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Leveraging unsupervised clustering in comprehensively phenotyped cohorts has identified six reproducible prediabetes subtypes integrating insulin sensitivity, insulin secretion, visceral and hepatic fat, and genetic risk. Three high-risk subtypes (progressing prediabetes with fatty liver, progressing prediabetes with \u03b2-cell failure, and slow progressors with hyperinsulinemic insulin resistance) show distinct trajectories toward diabetes and unique complication patterns. For example, \u201cslow progressors\u201d develop albuminuria and face excess mortality, despite only modest glycemic deterioration over 10\u201315 years, showing that complications can arise before diabetes diagnosis. Recognizing these subtypes sharpens risk stratification and opens a path toward precision prevention. Intensive lifestyle modification and bariatric surgery offer the greatest glycemic benefit in the fatty liver subtype, whereas early pharmacologic \u03b2-cell protection may be required for the \u03b2-cell failure cluster. GLP-1\u2013based therapies offer promising subtype-specific options and should be tested in randomized controlled studies. Future prediabetes intervention trials should move beyond diabetes incidence as the sole end point and systematically evaluate kidney, nerve, eye, and cardiovascular outcomes. While testing for long-term clinical end points might not be feasible in studies where individuals with prediabetes are recruited, the use of surrogate end points could facilitate the assessment of early complications. Such complication-focused, subtype-guided studies will determine whether early, tailored therapy can halt tissue damage and reduce the public health burden linked to prediabetes.<\/jats:p>","DOI":"10.2337\/dci25-0054","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T14:18:51Z","timestamp":1757600331000},"page":"226-235","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":21,"title":["Beyond Glucose\u2014Rethinking Prediabetes for Precision Prevention"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6120-0191","authenticated-orcid":false,"given":"Robert","family":"Wagner","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Diabetology, Medical Faculty, and University Hospital D\u00fcsseldorf 1 , Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"},{"name":"Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf 2 , D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research (DZD) 3 , Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-7151","authenticated-orcid":false,"given":"Elizabeth","family":"Selvin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health 4 , Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratika","family":"Sehgal","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine I, Ulm University Hospital 5 , Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsiaryna","family":"Prystupa","sequence":"additional","affiliation":[{"name":"Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University D\u00fcsseldorf 2 , D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research (DZD) 3 , Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2886-0726","authenticated-orcid":false,"given":"Shivani","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion & Reproduction, Imperial College London, and Department of Diabetes and Endocrinology, St Mary\u2019s Hospital, Imperial College Healthcare NHS Trust 6 , London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4987-1961","authenticated-orcid":false,"given":"Andreas","family":"Fritsche","sequence":"additional","affiliation":[{"name":"German Center for Diabetes Research (DZD) 3 , Neuherberg, Germany"},{"name":"Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of T\u00fcbingen 7 , T\u00fcbingen, Germany"},{"name":"Division of Diabetology, Endocrinology and Nephrology, Department of Internal Medicine, Eberhard-Karls University T\u00fcbingen, T\u00fcbingen 8 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8462-3832","authenticated-orcid":false,"given":"Martin","family":"Heni","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine I, Ulm University Hospital 5 , Ulm, Germany"},{"name":"Institute for Clinical Chemistry and Pathobiochemistry, University Hospital T\u00fcbingen 9 , T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"2026061811381495600_B1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1146\/annurev-publhealth-090419-102644","article-title":"Prediabetes and what it means: the epidemiological evidence","volume":"42","author":"Echouffo-Tcheugui","year":"2021","journal-title":"Annu Rev Public Health"},{"key":"2026061811381495600_B2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41591-020-1116-9","article-title":"Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes","volume":"27","author":"Wagner","year":"2021","journal-title":"Nat Med"},{"key":"2026061811381495600_B3","doi-asserted-by":"crossref","first-page":"920","DOI":"10.2337\/diacare.22.6.920","article-title":"Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. 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