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Cited by 362Hormonal and reproductive studiesDiabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.

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

Wittert, Gary, Bracken, Karen, Robledo, Kristy P, Grossmann, Mathis, Yeap, Bu B, Handelsman, David J, Stuckey, Bronwyn, Conway, Ann, Inder, Warrick, McLachlan, Robert, Allan, Carolyn, Jesudason, David, Fui, Mark Ng Tang, Hague, Wendy, Jenkins, Alicia, Daniel, Mark, Gebski, Val, Keech, Anthony·2021·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(20)30367-3
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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).

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Metadata

Authors
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.
Affiliations
  • South Australian Health and Medical Research Institute (AU)
  • The University of Sydney (AU)
  • The University of Melbourne (AU)
  • The University of Western Australia (AU)
  • The University of Queensland (AU)
  • Hudson Institute of Medical Research (AU)
  • Queen Elizabeth Hospital (AU)
Corresponding author
Wittert, Gary
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2021-01
Volume
9
Issue
1
Pages
32-45
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(20)30367-3
OpenAlex
W3111066920
Cited by
362
References
39
Citations by year
2026: 38 · 2025: 77 · 2024: 76 · 2023: 66 · 2022: 62 · 2021: 42
FWCI
32.23
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Diabetes & Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders
  • Queen Elizabeth Hospital Birmingham Charity
  • National Health and Medical Research Council (1030123)
  • University of Sydney
  • University of Adelaide
  • Fiona Stanley Hospital
  • Bayer
  • Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
testosterone undecanoate, type 2 diabetes prevention, impaired glucose tolerance, androgen deficiency, hypogonadism, lifestyle intervention, men, obesity, waist circumference, glucose tolerance, testosterone replacement therapy, diabetes progression, adverse events, hematocrit, prostate-specific antigen, serious adverse events, men's health, family history (medicine)
MeSH terms
Aged, Australia, Diabetes Mellitus, Type 2, Double-Blind Method, Humans, Life Style, Male, Middle Aged, Placebos, Prediabetic State, Remission Induction, Testosterone, Treatment Outcome, Glucose Intolerance, Disease Progression, Risk Reduction Behavior

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