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Wittert G, Bracken K, Robledo KP, et al. 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. Lancet Diabetes Endocrinol. 2021 Jan;9(1):32-45. doi: 10.1016/S2213-8587(20)30367-3. (Original study)
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).

Ratings
Discipline Area Score
Endocrine 7 / 7
Special Interest - Obesity -- Physician 6 / 7
Family Medicine (FM)/General Practice (GP) 5 / 7
General Internal Medicine-Primary Care(US) 5 / 7
Comments from MORE raters

Endocrine rater

Well-conducted and important trial. These findings raise the possibility of androgen replacement as an option for diabetes prevention, although safety concerns remain.

Endocrine rater

The study is the largest and longest of its kind. The results are reassuring as far as side effects from TRT.

Family Medicine (FM)/General Practice (GP) rater

This study was done among men who were 50-74 years old with low testosterone and were overweight/obese. It showed that testosterone treatment for 2 years decreased their risk of progressing to DM and improved sexual quality and performance. Both groups received intensive lifestyle change guidance through an interactive website. The article has good internal validity, but I would argue against including newly diagnosed DM. Although the results are insightful, application requires a conversation with the patient, especially those who do not have baseline symptoms related to low testosterone. The discussion needs to include the balance between the added benefit of decreased risk for DM and the cost and risks of testosterone treatment. Furthermore, we don`t know whether the treatment stopped after 2 years and whether they will continue to benefit from the decreased risk for DM.

General Internal Medicine-Primary Care(US) rater

While NNT = 24 benefit for the 2-hr post-meal goal, HbA1c had a difference of only 0.02, which has minimal clinical relevance, if any. However, the NNH =29, of which the only clinical life-threatening event of a coronary event was NNG=100 does not appear to inflict a great clinical risk. Of interest, while a prostate event was more significant (primarily BPH) in the testosterone treatment group, the incidence of prostate cancer in the testosterone group was lower than placebo. The statistical significant rating, however, of enhanced sexual performance would likely have the most impact on getting my patients to consider testosterone treatment. A reality check: most insurance providers would not cover for this as a marked diminished testosterone level must be documented on two occasions to receive coverage. So, the financial relevance places the applicability of these results in question.
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