In men with obesity and IGT, serum testosterone (T) is inversely associated with incident T2D. Hypothesizing that T treatment prevents or reverses T2D beyond the effects of a lifestyle program alone, we conducted a multi-center, double-blinded placebo-controlled trial. Men (N=1007), aged 50-74 yrs., waist circumference (WC)>95cm, serum T≤14nmol/L (chemiluminescent assay), and IGT or newly diagnosed T2D, established by an OGTT, were randomized to receive, on a 1:1 basis, either IM T undecanoate (Reandron, Bayer) (1000mg/4ml) or vehicle (V) at baseline, 6 weeks and then 3-monthly for 2 yrs. All participants were enrolled in a lifestyle program (Weight Watchers® (WW)). Co-primary 2-yr outcomes: (1) OGTT 2-hr glucose ≥11 mmol/L: 55/443 (12.4%) in the T and 87/413 (21.1%) in V groups; RR (95% CI) 0.59 (0.43-0.80), P<0.001; and (2) mean change from baseline in 2-hr glucose: -1.70 mmol/L and -0.95 mmol/L in the T and V groups, respectively (mean difference -0.75 (95% CI -1.10 to -0.40) P<0.001). The treatment effect was independent of baseline serum T. Secondary 2-year outcomes: Greater decreases from baseline in fasting glucose by 0.17 mmol/L, WC by 2.1 cm, total fat mass by 2.7kg, and abdominal fat mass by 2.3%, and greater increases in total muscle mass by 1.7kg, arm muscle mass by 0.36kg and hand grip strength by 2.2kg, occurred in the T vs. V group (all P<0.004). Compliance with the WW program was similar in the T (30%) vs. V (28%) groups (P=0.89). Safety: Hematocrit ≥ 0.54: 106/491 (21.6%) vs. 6/484 (1.2%) in the T vs. V groups (P<0.001). SAEs in T vs. V groups (total events 55 vs. 42): Arrythmias (8 vs. 3), IHD (7 vs. 13), cerebrovascular disease (4 vs. 3), BPH (8 vs. 3), prostate cancer (4 vs. 5), other cancers (10 vs. 4), depression (1 vs. 3). There were 2 deaths in each group. Beyond a lifestyle program, T treatment reduced the RR of T2D by ∼40% at least partially mediated by favorable changes in body composition. Clinical Trial Registration: ACTRN12612000287831.
G.A. Wittert: Research Support; Self; Bayer Inc., Lawley Pharmaceuticals, Lilly, Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins. K.P. Robledo: None. M. Grossmann: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Novartis Pharmaceuticals Canada Inc., Otsuka Pharmaceutical Co., Ltd., Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins Healthcare, Otsuka Pharmaceutical Co., Ltd. K. Bracken: None. B.B. Yeap: Advisory Panel; Self; Sanofi. Research Support; Self; Bayer AG, Lawley Pharmaceuticals. Speaker’s Bureau; Self; Besins, Sanofi. B.G.A. Stuckey: None. R.I. McLachlan: None. D.J. Handelsman: None. C. Allan: Advisory Panel; Self; Ferring Pharmaceuticals. Speaker’s Bureau; Self; Besins. W. Inder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc. Speaker’s Bureau; Self; Amgen, Novo Nordisk Inc., Pfizer Inc. D. Jesudason: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. A.C. Keech: Advisory Panel; Self; Amgen, Kowa Research Institute, Inc. Consultant; Self; Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Amgen. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. M. Ng Tang Fui: None. M. Daniel: None.
National Health and Medical Council of Australia (1030123); Eli Lilly and Company; Bayer AG; Weight Watchers; University of Adelaide