Men with obesity, particularly when visceral and associated with insulin resistance have lower serum testosterone (T) concentrations than age matched healthy men. The low serum T is an independent risk factor for incident type 2 diabetes (T2D) in these men. We aimed to determine whether T treatment for 2 years decreased this risk over and above the effects of a lifestyle program.
We undertook a parallel, 6-centre, randomised, double-blind, placebo-controlled phase 3 trial. Participants were men, aged 50–74 years, waist circumference (WC) ≥ 95 cm, serum testosterone ≤ 14 nmol/L and with either impaired glucose tolerance (IGT) or newly diagnosed T2D assessed by Oral Glucose Tolerance Test (OGTT), (N=1007, 20% with T2D). All men were enrolled in a lifestyle program (WW) and randomised to receive intramuscular testosterone undecanoate 1000mg or placebo 3 monthly for 2 years.
At 2-years, in T (504) vs placebo (503) treated men 12.4% (55/443) vs 21.1% (87/413) had T2D (p=0.0007), 2-h glucose was 1.70 (SD: 2.78) vs. 0.95 (SD: 2.47) mmol/L lower than at baseline (p<0.0001), and GTT normalised in 51.9% vs 43.3% (P=0.012). The treatment effect was independent of baseline serum T and associated with greater loss of fat mass and increased muscle mass and strength. Lifestyle program engagement, quality of life and psychosocial function measures were similar in each group.
Harms (T vs placebo): (i) Safety triggers: Haematocrit ≥0.54% in 22% (106/491) vs. 1% (6/484); increase in PSA in 23% (109/480) vs 19% (87/468); (ii) SAEs: Cardiovascular (19 vs 19), BPH (8 vs 3), prostate cancer (4 vs 5), other cancers (10 vs 4), depression (1 vs 3), deaths (2 vs 2).
Conclusion: Testosterone treatment for 2 years reduced T2D prevalence by 40% beyond the effects of a lifestyle program, and effect primarily mediated by favourable changes in body composition.