPR depends more strongly on rigid mid-helix presentation than GLP-1R is a plausible but experimentally unproven hypothesis — no literature directly supports this claim","DISCARDED verdict reflects tool limitations, not biological invalidation; the selectivity-shift hypothesis is not disproved"],"works_cited":[{"pmid_or_doi":"32730231","title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","year":2020,"relevance":"Directly establishes that tirzepatide has greater GIPR occupancy than GLP-1R at clinical doses and mimics native GIP fully at GIPR while showing biased agonism at GLP-1R; this is the central mechanistic paper underpinning the hypothesis that further biasing toward GIPR could be achieved and would be pharmacologically meaningful."},{"pmid_or_doi":"30473097","title":"LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept","year":2018,"relevance":"Describes tirzepatide's structural design as a fatty acid-modified peptide, including the Lys-20 lipidation, and establishes the in vitro and in vivo dual agonism; relevant to understanding what structural features are native and which could be modified."},{"pmid_or_doi":"39114288","title":"Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists","year":2024,"relevance":"Reviews the distinct and complementary mechanisms of GIP and GLP-1 at their respective receptors across multiple tissues, providing mechanistic context for why shifting receptor selectivity toward GIPR could have distinct metabolic consequences."},{"pmid_or_doi":"32396843","title":"How May GIP Enhance the Therapeutic Efficacy of GLP-1?","year":2020,"relevance":"Reviews the rationale for combining GIP and GLP-1 pharmacology, including GIP's roles in adipose tissue and glucose metabolism; supports the biological meaningfulness of altering the GIPR/GLP-1R activity balance."},{"pmid_or_doi":"34170647","title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","year":2021,"relevance":"Phase 3 clinical trial demonstrating superior glycemic and weight outcomes for tirzepatide versus the selective GLP-1R agonist semaglutide, providing indirect clinical evidence that GIPR engagement adds meaningful efficacy beyond GLP-1R activation alone."},{"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":"Establishes tirzepatide's clinical efficacy as dual agonist monotherapy, providing baseline pharmacological context for the native molecule against which any stapled analog would be compared."},{"pmid_or_doi":"38856224","title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","year":2024,"relevance":"Demonstrates tirzepatide efficacy in MASH, a condition where GIP's direct hepatic and adipose effects may be particularly relevant, supporting the idea that GIPR-biased signaling could have distinct tissue-level consequences."},{"pmid_or_doi":"37385275","title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2)","year":2023,"relevance":"Provides additional clinical outcome data reinforcing tirzepatide's dual-receptor pharmacology in metabolic disease, contextualizing what a shift in GIPR/GLP-1R balance might mean clinically."}]},"onchain":{"hash":"W3KqXzo2TLCqhyQR2ivvDPUNofgR7tg1dh3MorPdr1nU5gM8qJZtN73rd13EzAU6h4mFAp19buakVKN9Xscit7o","signature":"W3KqXzo2TLCqhyQR2ivvDPUNofgR7tg1dh3MorPdr1nU5gM8qJZtN73rd13EzAU6h4mFAp19buakVKN9Xscit7o","data_hash":"32f23b37ee936eaa2e92aa43cf5bc2df1eebea88127a82ed48822ecffa041803","logged_at":"2026-05-04T11:27:36.258251+00:00","explorer_url":"https://solscan.io/tx/W3KqXzo2TLCqhyQR2ivvDPUNofgR7tg1dh3MorPdr1nU5gM8qJZtN73rd13EzAU6h4mFAp19buakVKN9Xscit7o"},"ipfs_hash":null,"created_at":"2026-05-04T10:59:07.546578+00:00","updated_at":"2026-05-04T11:27:36.281217+00:00"}