T4DM study

The Lancet Diabetes & Endocrinology has published results from the T4DM (Testosterone for Diabetes Mellitus) a randomized, double-blind, placebo-controlled, phase 3b study, showing that testosterone treatment in men with low testosterone and diabetes or newly diagnosed diabetes for two years combined with lifestyle intervention significantly reduced type 2 diabetes (T2D) compared to placebo injection with lifestyle intervention in men with low testosterone levels.1

Hypogonadism

Hypogonadism is associated with several health consequences, such as cardiovascular disease, obesity, diabetes, osteoporosis, quality of life, and even economic impacts.

Explaining the T4DM study

Hypogonadism, commonly seen in overweight or obese men is associated with an increased risk of T2D.2 Observational studies have previously shown that testosterone treatment for men with hypogonadism improves metabolic parameters such as fasting glucose, insulin resistance, body composition resulting in the prevention of developing T2D, and may even revert T2D3-7. However, this was not yet confirmed with a randomized controlled trial. The T4DM Phase 3 study is the world’s first large-scale, placebo-controlled randomized trial assessing testosterone treatment for preventing or reversing T2D in overweight or obese men with low testosterone levels.

 

Study participants were men at high risk of T2D (pre-diabetes) or with newly-diagnosed T2D and low testosterone levels. They were enrolled in a community-based lifestyle program and randomized to receive intramuscular testosterone undecanoate 1000mg (504 men) or placebo (503 men) every 3 months for 2 years. Testosterone undecanoate intramuscular injection (1000 mg/4 mL) was supplied by Bayer (Reandron®) which is marketed in most countries as Nebido®.

Key Findings

The study found testosterone treatment for two years combined with a lifestyle program significantly reduced the prevalence of participants with T2D compared to lifestyle intervention only, in men with low testosterone levels.

 

The study met its two primary endpoints*

1. 

Reduction in T2D after two years

  • Testosterone treatment reduced T2DM compared to those in the placebo group after two years (12.4% (55/443) vs 21.1% (87/413) respectively), with a relative risk of 0.59 (95% CI: 0.43, 0.80; p=0.0007)

     

    A sub-group analysis showed that, after two years:

  • Of the men at high risk (pre-diabetes at baseline), 7.6% (27/355) of the testosterone group had progressed to T2D, compared with 14.9% (49/329) of the placebo group.
  • Of the men with newly-diagnosed T2D at baseline, 31.8% (28/88) of the testosterone group persisted with T2DM, compared with 45.2% (38/84) of the placebo group.
2. 

Mean change in 2-hour glucose from baseline after two years

  • There was a greater mean change from baseline in 2-hour glucose level in men treated with testosterone compared to placebo (-1.70 mmol/L vs -0.95 mmol/L respectively, with a mean difference of -0.75 mmol/L, p<0.0001/)

*T2D for outcomes was defined as glucose ≥11.1 mmol/L, measured through a 2-hour oral glucose tolerance test.

 

Of the secondary endpoints, testosterone was associated with a benefit in body composition with a mean decrease in total fat mass of 2.7kg and a mean increase in total muscle mass of 1.7kg; both were statistically significantly greater than placebo. The safety profile was consistent with the label and with that seen in previous studies,1,2,8,9 The safety profile of the study was reassuring, with 41 serious adverse events recorded in the placebo group and 55 in the testosterone group, and no difference in incident cardiovascular events or prostate cancer.1 The data from this study provide some reassurance regarding 2-year cardiovascular safety and are in accordance with a recent meta-analysis indicating the cardiovascular safety of testosterone treatment.12 A treatment-limiting increase in haematocrit to 54% or higher, a prespecified safety trigger, was flagged in 106 (22%) of 491 participants treated with testosterone.1 This proportion is within the range of treatment-limiting increases in haematocrit (2.5 – 40%) in other studies of testosterone treatment.10,11 This trigger led to the cessation of treatment for 26 participants (25 in the testosterone group).1

References

  • 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. The Lancet Diabetes & Endocrinology. Jan 2021;9(1):32-45. Return to content
  • Gyawali P, Martin SA, Heilbronn LK, et al. The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men. Acta Diabetol 2018; 55(8): 861-72. Return to content
  • Saad F, et al. Int J Obes. 2016;40(1):162–170. Return to content
  • Haider A, et al. Int J Endocrinol. 2014;683515. Return to content
  • Yassin A, et al. Diabetes Care. 2019;42(6):1104–1111. Return to content
  • Haider A, et al. Endocrinol Diabetes Metab Case Rep. 2017:17-0084. Return to content
  • Haider A, et al. SAGE Open Med Case Rep. 2019;7:2050313X18823454 Return to content
  • Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393-403. Return to content
  • Howells L, Musaddaq B, McKay AJ, Majeed A. Clinical impact of lifestyle interventions for the prevention of diabetes: an overview of systematic reviews. BMJ Open 2016;6:e013806.doi:10.1136/bmjopen-2016-013806 Return to content
  • Ip FF, di Pierro I, Brown R, Cunningham I, Handelsman DJ, Liu PY. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur J Endocrinol 2010; 162(2): 385-90. Return to content
  • Coviello AD, Kaplan B, Lakshman KM, et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab 2008; 93(3): 914-9. Return to content
  • Corona G, Rastrelli G, Di Pasquale G, et al. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med 2018; 15(6): 820-38. Return to content