{
  "cutoff": "2026-10-12",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "24174327",
      "year": "2013",
      "title": "Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.",
      "doi": "10.1126/scitranslmed.3007218",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24174327/",
      "interpretation": "Dual-incretin translational experiments establish alternative receptor architectures before retatrutide."
    },
    {
      "pmid": "23305646",
      "year": "2013",
      "title": "Fibroblast growth factor 21 mediates specific glucagon actions.",
      "doi": "10.2337/db12-1116",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23305646/",
      "interpretation": "Glucagon/FGF21genetic perturbation separates some weight/energy effects from glucose effects."
    },
    {
      "pmid": "35985340",
      "year": "2022",
      "title": "LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.",
      "doi": "10.1016/j.cmet.2022.07.013",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35985340/",
      "interpretation": "LY3437943discovery combines receptor/mouse perturbation and early humanexposure/weight observations."
    },
    {
      "pmid": "37366315",
      "year": "2023",
      "title": "Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.",
      "doi": "10.1056/NEJMoa2301972",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37366315/",
      "interpretation": "Randomized phase2obesityweight efficacy demonstrated through48weeks."
    },
    {
      "pmid": "37385280",
      "year": "2023",
      "title": "Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.",
      "doi": "10.1016/S0140-6736(23)01053-X",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37385280/",
      "interpretation": "Randomized phase2T2Dtrial addsdulagutide active comparison and dose boundaries."
    },
    {
      "pmid": "40353578",
      "year": "2025",
      "title": "Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.",
      "doi": "10.1056/NEJMoa2416394",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40353578/",
      "interpretation": "Directtirzepatide-versus-semaglutide comparison demonstrates why head-to-headandcross-trialclaims differ."
    },
    {
      "pmid": "40609566",
      "year": "2025",
      "title": "Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.",
      "doi": "10.1016/S2213-8587(25)00092-0",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40609566/",
      "interpretation": "RetatrutideDXAbodycomposition substudypublished with missingness limits."
    },
    {
      "pmid": "42250575",
      "year": "2026",
      "title": "Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.",
      "doi": "10.1016/S0140-6736(26)00967-0",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42250575/",
      "interpretation": "40-week retatrutide diabetesphase3report published with weight a secondaryendpoint."
    },
    {
      "pmid": "42814954",
      "year": "2026",
      "title": "Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity.",
      "doi": "10.1056/NEJMoa2604169",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42814954/",
      "interpretation": "29September2026TRIUMPH1reports80-week obesityweight and clinicalsubgroupoutcomes."
    },
    {
      "pmid": "42810372",
      "year": "2026",
      "title": "Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial.",
      "doi": "10.1016/S0140-6736(26)01861-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42810372/",
      "interpretation": "29September2026TRIUMPH2reports80-week weight efficacy inobesitywithT2D."
    }
  ],
  "gaps": [
    "Direct matched retatrutide versus modern obesity-dose semaglutide/tirzepatide superiority with comparable estimands and durability.",
    "Retatrutide-specific withdrawal/rechallenge and long-term weight/function maintenance rather than class extrapolation.",
    "Human contribution of each receptor at measured therapeutic exposure, including energy expenditure and intake partition.",
    "Hard cardiovascular/renal outcomes and longer safety follow-up; surrogate lipid and inflammation analyses are insufficient.",
    "Muscle strength/function and clinically important composition outcomes, withDXAmissingness disclosed.",
    "Independent identified retatrutide supply-batch quality and product-linked clinical evidence; no assay result from semaglutide characterizes everyretatrutide vial."
  ],
  "decisive_experiment": "A blinded randomized retatrutide versus contemporary obesity-dose dual/GLP1 comparator trial, matched eligibility, lifestyle support and treatment-regimen estimand over72weeks, with a prespecified retatrutide continuation-versus-withdrawal phase in baseline-defined tolerators and independent weight/function assessment. Add human energy-expenditure/intake/body-composition substudy without interpreting correlations as receptor necessity."
}