Adherence to testosterone therapy is critical for improvement in glucose control in men with type 2 diabetes

March 2021

The wide range of health benefits of testosterone therapy in men with hypogonadism is well documented. Despite this, studies investigating the effect of testosterone therapy on glycemic control in men with type 2 diabetes and hypogonadism, have shown inconsistent results.1-3 One explanation for this could be lack of adherence to testosterone therapy, causing insufficient sustained elevation in testosterone levels for benefits to occur.4-7 Medication adherence is generally defined as the extent to which patients take medications as prescribed by their health care providers.8

Here we summarise the results of a study that evaluated the effects of long-term testosterone therapy on HbA1c in men with co-occurring type 2 diabetes and hypogonadism, and whether men who were most adherent to testosterone therapy had greater improvement in glycemic control over time, compared to men who were less adherent to testosterone therapy.9

KEY POINTS

  • Testosterone therapy significantly improved glycemic control (HbA1c) in men with co-occurring type 2 diabetes and hypogonadism who had high adherence to testosterone therapy.
  • Improvement in glycemic control in men who had high adherence to testosterone therapy occurred regardless of BMI, pre-treatment HbA1c and age.
  • The higher the HbA1c when starting testosterone therapy, the greater the potential for reduction in HbA1c in men who adhere to testosterone therapy.
  • Men with suboptimal adherence to testosterone therapy had an increase in HbA1c.
  • Testosterone therapy may improve HbA1c independent of weight loss.

What is known about low testosterone, type 2 diabetes and testosterone therapy

Hypogonadism is an independent risk factor for development of type 2 diabetes,10 and the prevalence of hypogonadism is high in men with type 2 diabetes. Accordingly, in 2018 the American Diabetes Association (ADA) implemented the recommendation that testosterone levels should be measured in all men with type 2 diabetes and signs/symptoms of hypogonadism.11

While previous studies investigating the effect of testosterone therapy on glycemic control in men with type 2 diabetes and hypogonadism have been inconsistent,1-3 recent randomized controlled trials and long-term real-world evidence studies have shown remarkable benefits of testosterone therapy on insulin sensitivity,12 beta-cell dysfunction 13 and glycemic control,14 resulting in a significantly reduced incidence of type 2 diabetes,15, 16 and in some men even reversal of established type 2 diabetes.15, 17

In contrast to studies showing no effect,1-3 studies demonstrating that testosterone therapy significantly reduces risk of type 2 diabetes, and may reverse established type 2 diabetes, were of longer duration (at least 2 years) and ensured adherence to testosterone therapy among subjects.15-17 This is in accordance with findings from the BLAST study, which suggested that response to testosterone therapy is dependent on achieving high enough elevations in testosterone levels that are sustained throughout the entire course of testosterone therapy.4 A prerequisite for achievement of sustained therapeutic testosterone levels is adherence to testosterone therapy. For more information, see:

Adherence to testosterone therapy - short term treatment is not sufficient for achievement of maximal benefits

Until recently, no study has specifically evaluated the impact of adherence versus non-adherence to testosterone therapy on blood glucose control, assessed by HbA1c.

What this study adds

A retrospective study, utilizing electronic medical records, identified 1737 men with hypogonadism and type 2 diabetes. The date of initial hypogonadism diagnosis was used as the start date, and the date 5 years after the initial hypogonadism diagnosis was used as the follow-up date.

Subjects were categorized into groups according to adherence to testosterone therapy based on proportion of time that prescriptions for testosterone therapy were filled; > 75%, 51-75%, 26-50% and 0-25%, with >75% of time covered considered adherent to therapy. The primary goal was to assess the difference in HbA1c pre/post testosterone therapy among the various adherence groups, and to find out to what extent adherence impacts HbA1c.

In the entire group of men, pre-treatment and post-treatment median HbA1c was 6.8% and 7.1%, respectively. In contrast, the adherent group had a significant reduction in HbA1c, even after controlling for BMI, age, and pre-treatment HbA1c. The lowest adherence group had the greatest increase in HbA1c. It was estimated that among men with 0-25% adherence to testosterone therapy and a posttreatment HbA1c of 10, improving adherence to >75% would decrease HbA1c by 1% (to a post-treatment average HbA1c of 9%).

Commentary

Medication adherence is critical to treatment success.18 The main finding in the present study is that men with the highest adherence to testosterone therapy had the greatest improvement in HbA1c.9 Remarkably, even after adjusting for BMI, pre-treatment HbA1c and age, results showed that men with the highest adherence to testosterone therapy experienced a significant improvement in glycemic control. Furthermore, the higher the baseline HbA1c before start of testosterone therapy, the greater the reduction in HbA1c with high adherence. All groups had some reduction in BMI, which suggests that testosterone therapy may improve HbA1c independent of weight loss.

