Articles
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

https://doi.org/10.1016/S2213-8587(20)30367-3Get rights and content

Summary

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).

Introduction

Low serum testosterone concentrations, which are common in men who are overweight or obese, are associated with an increased risk of incident type 2 diabetes.1 In an analysis of longitudinal data from the Florey Adelaide Male Ageing Study, incident diabetes was increased in men with a serum testosterone concentration of less than 16 nmol/L (461 ng/dL).2 In a systematic review and meta-analysis,3 men with a serum testosterone concentration greater than 15·5 nmol/L (447 ng/dL) had a 42% reduced risk of type 2 diabetes compared with men with a serum testosterone of concentration 15·5 nmol/L or less.3

Research in context

Evidence before this study

We searched PubMed and ScienceDirect on Dec 1, 2011, and again on Nov 19, 2019, using the following search terms in various combinations: “testosterone”, “type 2 diabetes”, “obesity”, “metabolic syndrome”, “weight loss”, “skeletal muscle mass”, and “insulin resistance”, restricted to the English language. Obesity (with or without insulin resistance and abnormal glucose tolerance) is associated with lowered serum testosterone concentration, which is reversed by weight loss. A low serum testosterone concentration is associated with an increased risk of incident type 2 diabetes. Testosterone treatment decreases fat mass and increases muscle mass in men. In randomised controlled trials, testosterone treatment did not lower HbA1c in men with established type 2 diabetes, but it might improve insulin resistance in men with type 2 diabetes or metabolic syndrome. In a registry-based study, testosterone treatment prevented progression of prediabetes to type 2 diabetes and improved glucose metabolism in people with type 2 diabetes. Weight loss through lifestyle intervention (ie, diet and exercise) prevents the progression of prediabetes to diabetes, including reversal of newly diagnosed type 2 diabetes, but it is not known whether testosterone treatment augments the benefits of a lifestyle intervention.

Added value of this study

The findings of the T4DM trial showed that, among men aged 50–74 years with impaired glucose tolerance or newly diagnosed type 2 diabetes and with a waist circumference of 95 cm or higher, treatment with testosterone significantly reduced the risk of type 2 diabetes (relative risk 0·59) at 2 years compared with placebo, with a between-group difference in mean change from baseline in 2-h glucose (from an oral glucose tolerance test) of −0·75 mmol/L (–1·10 to −0·40). The beneficial effects on glucose metabolism were independent of baseline testosterone concentration. Compared with placebo, testosterone was associated with a greater decrease in fat mass, increase in skeletal muscle mass and strength, and improvement in sexual function. Concerning safety, compared with placebo, treatment with testosterone was not associated with excess cardiovascular or prostate cancer adverse events. However, there were increases in haematocrit and prostate-specific antigen associated with testosterone use. An increase in haematocrit to 54% or higher was flagged in 106 (22%) of 491 testosterone-treated participants, with 25 participants ceasing treatment prematurely as a result.

Implications of all the available evidence

Our findings suggest that testosterone treatment for 2 years, as an adjunct to a lifestyle programme, can prevent or revert type 2 diabetes in overweight men without pathological hypogonadism. This effect compares favourably to that of metformin in the Diabetes Prevention Program and was accompanied by increased muscle mass, grip strength, and sexual function. Increases in haematocrit might be treatment limiting. The minimum dose exposure, duration of treatment, durability of effect, and long-term safety and cardiovascular outcomes of testosterone treatment remain to be determined. We consider it premature to advocate for the widespread use of testosterone for diabetes prevention in men without pathological hypogonadism. Identification of subgroups of men more likely to benefit or most at risk of adverse outcomes might aid treatment decisions, but, if testosterone treatment is considered, there must be a concomitant lifestyle programme and careful monitoring of haematocrit, cardiovascular risk factors, and prostate health.

