Predicting Type 2 Diabetes and Testosterone Effects in high-risk Australian men: Development and external validation of a 2 year risk model

Kristy P Robledo; Ian C Marschner; Mathis Grossmann; David J Handelsman; Bu B Yeap; Carolyn A Allan; Celine Foote; Warrick J Inder; Bronwyn G A Stuckey; David Jesudason; Karen Bracken; Anthony C Keech; Alicia J Jenkins; Val Gebski; Meg Jardine; Gary Wittert

doi:10.1093/ejendo/lvae166

Predicting Type 2 Diabetes and Testosterone Effects in high-risk Australian men: Development and external validation of a 2 year risk model

Eur J Endocrinol. 2024 Dec 25:lvae166. doi: 10.1093/ejendo/lvae166. Online ahead of print.

Authors

Kristy P Robledo¹, Ian C Marschner², Mathis Grossmann^{3

4}, David J Handelsman^{5

6}, Bu B Yeap^{7

8}, Carolyn A Allan^{9

10}, Celine Foote¹¹, Warrick J Inder^{12

13}, Bronwyn G A Stuckey^{14

15

16}, David Jesudason^{17

18}, Karen Bracken¹⁹, Anthony C Keech², Alicia J Jenkins²⁰, Val Gebski², Meg Jardine², Gary Wittert^{21

22}

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Locked bag 77, Camperdown NSW 1450, Australia.
² NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia.
³ Department of Endocrinology, Austin Hospital, Heidelberg, VIC 3084, Australia.
⁴ Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia.
⁵ Andrology, ANZAC Research Institute, University of Sydney, Concord, NSW 2139, Australia.
⁶ Andrology Department, Concord Hospital, Concord, NSW 2139, Australia.
⁷ Medical School, University of Western Australia, Perth, WA 6009, Australia.
⁸ Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Murdoch, WA 6150, Australia.
⁹ Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
¹⁰ School of Clinical Sciences, Monash University, Clayton, VIC 3800, Australia.
¹¹ The George Institute for Global Health, UNSW, Sydney, Australia.
¹² Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
¹³ Medical School, University of Queensland, Herston, QLD 4029, Australia.
¹⁴ Keogh Institute for Medical Research, Nedlands, WA Australia 6009.
¹⁵ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands WA 6009, Australia.
¹⁶ Medical School, University of Western Australia, Nedlands, WA, Australia, 6009.
¹⁷ School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
¹⁸ Endocrinology Unit, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia.
¹⁹ University of Sydney, Camperdown, Australia.
²⁰ Baker Heart and Diabetes Institute, Melbourne, Australia.
²¹ Freemasons Centre for Male Health and Wellbeing. South Australian Health and Medical Research Institute.
²² University of Adelaide, North Terrace, Adelaide 5000.

PMID: 39720906
DOI: 10.1093/ejendo/lvae166

Abstract

Objective: 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 two 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 two 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 T4DM; 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 two years defined as 2-hour fasting glucose by oral glucose tolerance test (OGTT) ≥ 11.1mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.

Results: Baseline HbA1c and 2-hour OGTT glucose were dominant predictors, together with Testosterone, age, and an interaction between Testosterone and HbA1c (p=0.035, greater benefit with HbA1c≥5.6%, 38mmol/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-hour 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% (38mmol/mol) benefit most from Testosterone treatment, beyond a lifestyle program.

Keywords: risk prediction model; risk prediction model validation; risk score; testosterone; type 2 diabetes.