11 November 2013 Subscribe to our news feed

Testosterone undecanoate can improve sexual function and quality of life in males with type 2 diabetes

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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. Hackett G, Cole N, Bhartia M, et al. J Sex Med 2013; 10(6):1612-1617.

This editorial discusses the key findings and implications of a study published in 2013 by Hackett et al.1 (The BLAST study) that investigated the effect of testosterone replacement therapy on sexual function and quality of life parameters versus placebo in males with type 2 diabetes (T2D). The study was separated into two phases. The first phase was a 30-week, prospective, randomized, double-blind, placebo-controlled multicenter study conducted between September 2008 and June 2011 at eight UK Midland centers. A total of 190 males (age >18 years) with T2D received long-acting Testosterone Undecanoate (TU) 1000 mg or placebo for 30 weeks (at weeks 0, 6, and 18). The second phase was a 52-week follow-on with open-label TU therapy in 96 patients proceeding from the first phase. The primary outcome of the study was a statistically significant change from baseline in the 15-item International Index of Erectile Function (IIEF) domains. Notable secondary outcomes included health-related quality-of-life symptoms, as measured by the 17-item Ageing Male Symptom Scale (AMS) questionnaire.

Key Points

  • To date, the BLAST study is the largest and longest (82 week) study that has investigated the effects of TU therapy in males with T2D1

    • A total of 199 males age > 18 years with T2D were randomized to treatment, with 190 patients completing the 30-week, double-blind, placebo-controlled phase
    • Of the 106 patients who entered the open-label phase (weeks 30 to 82), final visit (week 82) data were available for 96 patients
  • The study was largely performed within the primary care setting by general practitioners who included eligible patents in the study following screening of the diabetic population recommended by Endocrine Society guidelines1,2

    • This is in contrast to similar studies, where patients were referred by general practitioners to specialist diabetes centers, from which they were recruited
  • In the total cohort, there were clear statistically significant improvements at 30 weeks in all IIEF domains for TU versus placebo (Figure 1)1

    • At 30 weeks, improvements with TU versus placebo included erectile function, p=0.005; intercourse satisfaction, p=0.015; sexual desire, p=0.001; orgasm, p=0.004
    • For erectile function, there were significant improvements at 18 and 30 weeks with TU versus placebo in males aged ≥60 years
    • Significant improvements at 18 weeks with TU versus placebo were seen for intercourse satisfaction (p=0.024) and overall satisfaction (p=0.051), orgasm (p=0.020), and sexual desire (p=0.001)
    • In males with baseline depression (Hospital Anxiety and Depression Scale [HADS] scores ≥11; n=48 [24%]), all IIEF domain scores fell compared with baseline for TU and placebo
  • Improvements in IIEF domains were seen as early as 6 weeks1

    • For TU versus placebo at 6 weeks, there were significant improvements in sexual desire
  • Sexual function scores continued to improve to the end of the 12-month open-label extension phase1

    • An improvement from baseline in erectile function was observed for the active group continuing on TU therapy and the placebo group proceeding to TU therapy (4.31 and 2.97, respectively)
    • In the active group continuing on TU therapy, there were greater increases in intercourse satisfaction (2.83) and orgasm (1.53) domains compared with placebo (1.11 and 0.5, respectively)
  • Health-related quality-of-life measures improved with TU versus placebo, but not in males with baseline depression1

    • At 30 weeks, AMS improved significantly (3.45 units improvement; p=0.02) in men without depression
  • In a subgroup (n=31) of males taking phosphodiesterase type 5 inhibitors (PDE5I), there was no change in erectile function during the double-blind phase, but large improvements during the open-label phase1

    • Fifteen patients taking PDE5Is in the double-blind phase (TU, n=7; placebo, n=8) proceeded to the open-label phase
    • By week 82, patients from the TU and placebo groups showed an improvement in erectile function score of 9.34 and 1.27, respectively; suggesting that clinical improvements in erectile function may take a longer period of time to achieve

