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Testosterone replacement therapy can improve metabolic and sexual parameters in men with type 2 diabetes

Image: Older man giving himself injection

The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Hackett G, Cole N, Bhartia M, et al. Int J Clin Pract 2014; 68(2): 203-215.

Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study. Hackett G, Cole N, Bhartia M, et al. J Sex Med 2013; 10(6): 1612-1627.

Testosterone deficiency syndrome (TDS) is an increasingly common problem and healthcare burden. Low serum levels of testosterone have been shown to be more common in men with type 2 diabetes mellitus (T2DM) than in the general population,1,2 with 40−50% of men with T2DM having testosterone levels <12 nmol/L.1-3 The BLAST study is the first double-blind placebo-controlled study to investigate the use of testosterone undecanoate (TU) in a primary care population of men with T2DM. The study investigated the effects of TU 1,000 mg in 211 men aged 18–80 years with T2DM and symptoms of hypogonadism involving a 30-week placebo-controlled phase followed by a 52-week open-label phase. This summary presents an overview of two reports from the BLAST study that investigated the effects of TU on achieving threshold serum testosterone levels4 and metabolic parameters.5

Key Points

  • Men with T2DM included in the BLAST study were divided into MILD (testosterone 8.1–12 nmol/L) or SEVERE (testosterone <8.0 nmol/L) groups according to their baseline testosterone levels and symptoms of hypogonadism4,5
  • Both the MILD and SEVERE groups achieved different trough testosterone levels following 30 weeks’ treatment with TU 1,000 mg4,5

    • In the MILD group, testosterone levels rose from 10.47 to 11.94 nmol/L
    • Testosterone levels in the SEVERE group rose from 7.73 to 9.93 nmol/L; a value still below the baseline testosterone level of the MILD group and those suggested in published guidelines (12 nmol/L)4
  • After 30 weeks’ treatment with TU, only the SEVERE group showed significant improvements in sexual function (Figure)4

    • Significant improvements were seen in erectile function (p=0.029), intercourse satisfaction (p=0.020), and sexual desire (p<0.001)
    • In the MILD group, no improvements were seen after 30 weeks
  • The mild group only showed improvements in metabolic and psychological parameters after 30 weeks’ treatment with TU4

    • Despite the MILD group having lower weight, BMI, and waist circumference at baseline, TU significantly reduced weight (p=0.003), BMI (p=0.002), and waist circumference (p<0.001)
    • TU improved the Hospital Anxiety and Depression Score [HADS]-depression score by 1.21 points (p=0.007) only in the MILD group
  • The presence of baseline depression (HADS ≥11) reduced the response of metabolic parameters to TU5

    • When men with HADS ≥11 were excluded from the analysis, TU significantly reduced weight, BMI, and waist circumference after 30 weeks
    • No significant improvements were seen in men suffering from baseline depression
  • TU significantly reduced HbA1c in men with T2DM, particularly in men with poorly controlled diabetes (baseline HbA1c ≥7.5%)

    • HbA1c was significantly reduced by 6 weeks and maintained at 18 weeks (both p=0.007)5
    • In the mild group, HbA1c levels were maintained at 30 weeks (p=0.029)5
    • In men with baseline HbA1c ≥7.5%, TU reduced HbA1c by 0.41% at 6 weeks, and this level was maintained at 30 weeks5
  • TU significantly improved subjective measurements of general health at 30 weeks: 12.4% vs. 1.1% of patients answered that treatment “definitely improved” their health and 32.6% vs. 16.3% “probably improved” their health (p<0.001)5
  • TU was not associated with any safety issues, with only four serious adverse events reported in 199 men4,5
  • These results suggest that testosterone level thresholds may exist, with improvement of specific sexual and metabolic parameters dependent on achieving certain testosterone levels, and all symptoms improving at trough levels ≥12 nmol/L4,5
  • Target testosterone trough levels of 15 nmol/L and improvements in symptoms were only achieved following 12 months’ treatment,4 suggesting that a period of 3−6 months recommended by current guidelines6-9 is insufficient and 12−18 months’ treatment are required to attain target therapeutic levels4,5

What is known

TDS has an estimated prevalence of 3.2% in men aged 60−69 years10 and epidemiological studies have suggested that low testosterone levels in young men may later lead to development of T2DM.11-13 Guidelines, including the European Association of Urology and International Society for the Study of Ageing Male, recommend screening of testosterone levels in men with high risk of TDS, particularly those with T2DM.14 Whilst the specific upper limits of TDS are under debate, it is accepted that men with low testosterone levels will present with symptoms of TDS. The European Male Ageing Study concluded that men with testosterone levels <11 nmol/L will present with symptoms of erectile dysfunction, loss of morning erections, and reduced sexual desire.10 US guidelines suggest a slightly lower upper limit of 10.4 nmol/L,4 whilst Bhasin et al. recommend a threshold of 12.1 nmol/L.15