The importance of achieving sustained therapeutic elevations in testosterone levels – which requires adherence to testosterone therapy - was also pointed out in previous studies, which found that only men who achieved normalization (i.e., high enough elevation) of testosterone levels during testosterone therapy had a reduced risk of heart attack, stroke and premature mortality.19-21 Adherence to long-term testosterone therapy is likewise critical for achievement and maintenance of reduction in waist size and improvement in erectile function.22 For more information about these studies, see:

“Normalization of testosterone level is associated with reduced incidence of heart attack, stroke and mortality in men”
https://www.nebido.com/hcp/testosterone-news-resources/research-news/normalization-of-testosterone-level-is-associated-with-reduced-incidence-of-heart-attack-stroke-and-mortality-in-men

“Effective testosterone treatment reduces incidence of atrial fibrillation”
https://www.nebido.com/hcp/testosterone-news-resources/research-news/testosterone-treatment-reduces-atrial-fibrillation-incidence

“Long-term treatment with testosterone undecanoate improves waist circumference, erectile function and reduces need for diabetes medications”
https://www.nebido.com/hcp/testosterone-news-resources/research-news/long-term-treatment-with-testosterone-undecanoate-improves-erectile-function-and-reduces-need-for-diabetes-medications

This underscores the importance of choosing a testosterone preparation that is convenient for the patient. Surveys of patient preferences and adherence rates have shown that patients prefer and are most adherent to treatment with long-acting testosterone undecanoate injections, compared to gels and short-acting testosterone injections. For more information, see “What testosterone treatment options are preferred by patients”. Gels require daily application and time to dry on the skin, while short-acting testosterone injections have to be administered every second week, and many patients cannot inject themselves. In contrast, long-acting testosterone undecanoate injection only need to be administered every 12 weeks (4-5 times per year), which is done at the office at follow-up appointments. This makes it a convenient hypogonadism treatment option that facilitates adherence. For more information, see:

“Testosterone therapy with Nebido® shows superior long-term adherence compared to gels and short-acting testosterone injectables”
https://www.nebido.com/hcp/testosterone-news-resources/research-news/testosterone-undecanoate-injection-treatment-superior-long-term-adherence-compared-to-gels-and-short-acting-testosterone-injections

“Effectiveness and tolerability of injectable testosterone undecanoate”
https://www.nebido.com/hcp/testosterone-news-resources/research-news/effectiveness-and-safety-of-testosterone-undecanoate-injection-for-hypogonadism-treatment

Furthermore, the present study confirms previous findings that men with the highest baseline HbA1c levels, i.e., worst glycemic control, have the greatest reduction in HbA1c during testosterone therapy.9,14,23 Considering that patients with poorly controlled diabetes, i.e., those having the highest HbA1c levels, in general do not engage in behaviors that improve diabetes,24 yet still have the greatest improvement in HbA1c with testosterone therapy,9,14 it follows that testosterone therapy in men with hypogonadism can significantly improve diabetes management in clinical practice. Informing patients about the importance of sticking to the testosterone administration schedule during treatment is an important first step towards improving adherence to testosterone therapy.

 

References

  • Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian journal of andrology. Jan-Feb 2014;16(1):146-52. Return to content
  • Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol (Oxf). Sep 2015;83(3):344-51. Return to content
  • Zhang J, Yang B, Xiao W, Li X, Li H. Effects of testosterone supplement treatment in hypogonadal adult males with T2DM: a meta-analysis and systematic review. World J Urol. Aug 2018;36(8):1315-1326. 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. 2020;38(1):68-77. Return to content
  • Yassin A, Nettleship JE, Talib RA, Almehmadi Y, Doros G. Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity, voiding function and prostate safety parameters. The aging male : the official journal of the International Society for the Study of the Aging Male. 2016;19(1):64-9. Return to content
  • 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). Jan 2016;84(1):107-14. Return to content
  • Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. Aug 4 2005;353(5):487-97. Return to content
  • Jenkins CR, Rittel A, Sturdivant RX, et al. Glycemic Benefits with Adherence to Testosterone Therapy in Men with Hypogonadism and Type 2 Diabetes Mellitus. Andrology. Feb 19 2021; Return to content
  • Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. 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. Apr 2000;23(4):490-4. Return to content
  • American Diabetes Association. Summary of Revisions: Standards of Medical Care in Diabetes 2018. Diabetes Care. Jan 2018;41(Suppl 1):S4-S6. Return to content
  • 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. Jan 2016;39(1):82-91. Return to content
  • 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. Apr 2018;60(1):175-184. Return to content
  • 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. Mar 2014;11(3):840-56. 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
  • Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111. Return to content
  • Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content
  • Jimmy B, Jose J. Patient medication adherence: measures in daily practice. Oman medical journal. May 2011;26(3):155-9. Return to content
  • Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. Oct 21 2015;36(40):2706-15. Return to content
  • Sharma R, Oni OA, Gupta K, et al. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. Journal of the American Heart Association. May 9 2017;6(5) Return to content
  • Oni OA, Dehkordi SHH, Jazayeri MA, et al. Relation of Testosterone Normalization to Mortality and Myocardial Infarction in Men With Previous Myocardial Infarction. Am J Cardiol. Jul 25 2019;124(8):1171-1178. 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
  • Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
  • Crowley MJ, Holleman R, Klamerus ML, Bosworth HB, Edelman D, Heisler M. Factors associated with persistent poorly controlled diabetes mellitus: clues to improving management in patients with resistant poor control. Chronic illness. Dec 2014;10(4):291-302. Return to content