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Long-Term Treatment with Testosterone Undecanoate Improves Waist Circumference, Erectile Function and Reduces Need for Diabetes Medications

Long-Term Treatment with Testosterone Undecanoate Improves Waist Circumference

STUDY: Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The World Journal of Men's Health. 2018 36: e33.

Hypogonadism is present in about 70% of men with type 2 diabetes.1 A growing body of evidence shows marked benefits of long-term testosterone therapy in hypogonadal men with and without type 2 diabetes, including improvements in waist circumference, body weight, BMI, glycemic control, dyslipidemia and inflammatory markers.2-12

Here we present the results from a 4-year follow-up of the UK BLAST study13, which was the first double-blind, placebo-controlled study conducted exclusively in men with hypogonadism and type 2 diabetes to assess metabolic effects of treatment with long-acting testosterone undecanoate injections for 30 weeks.14

Key Points

  • If testosterone therapy is stopped, weight loss and improvements in HbA1c and erectile function seen during testosterone therapy are lost.
  • Men who had been on testosterone therapy consistently for the entire 4-year period required fewer anti-diabetic agents.
  • In men on continuous long-term testosterone therapy weight and waist circumference declined for 82 weeks. Thereafter, while waist circumference continued to decline, weight increased.
  • Improvement in erectile function scores continued with continuous long-term testosterone therapy.

What is known about the effects of testosterone undecanoate treatment in men with type 2 diabetes

The BLAST (Burntwood Lichfield Atherstone Sutton Tamworth) study showed that compared to placebo, treatment with testosterone undecanoate resulted in a significant reduction in HbA1c at 6 and 18 weeks14, with a further reduction at 82 weeks (1 year after the initial 30 week placebo-controlled treatment period).15 The reduction was most marked in patients with poorly controlled diabetes (baseline HbA1c greater than 7.5%). There were also significant reductions in waist circumference, body weight, body mass index (BMI) and total cholesterol. A significant improvement in insulin resistance, assessed by HOMA-IR, additionally occurred after the 52-week extended treatment period. These improvements were proportional to the magnitude of elevation in testosterone levels during the treatment period.14,15
Besides highlighting the importance of achieving high enough elevations in testosterone levels (i.e. therapeutic testosterone levels) during testosterone therapy, the BLAST study also provides evidence that testosterone therapy needs to be sustained long-term for metabolic benefits to occur. There were no significant adverse events.14,15

A follow-up of the BLAST study participants for 3.8 years showed that all-cause mortality was significantly and independently reduced in men who stayed on testosterone therapy and phosphodiesterase 5-inhibitor (PDE5I) use, even after controlling for age and statin treatment.16,17

What this study adds

This additional analysis of the BLAST study participants aimed to determine if the improvements in HbA1c, body weight, waist circumference and erectile function seen after 30 weeks of testosterone therapy in the RCT were maintained long-term for 4 years when other treatments for diabetes and/or cardiovascular disease were potentially altered.13

The group comparisons in the present analysis were low testosterone/treated and low testosterone/untreated at the end of the 30-week BLAST randomised controlled trial and after 1-year follow-up (week 30 to 82). Thereafter, the low testosterone/treated group was further divided into a low testosterone/treated/stopped group and a low testosterone/treated/continuous group, depending on whether testosterone therapy was continued or not in addition to the patients’ normal diabetes treatment during the final 4-year phase.

Tables 1 to 4 show changes in waist circumference, weight, HbA1c and international index of erectile function (IIEF) EF scores, which are illustrated in figures 1 to 4.

Figure 1 and Table 1: Change in waist circumference after short-term and long-term treatment with testosterone undecanoate.

Figure 1: Change in waist circumference after short-term and long-term treatment with testosterone undecanoate.
From: Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The World Journal of Men's Health. 2018.
  30 weeks 82 weeks 4-year visit
Low T untreated
(baseline waist 113.6 cm)
-0.6 -2.1 -1.0
Low T treated
(baseline waist 114.4 cm)
-3 -4.8 Low T treated / stopped
-4

Low T treated / continuous
-6


Figure 2 and Table 2: Change in body weight after short-term and long-term treatment with testosterone undecanoate.

