{
  "abstract": "Semaglutide and tirzepatide are typically evaluated through dose escalation, yet many patients in routine care do not reach a recommended maintenance dose due to tolerability, access, cost, supply, or individualized goals. Here, we used repeated 0.25 mg only semaglutide and 2.5 mg only tirzepatide prescription records as real-world proxies for sustained treatment at the lowest approved dose, a prescribing pattern that may overlap with, but does not establish, intentional microdosing. We analyzed de-identified electronic health records (EHRs) from a federated system of 29 million patients. Among 490 072 semaglutide-treated patients, 814 met the stringent sustained low-dose criterion of at least three distinct 0.25-mg prescriptions spanning at least 6 months from the first to the last qualifying prescription and among 322 442 tirzepatide-treated patients, 1016 met the analogous criterion of at least three distinct 2.5-mg prescriptions spanning at least 6 months. In a matched head-to-head comparison aided by AI-enabled curation of clinical notes, sustained low-dose tirzepatide showed higher 24-month adverse event rates (P < .05) than sustained low-dose semaglutide for constipation (32.6% vs. 22.4%), acute kidney injury (2.7% vs. 0.4%), muscle cramps (8.3% vs. 4%), lumbar disc disease (3.3% vs. 0.3%), dyspnea on exertion (9.6% vs. 6.8%), lentigo (4.7% vs. 0.8%), and actinic keratosis (3.3% vs. 0.6%), whereas sustained low-dose semaglutide (vs. tirzepatide) had higher rates of including otitis (5.6% vs. 2.1%), diaphoresis (5.5% vs. 3.2%), and ankle swelling (6.9% vs. 3.7%). Sustained low-dose tirzepatide was associated with greater weight loss than semaglutide (mean 12-month percent weight change -5.5% vs. -2.2%; P < .05 at all timepoints). Analyses of prescription patterns supported the findings from clinical notes. For example, renal-supportive and hyperkalemia therapies increased after low-dose tirzepatide (5.6% to 9.5% at 12 months, P = .016) but not after low-dose semaglutide (8.2% to 6.6%, P = .382). Taken together, these observational associations motivate prospective studies to better characterize the outcomes and pharmacology of sustained initiation-dose semaglutide or tirzepatide, and related microdosing studies.",
  "abstract_shown": true,
  "affiliations": [
    "nference Inc., Cambridge, MA 02142, United States.",
    "Metabolism Agentic Intelligence Atlas (MAIA), Cambridge, MA 02142, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Karthik Murugadoss"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "A J Venkatakrishnan",
      "orcid": "0000-0003-2819-3214"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Venky Soundararajan",
      "orcid": "0000-0001-7434-9211"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4hk0dtmrp1yky.bib",
  "cited_by": 0,
  "doi": "10.1093/biomethods/bpag048",
  "fulltext_url": "https://europepmc.org/articles/PMC13651699",
  "id": "4hk0dtmrp1yky",
  "issns": [
    "2396-8923"
  ],
  "landing_url": "https://europepmc.org/article/MED/42857675",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2712|Diabetes Treatment and Management"
    ]
  ],
  "openalex": "W7204795908",
  "pdf_url": "https://europepmc.org/articles/PMC13651699?pdf=render",
  "pmcid": "PMC13651699",
  "pmid": "42857675",
  "published": "2026-08-31",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4hk0dtmrp1yky.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:18Z",
      "native_id": "MED:42857675",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42857675"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Diabetes Treatment and Management",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Comparison of cardiometabolic benefits and tolerability in patients on sustained low doses of semaglutide or tirzepatide.",
  "title_text": "Comparison of cardiometabolic benefits and tolerability in patients on sustained low doses of semaglutide or tirzepatide.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:18Z",
  "url": "https://research.draconitic.com/paper/4hk0dtmrp1yky",
  "venue": "Biology methods & protocols",
  "versions": []
}