First-in-class synthetic 39-amino acid dual GIP/GLP-1 receptor agonist ('twincretin') with imbalanced receptor binding profile and biased signaling at GLP-1R
FDA-approved May 2022 (Mounjaro for T2D), November 2023 (Zepbound for obesity), December 2024 (Zepbound for OSA) — extensively validated in 2,000+ peer-reviewed publications
Engineered with 2 Aib residues (DPP-4 resistance), C20 fatty diacid albumin-binding moiety (5-day half-life), enabling once-weekly dosing; cryo-EM structures elucidated for both GIPR-Gs and GLP-1R-Gs complexes
Unprecedented Weight Loss Efficacy: SURMOUNT-1 (Jastreboff et al., 2022, NEJM): 22.5% mean body weight reduction at 72 weeks, 39.7% participants achieved ≥25% loss, SURMOUNT-5 superior to semaglutide
Clinical Status: SURPASS-CVOT cardiovascular non-inferiority vs dulaglutide with 16% lower all-cause mortality (HR 0.84), SUMMIT trial 38% reduction CV death/worsening HF in HFpEF+obesity (HR 0.62), SYNERGY-NASH 73.3% MASH resolution at 15mg
First-in-class synthetic 39-amino acid dual GIP/GLP-1 receptor agonist ('twincretin') with imbalanced receptor binding profile and biased signaling at GLP-1R
FDA-approved May 2022 (Mounjaro for T2D), November 2023 (Zepbound for obesity), December 2024 (Zepbound for OSA) — extensively validated in 2,000+ peer-reviewed publications
Engineered with 2 Aib residues (DPP-4 resistance), C20 fatty diacid albumin-binding moiety (5-day half-life), enabling once-weekly dosing; cryo-EM structures elucidated for both GIPR-Gs and GLP-1R-Gs complexes
First-in-class synthetic 39-amino acid dual GIP/GLP-1 receptor agonist ('twincretin') with imbalanced receptor binding profile and biased signaling at GLP-1R
FDA-approved May 2022 (Mounjaro for T2D), November 2023 (Zepbound for obesity), December 2024 (Zepbound for OSA) — extensively validated in 2,000+ peer-reviewed publications
Engineered with 2 Aib residues (DPP-4 resistance), C20 fatty diacid albumin-binding moiety (5-day half-life), enabling once-weekly dosing; cryo-EM structures elucidated for both GIPR-Gs and GLP-1R-Gs complexes
Tirzepatide (LY3298176) is a first-in-class 39-amino acid dual GIP/GLP-1 receptor agonist ("twincretin") with imbalanced agonism favoring GIPR over GLP-1R. Features Aib residues at positions 2 and 13 (DPP-4 resistance), C20 fatty diacid at Lys20 (albumin binding, ~5-day half-life), and biased GLP-1R signaling favoring cAMP over beta-arrestin recruitment. FDA-approved as Mounjaro (T2D, May 2022) and Zepbound (obesity, Nov 2023).
First-in-Class Dual GIP/GLP-1 Agonist: 39-amino acid synthetic peptide (LY3298176), Eli Lilly design, imbalanced dual agonism (GIPR>GLP-1R), biased GLP-1R signaling (cAMP>beta-arrestin), 3,000+ publications, ~5-day half-life via C20 fatty diacid albumin binding
Unprecedented Metabolic Effects: HbA1c reduction 1.24-2.58%, 22.5% mean weight loss at 15mg (SURMOUNT-1), weight-independent insulin sensitization via GIPR, BCAA catabolism, central appetite suppression
Clinical Status: FDA-approved Mounjaro (T2D, May 2022), Zepbound (obesity, Nov 2023), OSA (Dec 2024); SURPASS-CVOT 38% reduction CV death/HF events, SYNERGY-NASH 73.3% MASH resolution