Figure 2: Change in body weight after short-term and long-term treatment with testosterone undecanoate.
From: Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The World Journal of Men's Health. 2018.
  30 weeks 82 weeks 4-year visit
Low T untreated
(baseline weight 100.4 kg)
-0.1 -0.9 1.8
Low T treated
(baseline weight 100.1 kg)
-1.2 -2.8 Low T treated / stopped
-0.2

Low T treated / continuous
-0.6


Figure 3 and Table 3: Change in HbA1c after short-term and long-term treatment with testosterone undecanoate.

Figure 3: Change in HbA1c after short-term and long-term treatment with testosterone undecanoate.
  30 weeks 82 weeks 4-year visit
Low T untreated
(baseline HbA1c=7.5%)
-0.14 -0.24 0.09
Low T treated
(baseline HbA1c=7.6%)
-0.1 -0.44 Low T treated / stopped
0.08

Low T treated / continuous
-0.22


Figure 4 and Table 4: Change in erectile function (IIEF) scores after short-term and long-term treatment with testosterone undecanoate.

Figure 4: Change in erectile function (IIEF) scores after short-term and long-term treatment with testosterone undecanoate.
  30 weeks 82 weeks 4-year visit
Low T untreated -1.9 -0.1 -2.0
Low T treated 1.0 4.8 Low T treated / stopped
-2.6

Low T treated / continuous
8.6

As shown in table 5, testosterone therapy markedly reduced the number of medications needed to control diabetes. In the low testosterone/untreated group 14.3%, 28.6%, 38.1%, and 17.1% of men were on 0, 1, 2, and ≥3 medications, respectively. The corresponding figures for the low testosterone/treated/stopped and low testosterone/treated/continuous groups were 12.8%, 41.0%, 25.6%, 20.5% and 48.8%, 41.5%, 4.9%, 4.9%, respectively.



Table 5: Number of medications prescribed to control diabetes in untreated and testosterone treated men.

  Low T
untreated
Low T
treated/stopped
Low T
treated/continuous
Number of diabetes medications used among men (%)
0 medication (diet only) 14.3 12.8 48.8
1 medication 28.6 41 41.5
2 medications 38.1 25.6 4.9
3 medications ≥17.1 20.5 4.9

Commentary

This is the first longitudinal long-term study (mean follow-up, 3.8 years) to describe the effect of testosterone therapy in men with type 2 diabetes undergoing routine primary care diabetes treatment of glycemic control.18

Reduction in waist circumference with concomitant body weight gain

In the group of men who continued testosterone therapy throughout the entire 4-year follow-up, a particularly interesting finding was observed; body weight and waist circumference both decreased significantly until the end of the 82-week period, thereafter body weight started to increase while waist circumference continued to decrease.18 In contrast, in the group of men who discontinued testosterone therapy after the 82-week time point, both body weight and waist circumference increased in tandem. This suggests that men who continued testosterone therapy long-term had an increase in lean mass (presumably muscle mass). Support for this interpretation comes from a randomized controlled trial showing that testosterone therapy can increase lean body mass by 3 kg while simultaneously reduce fat mass by the same amount, resulting in no change in body weight but a dramatic improvement in body composition and metabolic control.19 Thus, sole reliance on body weight and BMI can be very misleading by disguising valuable improvement in body composition, which in turn is associated with increased muscle strength, physical fitness and reduced frailty.20 This underscores the importance of measuring changes in waist circumference along with changes in body weight in clinical practice.

