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https://hdl.handle.net/2440/129790
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Type: | Journal article |
Title: | 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 |
Author: | Wittert, G. Bracken, K. Robledo, K.P. Grossmann, M. Yeap, B.B. Handelsman, D.J. Stuckey, B. Conway, A. Inder, W. McLachlan, R. Allan, C. Jesudason, D. Fui, M.N.T. Hague, W. Jenkins, A. Daniel, M. Gebski, V. Keech, A. |
Citation: | Lancet Diabetes and Endocrinology, 2021; 9(1):32-45 |
Publisher: | Lancet Publishing Group |
Issue Date: | 2021 |
ISSN: | 2213-8587 2213-8595 |
Statement of Responsibility: | Gary Wittert, Karen Bracken, Kristy P Robledo, Mathis Grossmann, Bu B Yeap ... David Jesudason ... et al. |
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 randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. FINDINGS: Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 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 (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 μg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group. INTERPRETATION: 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. FUNDING: Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers). |
Keywords: | Humans Diabetes Mellitus, Type 2 Prediabetic State Glucose Intolerance Disease Progression Testosterone Placebos Treatment Outcome Remission Induction Double-Blind Method Risk Reduction Behavior Life Style Aged Middle Aged Australia Male |
Rights: | © 2020 Elsevier Ltd. All rights reserved. |
DOI: | 10.1016/S2213-8587(20)30367-3 |
Published version: | http://dx.doi.org/10.1016/s2213-8587(20)30367-3 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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