Diet-induced weight loss is reported to prevent the progression of prediabetes to type 2 diabetes4 and to induce sustained normalisation of glucose tolerance, including in people with recent-onset type 2 diabetes.5 Diet-induced weight loss is also associated with modest reversal of reduced serum testosterone in men with obesity with no recognised pathological hypothalamo-pituitary-testicular (HPT) disorder.6 However, adherence to community-based lifestyle programmes can be poor and wanes with time, such that weight loss due to the lifestyle programme after 2 years is typically about 2–4 kg.7

In randomised controlled trials, testosterone treatment consistently leads to modest reductions in fat mass and increases in lean mass, body composition changes that are expected to be metabolically favourable.8 In a registry-based, uncontrolled, observational study9 of 229 men with a baseline serum testosterone concentration of 12·1 nmol/L (349 ng/dL) or less, 8 years or more of intramuscular testosterone undecanoate treatment prevented progression of prediabetes to type 2 diabetes and improved glucose metabolism in people with type 2 diabetes.

No large-scale, placebo-controlled randomised trial has assessed testosterone treatment for preventing or reversing type 2 diabetes in men who are overweight or obese. We aimed to determine the efficacy and safety of testosterone treatment to prevent progression of impaired glucose tolerance to type 2 diabetes or to reverse newly diagnosed type 2 diabetes beyond the effects of a lifestyle intervention.

Section snippets

Study design and participants

The Testosterone for Diabetes Mellitus (T4DM) trial was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. The T4DM study sites and steering committee members are listed in appendix 1 (p 2). The detailed T4DM study design has been previously reported,10 and the trial protocol and statistical analysis plan are in appendix 2.

Eligibility was confirmed at the baseline study visit. Eligible participants were men aged 50–74 years, with

Results

Of 19 022 men who underwent internet-based or telephone-based pre-screening, 1217 (6%) were eligible after laboratory screening and 1007 (5%) were enrolled and randomly assigned between Feb 5, 2013, and Feb 27, 2017 (figure 1), with 503 allocated to placebo and 504 allocated to testosterone. Baseline characteristics were similar in the placebo and testosterone groups (table 1). The final follow-up visit was on May 21, 2019. OGTT outcome data at 2 years were available for 413 (82%) of 503

Discussion

In men at high risk of, or with newly diagnosed, type 2 diabetes, who are enrolled in a lifestyle programme, testosterone treatment at standard physiological replacement doses for 2 years significantly reduced the proportion of participants with type 2 diabetes, based on a standard OGTT (RR 0·59, 95% CI 0·43 to 0·80), with a between-group difference in mean change from baseline in 2-h glucose of −0·75 mmol/L (–1·10 to −0·40). The rates seen for the categorical primary outcome at 2 years were

Data sharing

Deidentified data are available for sharing. To request data, please contact the corresponding author to be provided with a data access request form. Requests will be reviewed by the study statistician and steering committee. Applications from investigators with the academic capability and credibility to undertake the work proposed will be considered. The scientific merit of the proposal, including the appropriate methods, analysis, and publication plan will be assessed. Consideration will be

Acknowledgments

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,

References (40)

  • Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

    N Engl J Med

    (2002)
  • M Grossmann

    Low testosterone in men with type 2 diabetes: significance and treatment

    J Clin Endocrinol Metab

    (2011)
  • PA Dyson

    The therapeutics of lifestyle management on obesity

    Diabetes Obes Metab

    (2010)
  • G Corona et al.

    Testosterone supplementation and body composition: results from a meta-analysis of observational studies

    J Endocrinol Invest

    (2016)
  • A Yassin et al.

    Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry study

    Diabetes Care

    (2019)
  • IR White et al.

    Strategy for intention to treat analysis in randomised trials with missing outcome data

    BMJ

    (2011)
  • GT Ko et al.

    The reproducibility and usefulness of the oral glucose tolerance test in screening for diabetes and other cardiovascular risk factors

    Ann Clin Biochem

    (1998)
  • G Wittert et al.

    Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): design and implementation of a double-blind randomized controlled trial

    Diabetes Obes Metab

    (2019)
  • N Fuller et al.

    A within-trial cost-effectiveness analysis of primary care referral to a commercial provider for weight loss treatment, relative to standard care—an international randomised controlled trial

    Int J Obes (Lond)

    (2013)
  • The Active Australia Survey: a guide and manual for implementation, analysis and reporting

  • Cited by (0)

    *

    Joint second authors

    View full text