{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:08:23Z","timestamp":1790690903430,"version":"4.1.0"},"reference-count":34,"publisher":"The Endocrine Society","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>In a 28-week clinical trial of patients with Type 2 diabetes (T2D), tirzepatide 15\u2005mg (a dual glucose-dependent insulinotropic polypeptide\/glucagon-like peptide-1 [GLP-1] receptor agonist) and semaglutide 1\u2005mg (a GLP-1 receptor agonist) both improved fasting glucose, with tirzepatide showing superior efficacy. The longitudinal metabolic mechanisms underlying this difference remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The objective of this study was to compare the longitudinal metabolic effects of tirzepatide and semaglutide using model-based analysis of fasting measures, elucidate underlying mechanisms, and explore strategies to enhance outcomes in low responders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A mechanistic longitudinal model was developed based on the trial data from patients treated with tirzepatide or semaglutide. The model integrates fasting glucose, fasting insulin, insulin sensitivity, and \u03b2-cell function over time, enabling quantification of hepatic glucose production (HGP) and isolation of insulin-independent drug effects on HGP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\u03b2-Cell function, as assessed by the Homeostasis Model Assessment of Beta-Cell Function, initially increased and then declined as insulin sensitivity improved, a reversal of the canonical T2D progression pathway. Tirzepatide's superior fasting glucose control vs semaglutide was driven primarily by greater insulin-independent suppression of HGP. Low responders exhibited deficient HGP suppression, and simulations suggested that enhancing HGP suppression improves fasting glucose without inducing \u03b2-cell stress associated with sustained hypersecretion. Simulated enhancement of weight loss accelerated early glycemic improvement but did not further reduce long-term fasting glucose levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Greater suppression of HGP was associated with greater efficacy of tirzepatide 15\u2005mg vs semaglutide 1\u2005mg in improving fasting glucose. Therapeutic strategies targeting suppression of HGP may provide metabolic benefit beyond direct enhancement of \u03b2-cell function or additional weight loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag383","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:20:42Z","timestamp":1789672842000},"source":"Crossref","is-referenced-by-count":0,"title":["Quantitative insights into tirzepatide and semaglutide using longitudinal systems modeling"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9399-2325","authenticated-orcid":false,"given":"Boya","family":"Yang","sequence":"first","affiliation":[{"name":"Laboratory of Biological Modeling, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Over","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories, Eli Lilly and Company , 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