Men with obesity and 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.
In order to determine whether T treatment for 2 years decreased this risk beyond 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: T2D in 12.4% (55/443) vs 21.1% (87/413) (p=0.0007), 2-h glucose 0.75 mmol/L lower than at baseline (p<0.0001), GTT normalised 51.9% vs 43.3% (P=0.012) and HbA1c was similar. The treatment effect was independent of baseline serum T and associated with a decrease in fat mass. Muscle mass and strength, bone density, erectile function, sexual desire and satisfaction increased significantly in T treated men. Lifestyle program engagement, quality of life and psychosocial function measures were similar in each group.
Harms (T vs placebo): 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). Increased haematocrit ≥ 0.54 in 22% (106/491) vs. 1% (6/484), resulting in withdrawal of 25 men; and PSA in 23% (109/480) vs 19% (87/468).
Conclusion: Testosterone treatment for 2 years reduced T2D prevalence by 40% beyond the effects of a lifestyle program, an effect that is pharmacological, primarily mediated by favourable changes in body composition. Although without an increase in cardio-vascular risk, increases in haematocrit may be treatment limiting and longer-term durability and safety are uncertain.
Conclusion: Testosterone treatment for 2 years reduced T2D prevalence by 40% beyond the effects of a lifestyle program, an effect that is pharmacological, primarily mediated by favourable changes in body composition. Although without an increase in cardio-vascular risk, increases in haematocrit may be treatment limiting and longer-term durability and safety are uncertain.