Testosterone therapy to prevent type 2 diabetes in men at risk

By Dr. Fan Xi, MD

Obesity is a well-established cause of low testosterone that is potentially reversible with weight loss.(1-3) While theoretically obesity is a reversible cause of low testosterone, a very large amount of weight loss is necessary to raise endogenous testosterone levels enough to achieve resolution of hypogonadal symptoms. For the vast majority of men, it is extremely hard to achieve this amount of weight loss, and even harder to maintain it long-term.

Low testosterone in turn is associated with an increased risk of incident type 2 diabetes in men.(4) A high proportion of men with type 2 diabetes have low testosterone that is associated with obesity, insulin resistance and hyperglycemia. (5,6) A systematic review with meta-analysis showed that men with testosterone levels above 15.5nmol/L (447 ng/dL) have a 42% reduced risk of type 2 diabetes compared to men with testosterone below 15.5nmol/L. (7)

Here we summarize the rationale of the notable upcoming T4DM “Testosterone 4 Diabetes Mellitus” study, which is investigating whether testosterone treatment combined with lifestyle change can prevent type 2 diabetes in men who have low testosterone levels and prediabetes (also known as borderline diabetes).

Key Points

  • It is well documented that low testosterone is associated with elevated glucose levels and type 2 diabetes.
  • Multiple studies have shown that testosterone therapy significantly reduces levels of fasting blood sugar and insulin resistance.
  • The benefits of testosterone therapy are greatest when combined with lifestyle interventions.
  • The “Testosterone 4 Diabetes Mellitus” study, also known as the T4DM trial, is a large top-quality study designed to find out if testosterone therapy combined with lifestyle intervention (Weight Watchers®) for 2 years versus lifestyle intervention alone, improves glucose tolerance and reduces incidence of type 2 diabetes.
  • The first results from the T4DM trial are expected to get published end of 2019. The T4DM trial is a milestone study because it may have significant implications for patients in real life, both in regards to treatment of men with type2 diabetes and the diagnosis of hypogonadism.

What is known about testosterone, insulin sensitivity / resistance and diabetes

Low testosterone can cause elevated blood sugar levels both directly and indirectly. Low testosterone increases body fat and reduces lean body (muscle) mass, which in turn results in insulin resistance followed by elevated blood sugar levels.(9) Testosterone also directly affects the glucose transporter, which is required by most cells to take up glucose from the blood (blood sugar), and carbohydrate metabolism.

Several studies with long follow-up periods of up to 15 years show that low testosterone levels significantly increased risk for development of insulin resistance, the metabolic syndrome and type 2 diabetes, even in men who were not obese at baseline.(10-12) Among men with low testosterone, half already have prediabetes.(13,14) A comprehensive analysis found that a testosterone level below 16 nmol/L predicts 5 year risk of developing type 2 diabetes in men, independently of age, impaired fasting glucose, physical inactivity, waist circumference, body weight and blood fats (triglycerides). (15) This suggests that screening for low testosterone - in other words, measuring testosterone levels in men as part of routine health checkups - would identify a large group of men at risk for type 2 diabetes who otherwise would get missed by reliance on traditional risk factors.(15)

Several long-term “real life” studies of testosterone therapy for up to 6 years in men with low testosterone and the metabolic syndrome or type 2 diabetes show marked improvement in glycemic control (reduction in fasting glucose and HbA1c), weight loss and reduced overall cardiovascular risk.(16-18)

All medical organizations recommend lifestyle intervention for prevention and management of type 2 diabetes.(19,20) In this regard, it is particularly notable that the benefits of testosterone therapy are greatest when combined with lifestyle intervention. (21) Addition of testosterone therapy to a supervised diet and exercise program results in greater improvements in blood sugar control, waist circumference and cholesterol profile than that achieved with the supervised diet and exercise program alone. (21)

However, up to this point no large-scale study has evaluated the effect of testosterone therapy combined with lifestyle intervention versus lifestyle intervention alone. Therefore, the “Testosterone 4 Diabetes Mellitus” study, also known as the T4DM trial, was undertaken.

What the “Testosterone 4 Diabetes Mellitus” study will teach us

The T4DM study is designed to find out if testosterone treatment combined with lifestyle intervention (Weight Watchers®) for 2 years versus lifestyle intervention alone, improves glucose tolerance (defined as blood sugar levels after a consumption of a glucose drink) and reduces incidence of type 2 diabetes.(8)

Approximately 1000 overweight or obese men aged 50-74 years were recruited as subjects for the T4DM study. All men had testosterone levels of 14nmol/L or less, impaired glucose tolerance or newly diagnosed type 2 diabetes, as well as abdominal obesity (defined as waist circumference of 95 cm or higher).

