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Testosterone treatment is NOT associated with risk of adverse cardiovascular events – the RHYME study

It is well-documented that testosterone therapy effectively restores testosterone levels in hypogonadal men and improves many health outcomes, such as quality of life [1-4], libido [4, 5], metabolic parameters [5-9] and body composition.[4, 5, 9, 10]
 
However, a few conflicting studies raised concerns about the cardiovascular safety of testosterone therapy [11, 12], which in 2015 prompted the FDA to issue warnings to physicians and patients about potential cardiovascular risks of testosterone therapy.
 
In contrast, the European Medicines Agency (EMA) acknowledged the flaws of the conflicting studies and concluded that there is no consistent evidence of harm associated with testosterone therapy, regardless of mode of delivery.[13]
 
Here I summarize the cardiovascular results of the notable RHYME (The Registry of Hypogonadism in Men) study, which contrary to prior clinical trials, enrolled men with a wide range of comorbid illnesses and cardiovascular risk factors.[14] The aim was to evaluate the safety of testosterone therapy in a sufficiently diverse population to reflect real-world, clinical experience.[14]
 

Key Points

 
* In comparison to both untreated men and to age-matched population data, no increase in mortality or cardiovascular risk was observed with testosterone therapy, regardless of:
 
- The type of testosterone administered (injectable vs. topical preparations).
 
- Presence of other comorbidities. 
 
- Age of patients (no increased risk was seen in both younger and older hypogonadal men).
 
- The type of hypogonadism being treated (primary vs. secondary).
 
* These results strongly support the overall cardiovascular safety of testosterone therapy.
 
* The RHYME study refutes FDA’s labelling caution for potential risks of deep vein thrombosis with testosterone therapy.
 
 

What is known

 
The EMA conclusion is supported by the latest testosterone therapy guidelines from the European Association of Urology (EAU) [15], International Society for Sexual Medicine (ISSM) [16], European Menopause Andropause Society (EMAS) [17], Canadian Men's Health Foundation [18] and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE).[19]
 
Examples of recent studies proving that testosterone therapy does not increase (and may actually decrease) cardiovascular risk include the respectable T-Trial [20], new database analyses in large healthcare systems [21, 22] [23, 24], product registries [25, 26] and recent systematic reviews.[27, 28]
 

What this study adds

 
The RHYME study was a multi-national, longitudinal disease registry of men diagnosed with hypogonadism at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and cardiovascular outcomes. 
 
Of 999 patients enrolled with clinically diagnosed hypogonadism, 750 (75%) initiated some form of testosterone therapy. Registry participants, including both treated and untreated patients, contributed 23 900 person-months follow-up time. A total of 55 reported cardiovascular events occurred in 41 patients. Overall, five patients died of cardiovascular -related causes (3 on testosterone therapy, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall cardiovascular incidence rate was 1522 per 100 000 person-years. Cardiovascular event rates for men receiving testosterone therapy were not statistically different from untreated men. 
 
Regardless of treatment assignment, cardiovascular event rates were higher in older men and in those with increased cardiovascular risk factors or a prior history of cardiovascular events. 
 

Comments

 
The RHYME study was designed and conducted by an independent research organization (New England Research Institutes) as the first stage in a planned multi-national program of long-term studies of testosterone therapy.[29] It is notable in that it enrolled a diverse population reflective of real-world, clinical experience, and subjects were systematically monitored for up to 36 months, a substantially longer period of follow-up compared to recent RCT’s.[20, 30] The independent adjudication of all mortalities and cardiovascular outcomes is a strength of this study, as a previous study which alluded to increased cardiovascular events included trivial outcomes, such as syncope.[30] This study found that predictors of new-onset cardiovascular events in this multi-national, prospective hypogonadism registry were age and prior cardiovascular history, not testosterone use.
 
The conclusion that testosterone therapy - regardless of the type of testosterone administered – does not increase mortality or cardiovascular risk, compared to both untreated men and to age-matched population data, is reassuring. This is the first large cohort study of hypogonadal men that includes sizable samples of men with both primary and secondary hypogonadism, neither of which showed an increase in cardiovascular events with testosterone therapy.
 
This lack of association between testosterone use and cardiovascular-related adverse events was evident in both younger and older hypogonadal men, regardless of the type of hypogonadism being treated (primary vs. secondary) or mode of testosterone administration (injectable vs. topical preparations). None of the cardiovascular-related mortalities were judged to be related to testosterone therapy, but were significantly associated with prior or current cardiovascular conditions. These results are consistent with results from other patient registries in the US [25, 26] and Europe [7, 31-33] showing relative safety of testosterone therapy in hypogonadal men with multiple comorbid illnesses and cardiovascular risk factors.
 
Despite FDA’s specific labelling caution for potential risks of deep vein thrombosis with testosterone therapy [34], this recommendation is not supported by results from recent studies, such as a large-scale medical record database review [24], the T-Trial [20], and the current findings in RHYME (presented here).[14]
 

References:

 

1.            Tong, S.F., et al., Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl, 2012. 14(4): p. 604-11.

2.            Tan, W.S., et al., Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int, 2013. 111(7): p. 1130-40.

3.            Behre, H.M., et al., A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male, 2012. 15(4): p. 198-207.

4.            Srinivas-Shankar, U., 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): p. 639-50.

5.            Permpongkosol, S., N. Tantirangsee, and K. Ratana-olarn, Treatment of 161 men with symptomatic late onset hypogonadism with long-acting parenteral testosterone undecanoate: effects on body composition, lipids, and psychosexual complaints. J Sex Med, 2010. 7(11): p. 3765-74.

6.            Dhindsa, S., 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): p. 82-91.

7.            Traish, A.M., et al., Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract, 2014. 68(3): p. 314-29.

8.            Yassin, A., et al., 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): p. 107-14.

9.            Marin, P., et al., The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord, 1992. 16(12): p. 991-7.

10.          Finkelstein, J.S., et al., Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med, 2013. 369(11): p. 1011-22.

11.          Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013. 310(17): p. 1829-36.

12.          Finkle, W.D., et al., Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 2014. 9(1): p. e85805.

13.          European Medicines Agency, No consistent evidence of an increased risk of heart problems with testosterone medicines, 2014. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Testosterone-containing_medicines/human_referral_prac_000037.jsp&mid=WC0b01ac05805c516f (accessed December 29th, 2015).

14.          Maggi, M., et al., