Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial

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Gary Wittert 1, Karen Bracken 2, Kristy P Robledo 2, Mathis Grossmann 3, Bu B Yeap 4, David J Handelsman 5, Bronwyn Stuckey 6, Ann Conway 5, Warrick Inder 7, Robert McLachlan 8, Carolyn Allan 8, David Jesudason 9, Mark Ng Tang Fui 3, Wendy Hague 2, Alicia Jenkins 2, Mark Daniel 10, Val Gebski 2, Anthony Keech 2

Main idea: Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated.

Abstract

Background: Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme.

Methods: T4DM was a randomized, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centers. Men aged 50-74 years, with a waist circumference of 95 cm or higher, were enrolled in a lifestyle program. They were given an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose) and mean change from baseline in 2-h glucose, assessed by intention to treat. For safety assessment, we did masked monitoring of hematocrit and prostate-specific antigen and analyzed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Findings: At 2 years, 2-h glucose of 11 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group. The treatment effect was independent of baseline serum testosterone. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the Placebo group. There were two deaths in each group, and a safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants inThe placebo group. A trigger for an increase of 0.75 mg/mL or more in prostate-specific antigen occurred in 19% of 468 participants.

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