Transforming evidence into clinical practice

Description

Professor Hackett explains how research data on testosterone therapy can inform daily clinical practice to improve patient care of men with hypogonadism. Untreated hypogonadism is associated with significantly increased incidence of type 2 diabetes and all-cause mortality,1 and there is now convincing evidence that testosterone therapy can prevent progression to type 2 diabetes and improve outcomes in men with established type 2 diabetes.2

The Testosterone Trials (TTrials), one the most authoritative randomised, placebo-controlled, double-blind trials of men with functional hypogonadism (one main trial with 7 arms), aimed to investigate the effects of testosterone therapy for 1 year in 780 older men (65 years of age or older). The primary outcomes were sexual function, physical function, vitality, cardiovascular risk, cognitive function, anemia and bone mineral density.

The TTrials showed that all parameters of sexual function (including sexual desire and erectile function) significantly improved. Professor Hackett points out that couples in testosterone therapy group engaged in sexual activity 4 times per week. This improvement is large enough to save a relationship. Despite this, the authors of the TTrials described this as a “modest response”.

As a measure of physical function, walking distance significantly improved. Notably, the greatest improvement occurred between month 9 and 12 of testosterone therapy. There was no indication of leveling off, suggesting that there may have been continued improvement with longer duration testosterone therapy. For more information about the main TTrials report, see “Effects of testosterone treatment in older men

An analysis of changes in biomarkers of glycemic control showed that men in the testosterone therapy group had a significant reduction in insulin levels and insulin resistance (HOMA-IR). No effect was seen in HbA1c, which was to be expected because only 30% of men had type 2 diabetes. Despite the significant reduction in insulin levels and insulin resistance, the study authors concluded that testosterone therapy had no effect on glycemic control. Unfortunately, no subgroup analysis was done of the 30% of men with type 2 diabetes.

The bone report of the TTrials showed that men who had received testosterone therapy had a significant improvement in volumetric BMD (both spine and hip) compared to placebo treated men. Notably, the BMD improvement was of the same magnitude as that achieved with bisphosphonates. For more information about the main TTrials report, see “Effect of testosterone therapy on BMD and bone strength in men with low testosterone

The anemia report of the TTrials showed that testosterone therapy effectively treated anemia, including unexplained anemia, compared to placebo. This is an important finding, considering that anemia is a cardiovascular risk factor. Professor Hackett points out the widespread concern of hematocrit elevation, which only occurs in a minority of men, but ignorance of benefits seen in the larger population of men with anemia. For more information about the effect of testosterone therapy on anemia, see “Could testosterone therapy in hypogonadal men ameliorate anemia, a cardiovascular risk factor?”

The BLAST study, conducted by Professor Hackett and colleagues, was the first randomised controlled trial that exclusively enrolled men with hypogonadism and type 2 diabetes. It showed that testosterone therapy for 30 weeks significantly reduced HbA1c, body weight, BMI, waist circumference and total cholesterol, while improving erectile function (IIEF). After an additional 50 weeks (total duration of testosterone therapy 82 weeks) changes were more pronounced, and improvements in symptoms (AMS, Aging Males Symptoms) and anxiety and depression (HADS-D, hospital anxiety and depression scale) were also significant. This underscores the importance of long-term testosterone therapy for achievement of health benefits. The improvement in erectile function was especially marked in men on PDE5i, which Professor Hackett notes should nearly always be given together with testosterone therapy. For more information about long-term follow-up results, see “Long-term treatment with testosterone undecanoate improves waist circumference, erectile function and reduces need for diabetes medications

In a 4-year follow-up of men in the BLAST study who had not been treated with PDE5i (to avoid confounding), men who had been receiving testosterone therapy had a significant reduction in mortality compared to men not receiving testosterone therapy. The greatest mortality reduction was seen in the oldest men over the age of 70 years. Remarkably, men who had been receiving testosterone therapy had a lower mortality rate than men without hypogonadism who had not received testosterone therapy (comparison group). For more information about this study, see “Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Putting evidence into practice

  • Untreated hypogonadism is associated with significantly increased rates of type 2 diabetes and increased all-cause mortality. Ignoring the problem should no longer be acceptable.
  • Testosterone therapy is strongly endorsed to treat sexual dysfunction in men with low testosterone levels. Erectile dysfunction is an independent risk factor for heart disease; therefore, physicians should be screening for erectile dysfunction.
  • Evidence supports screening for hypogonadism for men with type 2 diabetes, pre-diabetes, metabolic syndrome, obesity and erectile dysfunction.
  • There is minimal evidence to justify lifestyle management as the sole approach in symptomatic men with functional hypogonadism.
  • There is now convincing evidence that testosterone therapy can reduce progression to type 2 diabetes. Evidence calls for a change in clinical practice in men with type 2 diabetes.

The Testosterone Trials (TTrials), one the largest randomised, placebo-controlled, double-blind trials of men with functional hypogonadism (one main trial with 7 arms), aimed to investigate the effects of testosterone therapy for 1 year in 780 older men (65 years of age or older).3 The primary outcomes were sexual function, physical function, vitality, cardiovascular risk, cognitive function, anemia and bone density.

