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

Disease, symptoms and diagnosis

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Half of men who have either type 2 diabetes or obesity, also have testosterone deficiency. Often, they don't realise that the symptoms that they are experiencing, such as tiredness, hot flushes and headaches, are caused by this. Additionally, sexual symptoms are common but many men find them difficult to talk about, even though they can have a large impact on their lives. Hypogonadism can be very difficult for many men - doctors don't always identify their condition, and it can be isolating and confusing.

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

  • Salonia A, Bettocchi C, Carvalho J, et al. 2020 EAU Guidelines on Sexual and Reproductive Health. Return to content
  • Morgentaler A, Traish A, Hackett G, Jones TH, Ramasamy R. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev. 2019;7(4):636-649. Return to content
  • Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline (unabridged). J Urol. 2018;200(2):423-432. Return to content
  • Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. 2017;14(12):1504-1523. Return to content
  • Khera M, Adaikan G, Buvat J, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). The journal of sexual medicine. 2016;13(12):1787-1804. Return to content
  • Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686. Return to content
  • Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Sept 17, 2019). CMAJ. 2015;187(18):1369-1377. Return to content
  • Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135. Return to content
  • Bawor M, Bami H, Dennis BB, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend. 2015;149:1-9. Return to content
  • Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3 Suppl 1):S12-18. Return to content
  • Aloisi AM, Aurilio C, Bachiocco V, et al. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34 Suppl 1:S162-168. Return to content
  • Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. The journal of pain : official journal of the American Pain Society. 2002;3(5):377-384. Return to content
  • Corona G, Ricca V, Bandini E, et al. Selective serotonin reuptake inhibitor-induced sexual dysfunction. The journal of sexual medicine. 2009;6(5):1259-1269. Return to content
  • Corona G, Boddi V, Balercia G, et al. The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. The journal of sexual medicine. 2010;7(4 Pt 1):1547-1556. Return to content
  • Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC medicine. 2013;11:57. Return to content
  • Cohen PG. Statins and male hypogonadism. The journal of sexual medicine. 2011;8(6):1826. Return to content
  • Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men. Arch Intern Med. 1996;156(11):1173-1177. Return to content
  • Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab. 2003;88(7):3167-3176. Return to content
  • Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf). 2003;58(6):710-717. Return to content
  • Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. 2015;187(18):1369-1377. Return to content
  • Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;18(1):5-15. Return to content
  • Morgentaler A, Traish AM, Khera M. A Critique of the AUA Guidelines on Testosterone Deficiency. The journal of sexual medicine. 2020;17(4):561-564. Return to content
  • Vermeulen A, Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. J Clin Endocrinol Metab. 1992;74(4):939-942. Return to content
  • Antonio L, Wu FC, O'Neill TW, et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. J Clin Endocrinol Metab. 2016;101(7):2647-2657. Return to content
  • O'Connor DB, Lee DM, Corona G, et al. The relationships between sex hormones and sexual function in middle-aged and older European men. J Clin Endocrinol Metab. 2011;96(10):E1577-1587. Return to content
  • Boeri L, Capogrosso P, Ventimiglia E, et al. Does Calculated Free Testosterone Overcome Total Testosterone in Protecting From Sexual Symptom Impairment? Findings of a Cross-Sectional Study. The journal of sexual medicine. 2017;14(12):1549-1557. Return to content
  • Rastrelli G, Corona G, Cipriani S, Mannucci E, Maggi M. Sex hormone-binding globulin is associated with androgen deficiency features independently of total testosterone. Clin Endocrinol (Oxf). 2018;88(4):556-564. Return to content
  • Gades NM, Jacobson DJ, McGree ME, et al. The associations between serum sex hormones, erectile function, and sex drive: the Olmsted County Study of Urinary Symptoms and Health Status among Men. The journal of sexual medicine. 2008;5(9):2209-2220. Return to content
  • Ahn HS, Park CM, Lee SW. The clinical relevance of sex hormone levels and sexual activity in the ageing male. BJU Int. 2002;89(6):526-530. Return to content
  • Krakowsky Y, Conners W, Morgentaler A. Serum Concentrations of Sex Hormone-binding Globulin Vary Widely in Younger and Older Men: Clinical Data from a Men's Health Practice. Eur Urol Focus. 2019;5(2):273-279. Return to content
  • Guay AT, Traish AM, Hislop-Chestnut DT, Doros G, Gawoski JM. Are there variances of calculated free testosterone attributed to variations in albumin and sex hormone-binding globulin concentrations in men? Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2013;19(2):236-242. Return to content
  • Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: a closer look at the cellular and molecular mechanisms of androgen action. The journal of sexual medicine. 2008;5(4):998-1012. Return to content
  • Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335-4343. Return to content
  • Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab. 2004;89(8):3813-3817. Return to content
  • Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135. Return to content
  • Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Available at https://journals.aace.com/doi/pdf/10.4158/EP161365.GL (accessed 4 July, 2020) Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016;22 Suppl 3:1-203. Return to content
  • Salter CA, Mulhall JP. Guideline of guidelines: testosterone therapy for testosterone deficiency. BJU Int. 2019;124(5):722-729. Return to content
  • Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic Hypogonadism in Men With Diabesity. Diabetes Care. 2018;41(7):1516-1525. Return to content

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