{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:37:23Z","timestamp":1791981443232,"version":"4.4.0"},"reference-count":31,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100007885","name":"European Association for the Study of Diabetes","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007885","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Different precision treatment approaches have been proposed for type 2 diabetes, but robust comparisons are lacking. We compared the utility of proposed approaches targeting glucose-lowering therapy in the TriMaster three-way crossover trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We evaluated four previously reported precision treatment strategies for their ability to predict overall 4-month HbA1c response and within-person differential response to sitagliptin, canagliflozin, and pioglitazone in 309 adults with type 2 diabetes who received all three medications. Approaches included allocation to clusters based on routine features and HOMA, direct outcome prediction using a routine-features treatment-selection model, type 2 diabetes cluster-specific partitioned polygenic scores (PPSs), and a model based on discriminative dimensionality reduction tree (DDRTree) analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The routine-features model and cluster approach were both strongly associated with overall and differential HbA1c responses (P &amp;lt; 0.0001). The routine-features model identified the most effective therapy with significant benefit across all drug comparisons, whereas clinical clusters showed benefit for only one cluster-drug comparison (severe insulin-resistant diabetes: SGLT2i vs. thiazolidinedione [TZD], P = 0.005). DDRTree was not associated with treatment response. Of eight PPSs, only two showed modest association with differential response (lipodystrophy PPS had a greater response to SGLT2 vs. TZD; and \u03b2-cell dysfunction, negative proinsulin PPS had a greater response to TZD vs. dipeptidyl peptidase 4 inhibitor). Treatment allocation based on the routine-features model resulted in greater HbA1c reduction than cluster-based allocation (0.27% [95% CI 0.18, 0.35], 2.9 mmol\/mol [95% CI 2.0, 3.8] vs. 0.16% [95% CI 0.07, 0.25], 1.7 mmol\/mol [95% CI 0.8, 2.7]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Clinical features are more strongly associated with differential glycemic response than PPS, and direct outcome prediction outperforms data-driven subgrouping for optimizing short-term HbA1c reduction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc26-0118","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:16:11Z","timestamp":1781788571000},"page":"1458-1466","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":1,"title":["To Cluster or Not to Cluster? A Comparison of Approaches to Targeting Type 2 Diabetes Glucose-Lowering Therapy in the TriMaster Crossover Trial"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-3653","authenticated-orcid":false,"given":"Laura M.","family":"G\u00fcdemann","sequence":"first","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Angwin","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rury R.","family":"Holman","sequence":"additional","affiliation":[{"name":"Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford 2 , Oxford, U.K."},{"name":"National Institute for Health and Care Research Oxford Biomedical Research Centre, Churchill Hospital 3 , Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-2593","authenticated-orcid":false,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow 4 , Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewan R.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Reproductive Medicine, Ninewells Hospital and Medical School, University of Dundee 5 , Dundee, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Murray Leech","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashyap A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5620-473X","authenticated-orcid":false,"given":"Andrew T.","family":"Hattersley","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverley M.","family":"Shields","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences, University of Exeter Medical School 1 , Exeter, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0883-7599","authenticated-orcid":false,"given":"Angus 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