Robledo, K.P.Marschner, I.C.Grossmann, M.Handelsman, D.J.Yeap, B.B.Allan, C.A.Foote, C.Inder, W.J.Stuckey, B.G.A.Jesudason, D.Bracken, K.Keech, A.C.Jenkins, A.J.Gebski, V.Jardine, M.Wittert, G.2025-05-012025-05-012025European Journal of Endocrinology (EJE), 2025; 192(1):15-240804-46431479-683Xhttps://hdl.handle.net/2440/144348Objective: We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect. Design: Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357). Methods: Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) ≥11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression. Results: Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c ≥ 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant’s absolute risk of type 2 diabetes. Conclusions: Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c ≥ 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.en© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.risk prediction modelrisk prediction model validationrisk scoretestosteronetype 2 diabetesHumansDiabetes Mellitus, Type 2Glucose IntoleranceTestosteroneBlood GlucoseGlucose Tolerance TestPrognosisRisk AssessmentRisk FactorsLife StyleAgedMiddle AgedAustraliaMaleGlycated HemoglobinJournal article10.1093/ejendo/lvae166724334Wittert, G. [0000-0001-6818-6065]