TY - JOUR
T1 - Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM)
T2 - a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial
AU - Wittert, Gary
AU - Bracken, Karen
AU - Robledo, Kristy P.
AU - Grossmann, Mathis
AU - Yeap, Bu B.
AU - Handelsman, David J.
AU - Stuckey, Bronwyn
AU - Conway, Ann
AU - Inder, Warrick
AU - McLachlan, Robert
AU - Allan, Carolyn
AU - Jesudason, David
AU - Fui, Mark Ng Tang
AU - Hague, Wendy
AU - Jenkins, Alicia
AU - Daniel, Mark
AU - Gebski, Val
AU - Keech, Anthony
N1 - Funding Information:
This study was funded by the Australian NHMRC (project grant 1030123), Bayer, Eli Lilly, and the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide. WW (formerly Weight Watchers) provided access to the lifestyle intervention at no cost. Bayer provided the testosterone and matching placebo used in the study at no cost. We thank the T4DM study participants; Sonic Healthcare (Australia); and the study nurses, Glenda Fraser (ANZAC Research Institute and Concord Hospital, Sydney, NSW, Australia), Jenny Healy (Austin Hospital, Melbourne, VIC, Australia), Helen Daniels and Chyn Soh (Fremantle Hospital and Fiona Stanley Hospital, both in Perth, WA, Australia), Jody Sawyer (Princess Alexandra Hospital, Brisbane, QLD, Australia), Rosemary Cox and Fiona Cossey (Queen Elizabeth Hospital, Adelaide, SA, Australia), and Lee Mahoney (Keogh Institute for Medical Research, Perth, WA, Australia). We also thank Simone Marschner, Andrzej Januszewski, Caitlin Van Holst Pellekaan, Cecilia Taing, and Sandra Healey for their contribution to central coordination of the study at the NHMRC Clinical Trials Centre (University of Sydney, Sydney, NSW, Australia), Margaret McGee (University of Adelaide, Adelaide, SA, Australia) for providing administrative and project support in the trial, and Sue Shanley (University of Adelaide, Adelaide, SA, Australia) for her initial clinical trial coordination at Queen Elizabeth Hospital site, Adelaide, SA, Australia.
Funding Information:
This study was funded by the Australian NHMRC (project grant 1030123), Bayer, Eli Lilly, and the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide. WW (formerly Weight Watchers) provided access to the lifestyle intervention at no cost. Bayer provided the testosterone and matching placebo used in the study at no cost. We thank the T4DM study participants; Sonic Healthcare (Australia); and the study nurses, Glenda Fraser (ANZAC Research Institute and Concord Hospital, Sydney, NSW, Australia), Jenny Healy (Austin Hospital, Melbourne, VIC, Australia), Helen Daniels and Chyn Soh (Fremantle Hospital and Fiona Stanley Hospital, both in Perth, WA, Australia), Jody Sawyer (Princess Alexandra Hospital, Brisbane, QLD, Australia), Rosemary Cox and Fiona Cossey (Queen Elizabeth Hospital, Adelaide, SA, Australia), and Lee Mahoney (Keogh Institute for Medical Research, Perth, WA, Australia). We also thank Simone Marschner, Andrzej Januszewski, Caitlin Van Holst Pellekaan, Cecilia Taing, and Sandra Healey for their contribution to central coordination of the study at the NHMRC Clinical Trials Centre (University of Sydney, Sydney, NSW, Australia), Margaret McGee (University of Adelaide, Adelaide, SA, Australia) for providing administrative and project support in the trial, and Sue Shanley (University of Adelaide, Adelaide, SA, Australia) for her initial clinical trial coordination at Queen Elizabeth Hospital site, Adelaide, SA, Australia.