A greater awareness of TDS in recent years has increased its detection in males with T2DM, and the demand for treatment of sexual dysfunction has increased the use of testosterone replacement therapy (TRT) in this population. Previous studies have demonstrated that TRT improves sexual function16 and metabolic parameters17,18 in men. Published guidelines now recommend TRT for men with testosterone levels ≤8 nmol/L, and a 3−6 month treatment period should be considered in those with testosterone levels of 8−12 nmol/L.6-8

What this study adds

Increasing testosterone levels in men with severe hypogonadism (≤8 nmol/L) resulted in significant improvements in sexual function (Figure) similar to those previously reported.16 Despite only modest improvements in testosterone levels in men with milder hypogonadism (8.1−12 nmol/L), significant improvements were also seen with regard to reductions in weight, BMI, waist circumference, and levels of HbA1c that were similar to previous studies.17-21 These results suggest that symptom thresholds may exist, and improvements in specific symptoms are seen once these threshold testosterone levels are achieved. These data complement those presented by Zitzmann et al.,22 who previously suggested symptom thresholds (in 434 hypogonadal men), which included loss of erections at 8 nmol/L, diabetes and depression at 10 nmol/L, and reduced vigour at 15 nmol/L. These specific symptom thresholds may be of great interest to sexual medicine physicians and endocrinologists looking to target certain symptoms in men with varying severities of hypogonadism.

In the BLAST studies, marked improvements in sexual and metabolic parameters seen in the 52-week open-label phase are likely attributable to the higher therapeutic testosterone level (14–15 nmol/L) being achieved after a minimum of eight injections of TU. These findings support claims from other studies19,23 that the full benefits of TU may take many months to fully present, and a duration of 3–6 months for TRT currently recommended by guidelines may be insufficient. In addition, previous studies investigating TU may have used too short a duration of therapy for benefits to be seen.5,23

The effects of TU on metabolic and sexual factors were less marked in men with depression at baseline, although there were modest improvements in depression scores beyond 12 months of treatment.5 After 52 weeks open-label medication, 70% of all men believed that TU had improved their health, measured using a subjective global efficacy question.5 It should be noted that whilst such subjective improvements may be undervalued by clinicians, they may be of great value to patients.

Figure: Change in International Index of Erectile Function domain scores at 30 weeks from the BLAST study

References

1. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. The Journal of clinical endocrinology and metabolism 2004;89(11):5462-5468.
2. Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30(4):911-917.
3. Hackett G, Cole N, Deshpande A, et al. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. Br J Diabetes Vasc Dis 2009;9:216-2315.
4. Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract 2013
5. Hackett G, Cole N, Bhartia M, et al. Testosterone Replacement Therapy Improves Metabolic Parameters in Hypogonadal Men with Type 2 Diabetes but Not in Men with Coexisting Depression: The BLAST Study. The journal of sexual medicine 2013
6. Dohle G, Arver S, Betocchi C, et al. EAU Guidelines on Male Hypogonadism. 2012:28.
7. Nehra A, Jackson G, Miner M, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2012;87(8):766-778.
8. Hackett G, Kell P, Ralph D, et al. British Society for Sexual Medicine guidelines on the management of erectile dysfunction. J Sex Med 2008;5(8):1841-1865.
9. Buvat J, Maggi M, Guay A, et al. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. The journal of sexual medicine 2013;10(1):245-284.
10. 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):123-136.
11. Oh JY, Barrett-Connor E, Wedick NM, et al. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002;25(1):55-60.
12. Stellato RK, Feldman HA, Hamdy O, et al. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23(4):490-494.
13. Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl 2011;34:528-540.
14. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005;48(1):1-4.
15. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts.
16. Hackett G, Cole N, Bhartia M, et al. Testosterone Replacement Therapy with Long-Acting Testosterone Undecanoate Improves Sexual Function and Quality-of-Life Parameters vs. Placebo in a Population of Men with Type 2 Diabetes. J Sex Med 2013;10(6):1612-1627.
17. Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf) 2010;73(5):602-612.
18. Jones T, Arver S, Behre H, et al. Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study). Diabetes Care 2011;34(4):828-837.
19. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. The journal of sexual medicine 2013;10(2):579-588.
20. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6):899-906.
21. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009;30(6):726-733.
22. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. The Journal of clinical endocrinology and metabolism 2006;91(11):4335-4343.
23. Saad F, Aversa A, Isidori AM, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol 2011;165(5):675-685.

Last updated: 2018
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