{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:08:52Z","timestamp":1789016932632,"version":"build-2803163510"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Tirzepatide (TZP) is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that shows full agonism at the GIP receptor (GIPR) and reduced potency with G-protein-biased partial agonism at the GLP-1 receptor (GLP-1R)\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Weight-loss response may attenuate during prolonged therapy, and some patients remain on lower doses after dose reduction for tolerability. Whether clinically relevant GLP-1R signalling capacity remains available for intermittent additional stimulation under these conditions is unknown. It is proposed that adding intermittent low-dose liraglutide to a stable low-dose TZP background, termed Receptor-Primed Episodic Agonism (RPEA), could be investigated as a way to re-engage GLP-1R signalling without increasing the TZP dose. Liraglutide has an elimination half-life of approximately 13\u00a0h, but residual systemic exposure may remain at 48\u00a0h and repeated q48h administration may accumulate; the interval therefore requires formal PK characterisation rather than being assumed to provide complete washout. RPEA is defined generally as intermittent short-acting full GLP-1R agonism on a stable TZP background; liraglutide, 0.6 mg, and q48\u201372h are illustrative candidates rather than defining features. An incremental response alone would not demonstrate priming; the defining test is a background-by-challenge interaction exceeding a prespecified additive null and not explained by a pharmacokinetic interaction. The concept rests on four explicitly unproven propositions: (i) residual GLP-1R signalling capacity during low-dose TZP; (ii) an incremental pharmacodynamic effect from episodic full GLP-1R agonism; (iii) less cumulative receptor adaptation with intermittent than continuous full-agonist exposure; and (iv) pharmacodynamic effects that may not track plasma concentration exactly. RPEA generates falsifiable preclinical and clinical questions but is not a recommendation for clinical use. No safety data are available for this off-label two-agent combination, and current prescribing information for both products does not recommend coadministration with another GLP-1 receptor agonist. The combination must not be used outside an ethics-approved clinical trial.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1922908","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:29:25Z","timestamp":1789014565000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pulsatile liraglutide on a biased tirzepatide background: a hypothesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ivan","family":"Kopitovic","sequence":"first","affiliation":[{"name":"Faculty of Medicine, University of Novi Sad","place":["Novi Sad, Serbia"]},{"name":"Institute for Pulmonary Diseases of Vojvodina","place":["Sremska Kamenica, Serbia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide once weekly 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Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1922908\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:29:27Z","timestamp":1789014567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1922908\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":14,"alternative-id":["10.3389\/fendo.2026.1922908"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1922908","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]},"article-number":"1922908"}}