Continuous long-term improvement in erectile function

Another notable finding in this study is that in men who discontinued testosterone therapy after 82 weeks, improvements in HbA1c and erectile function that were achieved during testosterone therapy quickly started to deteriorate. In contrast, among men who continued testosterone therapy for 4 years, erectile function continued to markedly improve. This progressive marked improvement in erectile function for nearly 4 years - independent of PDE5I – is highly remarkable as it was previously believed that maximal improvements in erectile function are usually achieved after 3-6 months of testosterone therapy.21 Several clinical guidelines recommend that men with borderline hypogonadism should be given a therapeutic trial of testosterone therapy for 3 months22, 6 months23 or 12 months24 to see if it works. Erectile dysfunction is one of the primary symptoms associated with hypogonadism25 and therefore improvement in erectile function is a major measure of the effectiveness of testosterone therapy. Hence, it is critical for healthcare professionals to be informed that patients with hypogonadism who have been on testosterone therapy for 3-12 months but not experienced the expected improvement in erectile function yet will likely do so if they stay on testosterone therapy consistently for a longer time period.

It has been stated that PDE5I and not testosterone therapy should be the first-line treatment for men with erectile dysfunction.26 However, data support the practice of combining PDE5I with testosterone therapy because each has independent beneficial effects on erectile function, as well as reduced all-cause mortality.16,17

Reduced requirement of diabetes medications in men receiving testosterone undecanoate treatment

An additional important finding in this long-term study is that men on continued non-interrupted long-term testosterone undecanoate treatment required fewer medications to control their diabetes. This is of major clinical importance and could potentially have a significant impact on healthcare practice. Testosterone is known as being the “libido hormone”, but it is a powerful metabolic hormone as well.27 The reduced requirement for diabetes medications in this study is in accordance with data from more longer-term studies, which have demonstrated that testosterone therapy for at least 7 years can result in remission of type 2 diabetes and complete discontinuation of diabetes medications.3,8

References:

1. Hackett GI, Cole NS, Deshpande AA, Popple MD, Kennedy D, Wilkinson P. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. The British Journal of Diabetes & Vascular Disease. 2009;9(5):226-231.
2. Haider KS, Haider A, Doros G, Traish A. Long-Term Testosterone Therapy Improves Urinary and Sexual Function, and Quality of Life in Men with Hypogonadism: Results from a Propensity Matched Subgroup of a Controlled Registry Study. J Urol. 2018;199(1):257-265.
3. Haider A, Haider KS, Saad F. Remission of Type 2 Diabetes in 12% (16 of 133) Hypogonadal Men Receiving Long-Term Testosterone Therapy in a Real-Life Registry Study. Diabetes. 2018;67(Supplement 1).
4. Dimitriadis GK, Randeva HS, Aftab S, et al. Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine. 2018.
5. Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433.
6. Saad F, Yassin D, Dorsos G, Yassin A. Most hypogonadal men with type 2 diabetes mellitus (T2DM) achieve HbA1c targets when treated with testosterone undecanoate injections (TU) for up to 12 years. Diabetes. 2017;66(Suppl.1):A305 (abstract).
7. Rosen RC, Wu F, Behre HM, et al. Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). The journal of sexual medicine. 2017;14(9):1104-1115.
8. Haider A, Haider KS, Saad F. Remission of type 2 diabetes in a hypogonadal man under long-term testosterone therapy. Endocrinology, diabetes & metabolism case reports. 2017;2017.
9. Haider A, Haider KS, Doros G, Saad F. No progression from prediabetes to type 2 diabetes (T2DM) in 45 hypogonadal men receiving testosterone therapy (TTh) for up to 9 years: Real-life data from a registry study. Diabetologia. 2017;60(Suppl.1):S395 (abstract).
10. Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016;48(7):793-799.
11. Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin Endocrinol (Oxf). 2016;84(1):107-114.
12. Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes (Lond). 2016;40(1):162-170.
13. Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2018;36:e33.
14. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. 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. 2014;11(3):840-856.
15. 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. 2014;68(2):203-215.
16. Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract. 2016;70(3):244-253.
17. Hackett G, Jones PW, Strange RC, Ramachandran S. Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes. World journal of diabetes. 2017;8(3):104-111.
18. Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2018.
19. Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91.
20. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639-650.
21. Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675-685.
22. 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 Jan 10, 2016). CMAJ. 2015;187(18):1369-1377.
23. 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.
24. 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.
25. 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.
26. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624.
27. Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217(3):R25-45.
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Last updated: 2019
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