Treatments

Subjects were randomly allocated to receive testosterone treatment or placebo, for 2 years. The lifestyle intervention was provided by Weight Watchers®, with an interactive website providing diet and activity guidelines, and self-monitoring tools allowing men to log food, physical activity and weigh-in details. Men were encouraged to achieve a 5% reduction in body weight each year and to monitor and record their own body weight weekly. Adherence with the overall lifestyle program was monitored via website logins and activity, meeting attendance and information collected at 3-monthly clinic visits.

Treatment effects

Besides examining the effects of testosterone therapy on glucose tolerance and development of type 2 diabetes, the following secondary endpoints will be examined:

  • Initiation of antidiabetic pharmacotherapy
  • Glucose metabolism: fasting plasma glucose, insulin and HbA1c
  • Body weight, waist circumference
  • Body composition: DEXA measurements of body fat and lean (muscle) body mass
  • Muscle strength (handgrip test)
  • Hormone profile: testosterone, estrogen
  • Sexual function and lower urinary tract symptoms (LUTS)
  • Cholesterol profile: total cholesterol, LDL, triglycerides, HDL)
  • Psychosocial function
  • Compliance with the lifestyle intervention program
  • Health care expenditure

Sub-studies

Three sub-studies of T4DM will be conducted to determine the effects of testosterone therapy on:

1. Bone quality and bone mineral density (T4Bone).
2. Motivation and behaviour (T4M&B).
3. Telomere length (T4Telomeres).

Two additional sub-studies will investigate the effects of extended testosterone therapy for up to 4 years (T4DM run-on), and rate of recovery of the body’s  testosterone production at the end of the initial 2-year treatment period (T4DM run-off), respectively.

Commentary

The first results from the T4DM study are expected to get published end of 2019. With 1000 subjects, this is the largest high-quality study investigating the effects  of testosterone therapy. The Testosterone Trials (TTrials) had 790 subjects and lasted 1 year. The TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trial lasted 3 years, but only included 156 subjects. A particularly notable aspect of the T4DM study is that it includes men with a baseline testosterone level of up to14 nmol/L (404 ng/dL). This threshold is higher than the threshold recommended by most clinical guidelines for the diagnosis of hypogonadism, which is 12 nmol/L (345 ng/dL). The higher threshold of 14 nmol/L was chosen because the association of low testosterone levels and insulin resistance in men with type 2 diabetes remains present within the “normal” testosterone level range, and does not have a clear cutoff point. (5)

The T4DM trial will be the first ever study to investigate the effects of testosterone therapy on two emerging research areas; motivation for physical activity and telomere length, which is a biomarker of aging, in humans.(22) In the context of lifestyle change, the potential effect of testosterone therapy on motivation to increase physical activity levels is of particular interest.

References

1. Shi Z, Araujo AB, Martin S, O'Loughlin P, Wittert GA. Longitudinal changes in testosterone over five years in community-dwelling men. J Clin Endocrinol Metab. 2013;98(8):3289-3297.

2. Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity associated hypogonadotropic hypogonadism: a systematic review and meta analysis. Eur J Endocrinol. 2013;168(6):829-843.

3. Ng Tang Fui M, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian journal of andrology. 2014;16(2):223-231.

4. Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018;7(1):220-231.

5. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834-1840.

6. Atlantis E, Lange K, Martin S, et al. Testosterone and modifiable risk factors associated with diabetes in men. Maturitas. 2011;68(3):279-285.

7. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295(11):1288-1299.

8. Wittert G, Atlantis E, Allan C, et al. Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double blind randomised controlled trial. Diabetes, obesity & metabolism. 2018.

9. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24 month, randomized, double-blind, placebo-controlled study. The journal of sexual medicine. 2010;7(10):3495-3503.

10. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. 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.

11. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care. 2007;30(2):234-238.

12. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91(3):843-850.

13. Rabijewski M, Papierska L, Piatkiewicz P. The prevalence of prediabetes in population of Polish men with late-onset hypogonadism. The aging male : the official journal of the International Society for the Study of the Aging Male. 2014;17(3):141-146.

14. Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men with Hypogonadism Prevents Progression from Prediabetes to Type 2 Diabetes: 8 Year Data from a Registry Study. Submitted for publication. In:2019.

15. Atlantis E, Fahey P, Martin S, et al. Predictive value of serum testosterone for type 2 diabetes risk assessment in men. BMC endocrine disorders. 2016;16(1):26.

16. Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470.

17. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract. 2014;8(4):e339-349.

18. Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International journal of endocrinology. 2014;2014:683515.

19. Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: a consensus on Type 2 diabetes prevention. Diabet Med. 2007;24(5):451-463.

20. American Diabetes Association. 3. Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes - 2019 Diabetes Care. 2019;42(Supplement 1):S29-S33.

21. Heufelder AE, Saad F, Bunck MC, Gooren L. 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. Mather KA, Jorm AF, Parslow RA, Christensen H. Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci. 2011;66(2):202-213.

 

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