{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "26358288",
      "year": "2016",
      "title": "A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes.",
      "doi": "10.2337/dc15-0165",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26358288/",
      "interpretation": "Early weekly dose-finding establishes short exposure-response evidence and selects higher doses for phase 3; it is not long microdose maintenance."
    },
    {
      "pmid": "28110911",
      "year": "2017",
      "title": "Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.",
      "doi": "10.1016/S2213-8587(17)30013-X",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28110911/",
      "interpretation": "SUSTAIN 1 provides placebo-controlled 0.5/1 mg diabetes results at 30 weeks."
    },
    {
      "pmid": "28266779",
      "year": "2017",
      "title": "Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.",
      "doi": "10.1111/dom.12932",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28266779/",
      "interpretation": "A small 1 mg weekly crossover study directly measures reduced intake and appetite."
    },
    {
      "pmid": "30122305",
      "year": "2018",
      "title": "Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.",
      "doi": "10.1016/S0140-6736(18)31773-2",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30122305/",
      "interpretation": "Daily obesity dose-ranging demonstrates weight effects under a distinct injection schedule."
    },
    {
      "pmid": "31897524",
      "year": "2020",
      "title": "Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial.",
      "doi": "10.1007/s00125-019-05065-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31897524/",
      "interpretation": "SUSTAIN 8 DXA highlights absolute lean loss versus higher lean proportion without function testing."
    },
    {
      "pmid": "33567185",
      "year": "2021",
      "title": "Once-Weekly Semaglutide in Adults with Overweight or Obesity.",
      "doi": "10.1056/NEJMoa2032183",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33567185/",
      "interpretation": "STEP 1 establishes 2.4 mg efficacy in BMI-defined non-diabetic adults at 68 weeks."
    },
    {
      "pmid": "33755728",
      "year": "2021",
      "title": "Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.",
      "doi": "10.1001/jama.2021.3224",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33755728/",
      "interpretation": "STEP 4 demonstrates standard-dose continuation sensitivity after a tolerability run-in."
    },
    {
      "pmid": "34514682",
      "year": "2022",
      "title": "Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss.",
      "doi": "10.1111/dom.14551",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34514682/",
      "interpretation": "Pooled STEP analyses separate gastrointestinal events from most observed weight loss without direct mediator manipulation."
    },
    {
      "pmid": "36655300",
      "year": "2023",
      "title": "Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5.",
      "doi": "10.1002/oby.23673",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36655300/",
      "interpretation": "STEP 5 adds longer-term craving/eating-control measures, with early-only hunger/fullness contrasts."
    },
    {
      "pmid": "37952131",
      "year": "2023",
      "title": "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.",
      "doi": "10.1056/NEJMoa2307563",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37952131/",
      "interpretation": "SELECT demonstrates hard cardiovascular benefit at the tested standard exposure."
    },
    {
      "pmid": "40631351",
      "year": "2025",
      "title": "Semaglutide Therapy and Accelerated Sarcopenia in Older Adults with Type 2 Diabetes: A 24-Month Retrospective Cohort Study.",
      "doi": "10.2147/DDDT.S531778",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40631351/",
      "interpretation": "An older-diabetes retrospective cohort raises a context-specific functional concern requiring causal follow-up."
    },
    {
      "pmid": "41068996",
      "year": "2026",
      "title": "Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The SEMALEAN study.",
      "doi": "10.1111/dom.70141",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41068996/",
      "interpretation": "SEMALEAN reports improved grip despite early lean loss in an uncontrolled standard-dose cohort."
    },
    {
      "pmid": "41725422",
      "year": "2026",
      "title": "Flexible dose of semaglutide reduces early discontinuation while maintaining comparable outcomes in obese patients: FLEX-SEMA 2.4 mg, an Italian real-world study.",
      "doi": "10.1111/dom.70538",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41725422/",
      "interpretation": "FLEX-SEMA documents response-selected flexible dosing; original-body threshold bins require correction of the indexed summary."
    },
    {
      "pmid": "41732031",
      "year": "2026",
      "title": "Reduced-Frequency GLP1 Therapy Maintains Weight, Body Composition, and Metabolic Syndrome Improvements: A Case Series.",
      "doi": "10.1002/oby.70137",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41732031/",
      "interpretation": "A selected reduced-frequency case series suggests a distinct de-escalation question rather than microdose initiation."
    },
    {
      "pmid": "42217114",
      "year": "2026",
      "title": "Retrospective Assessment of Food Noise Changes After Initiation of Injectable Semaglutide for Weight Management in the USA: The INFORM Survey.",
      "doi": "10.1007/s12325-026-03636-x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42217114/",
      "interpretation": "INFORM introduces semaglutide-specific FNQ recall data but cannot establish necessary mediation."
    },
    {
      "pmid": "42323166",
      "year": "2026",
      "title": "Short- and long-term effects of semaglutide 2.4 mg on energy intake, appetite, and food reward: a 60-week, double-blind randomized controlled trial.",
      "doi": "10.1016/j.ajcnut.2026.101403",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42323166/",
      "interpretation": "A 60-week randomized study separates persistent objective intake/weight effects from waning subjective appetite contrasts."
    }
  ],
  "gaps": [
    "Direct randomized below-0.5 mg weekly maintenance at 24-68 weeks in the registered baseline BMI population.",
    "Separate low-dose initiation from de-escalation after successful higher-dose loss; retain response/tolerance selection explicitly.",
    "Matched noninferiority and simultaneous benefit-harm comparison against 2.4 mg, rather than final-dose observational nulls.",
    "Prospective validated food-noise measurement and necessary-mediator testing distinct from appetite, cravings, nausea and one-meal intake.",
    "Integrated absolute muscle mass, muscle quality, objective strength/function and nutrition across baseline age/diabetes strata.",
    "Arm-specific low-dose phase 2 data and independent checking of complete bodies/supplements; three selected partial-body checks do not constitute a full-paper audit."
  ],
  "decisive_experiment": "A blinded randomized study in baseline-defined adults meeting the registered BMI criteria, stratified by diabetes, assigns a specified weekly injectable maintenance exposure below 0.5 mg, matched placebo and 2.4 mg with identical behavioral support. Prespecify 52-week weight change and at least 5% responder status, estimands, missingness, adverse events and objective strength/function. A separately randomized de-escalation arm can test maintenance after standard-dose loss without redefining the initial-treatment claim."
}