Funding Information:
GW, KB, KPR, MG, BBY, BS, AC, WI, RM, CA, DJ, MNTF, WH, AJ, VG, and AK report grants from the Australian National Health and Medical Research Council (NHMRC), grants and non-financial support with the testosterone and matching placebo used in the study from Bayer, grants from Eli Lilly, and non-financial support (ie, free access to the lifestyle programme for study participants) from WW (formerly Weight Watchers), related to the present study. GW also reports grants from the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide, related to the conduct of the present study, as well as grants and honoraria from Lawley Pharmaceuticals and Elsevier, and speaker fees from Bayer and Besins, unrelated to the present study. DJH reports grants from the NHMRC, grants and non-financial support from Bayer (testosterone and matching placebo used in this study), and non-financial support from WW (ie, free access to the lifestyle programme for study participants), related to the present study. DJH also reports grants from Besins and Lawley Pharmaceuticals, unrelated to the present study, and has provided expert testimony to anti-doping and professional standards tribunals and testosterone tort litigation. BBY also reports conference support and honoraria from, and an advisory role for Eli Lilly and Besins; conference support and honoraria from Bayer; research grants and research support from, and an advisory role for Lawley Pharmaceuticals; and honorarium from and an advisory role for Ferring, unrelated to the present study. BS also reports speaker honoraria from Besins, unrelated to the present study. CA also reports being on an advisory panel for Ferring and speaker's bureau from Besins, unrelated to the present study. DJ also reports honoraria from Eli Lilly, Merck, and Boehringer Ingelheim, unrelated to the present study. MG also reports grants and consultancy fees as an advisory board member from Otsuka and speaker fees from Besins, unrelated to the present study. AJ also reports grants from Abbott, non-financial support (provision of trial drug and placebo, unrelated to the present study) from Mylan, grants from the NHMRC, grants and non-financial support (provision of devices for a study unrelated to the present study) from Medtronic, grants from JDRF, grants from the Leona M and Harry B Helmsley Charitable Trust, being an honorary board member for Insulin for Life, grants from the International Diabetes Federation (IDF), and being an honorary board member for the IDF Western Pacific Region Executive Council, unrelated to the present study. AK also reports honoraria and research funding from, and being an advisory board member for Amgen; grants, honoraria, and support for educational activity from Mylan and Novartis; honoraria from, and being on an advisory board for AstraZeneca, Sanofi, and Bayer; sitting fees from Kowa; and hororaria from Pfizer, unrelated to the present study. MD declares no competing interests.
Publisher Copyright:
© 2021 Elsevier Ltd
Funding Information:
This study was funded by the Australian NHMRC (project grant 1030123), Bayer, Eli Lilly, and the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide. WW (formerly Weight Watchers) provided access to the lifestyle intervention at no cost. Bayer provided the testosterone and matching placebo used in the study at no cost. We thank the T4DM study participants; Sonic Healthcare (Australia); and the study nurses, Glenda Fraser (ANZAC Research Institute and Concord Hospital, Sydney, NSW, Australia), Jenny Healy (Austin Hospital, Melbourne, VIC, Australia), Helen Daniels and Chyn Soh (Fremantle Hospital and Fiona Stanley Hospital, both in Perth, WA, Australia), Jody Sawyer (Princess Alexandra Hospital, Brisbane, QLD, Australia), Rosemary Cox and Fiona Cossey (Queen Elizabeth Hospital, Adelaide, SA, Australia), and Lee Mahoney (Keogh Institute for Medical Research, Perth, WA, Australia). We also thank Simone Marschner, Andrzej Januszewski, Caitlin Van Holst Pellekaan, Cecilia Taing, and Sandra Healey for their contribution to central coordination of the study at the NHMRC Clinical Trials Centre (University of Sydney, Sydney, NSW, Australia), Margaret McGee (University of Adelaide, Adelaide, SA, Australia) for providing administrative and project support in the trial, and Sue Shanley (University of Adelaide, Adelaide, SA, Australia) for her initial clinical trial coordination at Queen Elizabeth Hospital site, Adelaide, SA, Australia.
Funding Information:
This study was funded by the Australian NHMRC (project grant 1030123), Bayer, Eli Lilly, and the Freemasons Centre for Male Health and Wellbeing at the University of Adelaide. WW (formerly Weight Watchers) provided access to the lifestyle intervention at no cost. Bayer provided the testosterone and matching placebo used in the study at no cost. We thank the T4DM study participants; Sonic Healthcare (Australia); and the study nurses, Glenda Fraser (ANZAC Research Institute and Concord Hospital, Sydney, NSW, Australia), Jenny Healy (Austin Hospital, Melbourne, VIC, Australia), Helen Daniels and Chyn Soh (Fremantle Hospital and Fiona Stanley Hospital, both in Perth, WA, Australia), Jody Sawyer (Princess Alexandra Hospital, Brisbane, QLD, Australia), Rosemary Cox and Fiona Cossey (Queen Elizabeth Hospital, Adelaide, SA, Australia), and Lee Mahoney (Keogh Institute for Medical Research, Perth, WA, Australia). We also thank Simone Marschner, Andrzej Januszewski, Caitlin Van Holst Pellekaan, Cecilia Taing, and Sandra Healey for their contribution to central coordination of the study at the NHMRC Clinical Trials Centre (University of Sydney, Sydney, NSW, Australia), Margaret McGee (University of Adelaide, Adelaide, SA, Australia) for providing administrative and project support in the trial, and Sue Shanley (University of Adelaide, Adelaide, SA, Australia) for her initial clinical trial coordination at Queen Elizabeth Hospital site, Adelaide, SA, Australia.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85097737438&partnerID=8YFLogxK
U2 - 10.1016/S2213-8587(20)30367-3
DO - 10.1016/S2213-8587(20)30367-3
M3 - Article
C2 - 33338415
AN - SCOPUS:85097737438
SN - 2213-8587
VL - 9
SP - 32
EP - 45
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
IS - 1
ER -