What is known

Patients with T2D are at high risk of comorbidities. The high prevalence of hypogonadism in T2D, independent of obesity, has been well-reported.2-6 Furthermore, the prevalence of clinically assessed depression in males with T2D was determined as 9.8% in a meta-analysis of 51,331 patients across 10 controlled studies.7 In a separate meta-analysis of 22 studies that focused on the impact of diabetic complications on depression, sexual dysfunction was most commonly associated with depression. To effectively diagnose and manage such comorbidities, guidelines published by the UKs National Institute for Health and Clinical Excellence (NICE) recommend a yearly screening for erectile dysfunction in males with T2D,8 whilst separate guidelines for erectile dysfunction recommend measurement of testosterone levels in males at high risk, such as those with T2D.9 As a result, clinicians who adhere to these guidelines are likely to be faced with patients who present with T2D, low testosterone levels, depression, and erectile dysfunction.

What these studies add

The results from the BLAST study confirm the beneficial effects of TU on IIEF domains and health-related quality of life in males with T2D, and complement previously published data.10,11 However, data from this 82-week study illustrate the effect of depression on the response to testosterone replacement therapy; with baseline depression diminishing any response to sexual function altogether. Adding to this, a significant reduction in AMS was observed only in patients without depression. Depression has been shown to independently impact sexual function, as well as reduce diabetes medication response and adherence, which should be considered during treatment decisions.12-14

The addition of a subgroup of males taking PDE5Is is novel, as similar studies investigating testosterone replacement therapy in diabetic males fail to identify whether PDE5Is were excluded.15-17 Males with T2D within this subgroup showed no improvement in IIEF domains during the double-blind phase, but showed large improvements after a further 12 months of open-label treatment. This delayed improvement may be explained through the achievement of sustained levels of TU beyond ≥5 injections, and the long 54-day half-life of long-acting TU. This is of clinical importance, as current guidelines recommend only 3 to 6 months of testosterone replacement therapy and the duration of TU therapy in previously published studies may have been too short for benefits in sexual function to present. As a result, males with T2D should be screened for low testosterone levels and depression, and considered for testosterone replacement therapy beyond the 6 months currently recommended.

Figure 1: Change in sexual function scores from baseline to 30 weeks in the total population treated with TU (1,000mg) or placebo at weeks 0, 6 and 18

References

1. 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.
2. Bhasin S, Cunningham G, Hayes F, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91(6):1995-2010.
3. Isidori A, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63(4):381-394.
4. 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;9:226-231.
5. Bacon C, Hu F, Giovannucci E, et al. Association of type and duration of diabetes with erectile dysfunction in a large cohort of men. Diabetes Care 2002;25(8):1458-1463.
6. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89(11):5462-5468.
7. Anderson R, Freedland K, Clouse R, et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001;24(6):1069-1078.
8. Home P, Mant J, Diaz J, et al. Management of type 2 diabetes: summary of updated NICE guidance. BMJ 2008;336:1306
9. 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.
10. Khera M, Bhattacharya R, Blick G, et al. Improved sexual function with testosterone replacement therapy in hypogonadal men: real-world data from the Testim Registry in the United States (TRiUS). J Sex Med 2011;8(11):3204-3213.
11. Corona G, Rastrelli G, Forti G, et al. Update in testosterone therapy for men. J Sex Med 2011;8(3):639-654.
12. Dinan TG. Inflammatory markers in depression. Curr Opin Psychiatry 2009;22(1):32-36.
13. Papelbaum M, Moreira RO, Coutinho W, et al. Depression, glycemic control and type 2 diabetes. Diabetol Metab Syndr 2011;3(1):26.
14. Ciechanowski P, Katon W, Russo J. Impact of Depressive Symptoms on Adherence, Function, and Costs. Arch Intern Med 2000;160(21):3278-3285.
15. Giltay E, Tishova Y, Mskhalaya G, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med 2010;7(7):2572-2582.
16. 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.
17. 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.

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