The TTrials showed that all parameters of sexual function (including sexual desire and erectile function) significantly improved. Professor Hackett points out that couples in the testosterone therapy group engaged in sexual activity 4 times per week. This improvement is large enough to save a relationship. Despite this, the authors of the TTrials described this as a “modest response”.

As a measure of physical function, walking distance significantly improved. Notably, the greatest improvement occurred between month 9 and 12 of testosterone therapy. There was no indication of leveling off, suggesting that there may have been continued improvement with longer duration testosterone therapy. For more information about the main TTrials report, see “Effects of testosterone treatment in older men

An analysis of changes in biomarkers of glycemic control showed that men in the testosterone therapy group had a significant reduction in insulin levels and insulin resistance (HOMA-IR).4 No effect was seen in HbA1c, which was to be expected because only 30% of men had type 2 diabetes. Despite the significant reduction in insulin levels and insulin resistance, the study authors concluded that testosterone therapy had no effect on glycemic control. Unfortunately, no subgroup analysis was done of the 30% of men with type 2 diabetes.

The bone report of the TTrials showed that men who had received testosterone therapy had a significant improvement in volumetric BMD (both spine and hip) compared to placebo treated men.5 Notably, the BMD improvement was of the same magnitude as that achieved with bisphosphonates. For more information about the main TTrials report, see “Effect of testosterone therapy on BMD and bone strength in men with low testosterone

The anemia report of the TTrials showed that testosterone therapy effectively treated anemia, including unexplained anemia, compared to placebo.6 This is an important finding, considering that anemia is a cardiovascular risk factor. Professor Hackett points out the widespread concern of hematocrit elevation, which only occurs in a minority of men, but ignorance of benefits seen in the larger population of men with anemia. For more information about the effect of testosterone therapy on anemia, see “Could testosterone therapy in hypogonadal men ameliorate anemia, a cardiovascular risk factor?”

The BLAST study, conducted by Professor Hackett and colleagues, was the first randomised controlled trial that exclusively enrolled men with hypogonadism and type 2 diabetes.7 It showed that testosterone therapy for 30 weeks significantly reduced HbA1c, body weight, BMI, waist circumference and total cholesterol, while improving erectile function (IIEF). After an additional 50 weeks (total duration of testosterone therapy 82 weeks) changes were more pronounced, and improvements in symptoms (AMS, Aging Males Symptoms) and anxiety and depression (HADS-D, hospital anxiety and depression scale) were also significant.1 This underscores the importance of long-term testosterone therapy for achievement of health benefits. The improvement in erectile function was especially marked in men on PDE5i, which Professor Hackett notes should nearly always be given together with testosterone therapy. For more information about the long-term follow-up results of the BLAST study, see “Long-term treatment with testosterone undecanoate improves waist circumference, erectile function and reduces need for diabetes medications

In a 4-year follow-up of men in the BLAST study who had not been treated with PDE5i (to avoid confounding), men who had been receiving testosterone therapy had a significant reduction in mortality compared to men not receiving testosterone therapy.8 The greatest mortality reduction was seen in the oldest men over the age of 70 years. Remarkably, men who had been receiving testosterone therapy had a lower mortality rate than men without hypogonadism who had not received testosterone therapy (comparison group). For more information about this study, see “Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes

Putting evidence into practice

  • Untreated hypogonadism is associated with significantly increased rates of type 2 diabetes and increased all-cause mortality. Ignoring the problem should no longer be acceptable.
  • Testosterone therapy is strongly endorsed to treat sexual dysfunction in men with low testosterone levels. Erectile dysfunction is an independent risk factor for heart disease; therefore, physicians should be screening for erectile dysfunction.
  • Evidence supports screening for hypogonadism for men with type 2 diabetes, pre-diabetes, metabolic syndrome, obesity and erectile dysfunction.
  • There is minimal evidence to justify lifestyle management as the sole approach in symptomatic men with functional hypogonadism.
  • There is now convincing evidence that testosterone therapy can reduce progression to type 2 diabetes. Evidence calls for a change in clinical practice in men with type 2 diabetes.

 

Speakers

Professor Geoff Hackett

Professor Geoff Hackett
Aston University & University Hospitals Birmingham NHS Foundation Trust

References

  • 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. Mar 2016;70(3):244-53. Return to content
  • 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
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. Feb 18 2016;374(7):611-24. Return to content
  • Mohler ER, 3rd, Ellenberg SS, Lewis CE, et al. The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials. J Clin Endocrinol Metab. Feb 1 2018;103(2):681-688. Return to content
  • Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA internal medicine. Apr 1 2017;177(4):471-479. Return to content
  • Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA internal medicine. Apr 1 2017;177(4):480-490. Return to content
  • 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. Feb 2014;68(2):203-15. Return to content
  • 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. Jan 2020;38(1):68-77. Return to content