Oral Presentation ESA-SRB-APEG-NZSE 2022

A mediation analysis of the effect of testosterone treatment in the T4DM trial (#172)

Gary Wittert 1 , Kristy Robledo 2 , David Handelsman 3 , Mathis Grossmann 4 , Bu Yeap 5 , Bronwyn Stuckey 6 , Warrick Inder 7 , Karen Bracken 2 , David Jesudason 8 , Carolyn Allan 9 , Ian Marschner 10
  1. Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide , SA, Australia
  2. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
  3. Anzac Research Institute, University of Sydney, Sydney, NSW, Australia
  4. Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia
  5. Medical School, University of Western Australia, Perth, WA, Australia
  6. Keogh Institute for Medical Research, University of Western Australia, Perth, WA, Australia
  7. Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  8. Endocrinology, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
  9. Andrology, Monash Health, Melbourne, Victoria, Australia
  10. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

Background: In the T4DM study of males at high risk of, or with newly diagnosed type 2 diabetes (T2D), testosterone (T) treatment reduced T2D at 2 years by 40% beyond lifestyle change alone [1].

Aim: To test whether the T treatment effect on glycaemia is mediated through changes in fat mass, skeletal muscle mass and strength, and oestradiol (E2).

Methods: A randomised placebo-controlled trial enrolling 1007 men, 50-74 years, waist circumference ≥ 95cm, serum T ≤ 14nmol/L (chemiluminescent RIA) and either IGT or newly diagnosed T2D on an OGTT. Participants were enrolled in a lifestyle program and randomised 1:1 to 3 monthly IM injections of 1gm testosterone undecanoate or placebo. Mediation analyses used standard methodology with natural effects models, for the 2 primary outcomes of T2D at 2 years - OGTT ≥ 11.1mmol/L and 2-hour glucose change from baseline, modeled by logistic regression and linear regression respectively. Potential mediators of interest were fat mass, % abdominal fat, lean mass (DXA) and non-dominant hand-grip strength (handgrip dynamometry) and Oestradiol (LCMS) (with and without adjustment for SHBG). Mediation was adjusted for baseline covariates (risk factors and baseline mediators). Direct and indirect effects were estimated.

Results: There were complete data for 709 participants (70%). The unadjusted OR for T2D at 2 years was 0.53 (95% CI: 0.35-0.79), and 0.48 (95% CI: 0.30-0.76) adjusting for baseline covariates. Addition of the potential mediators attenuated the treatment effect, OR 0.75 (95% CI: 0.42-1.36). In mediation analyses 65% of the total effect for 2-hour glucose ≥ 11.1mmol/L, and 66% of change in 2-hour glucose from baseline were mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; p<0.001).

Conclusion: Fat mass mediated only part of the T-treatment effect on glucose metabolism; further work on the causal pathways is warranted.

  1. [1] Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle program (T4DM): A randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The Lancet Diabetes & Endocrinology 2021;9:32–45. https://doi.org/10.1016/S2213-8587(20)30367-3.