Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia.
Lancet Diabetes Endocrinol. 2021 Jan;9(1):32-45. doi: 10.1016/S2213-8587(20)30367-3.
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.
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.
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.
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.
Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).
超重或肥胖的男性常伴有血清睾酮浓度降低，这与 2 型糖尿病风险增加有关。我们旨在确定睾酮治疗是否能预防或逆转 2 型糖尿病的进展，而不仅仅是基于社区生活方式项目的影响。
T4DM 是一项在澳大利亚六家三级护理中心进行的随机、双盲、安慰剂对照、为期 2 年的 3b 期试验。研究对象为年龄在 50-74 岁之间、腰围 95cm 或以上、血清睾酮浓度 14.0nmol/L 或以下但无病理性性腺功能减退症和糖耐量受损（口服葡萄糖耐量试验[OGTT]2 小时血糖 7.8-11.0mmol/L）或新诊断为 2 型糖尿病（OGTT 2 小时血糖≤15.0mmol/L）的男性。这些男性参加了生活方式项目，并随机（1:1）接受肌内注射十一酸睾酮（1000mg）或安慰剂，基线时、6 周后、然后每 3 个月一次，共 2 年。随机分组由中央进行，包括按中心、年龄组、腰围、2 小时 OGTT 血糖、吸烟和 2 型糖尿病一级家族史分层。主要终点是 2 型糖尿病（2 小时 OGTT 血糖≥11.1mmol/L）和 2 小时 OGTT 血糖从基线的平均变化，采用意向治疗进行评估。为了进行安全性评估，我们对血细胞比容和前列腺特异性抗原进行了盲法监测，并分析了预先指定的严重不良事件。这项研究在澳大利亚和新西兰临床试验注册中心注册，注册号为 ACTRN12612000287831。
在 2013 年 2 月 5 日至 2017 年 2 月 27 日期间，在 19022 名接受预筛选的男性中，有 1007 名（5%）被随机分配到安慰剂（n=503）和睾酮（n=504）组。在 2 年时，有 413 名有可用数据的参与者中，有 87 名（21%）的 2 小时 OGTT 血糖为 11.1mmol/L 或更高，而在 443 名接受睾酮治疗的参与者中，有 55 名（12%）的 2 小时 OGTT 血糖为 11.1mmol/L 或更高（相对风险 0.59，95%CI 0.43-0.80；p=0.0007）。安慰剂组的 2 小时 OGTT 血糖从基线的平均变化为-0.95mmol/L（SD 2.78），而睾酮组为-1.70mmol/L（SD 2.47）（平均差异-0.75mmol/L，-1.10 至-0.40；p<0.0001）。治疗效果与基线血清睾酮无关。在安慰剂组的 484 名参与者中，有 6 名（1%）的血细胞比容大于 54%，而在睾酮组的 491 名参与者中，有 106 名（22%）的血细胞比容大于 54%，在安慰剂组的 468 名参与者中，有 87 名（19%）的前列腺特异性抗原增加了 0.75μg/mL 或更多，而在睾酮组的 480 名参与者中，有 109 名（23%）的前列腺特异性抗原增加了 0.75μg/mL 或更多。在安慰剂组的 503 名患者中，有 37 名（7.4%，95%CI 5.4-10.0）发生了预先指定的严重不良事件，而在睾酮组的 504 名患者中，有 55 名（10.9%，8.5-13.9）发生了严重不良事件。两组各有 2 人死亡。
睾酮治疗 2 年可降低 2 型糖尿病的发生率，其效果超出了生活方式项目的影响。血细胞比容的增加可能是治疗的限制因素。干预措施的长期耐久性、安全性和心血管影响仍有待进一步研究。
澳大利亚国家健康与医学研究委员会、拜耳、礼来、阿德莱德大学和 WW（前身为 Weight Watchers）。
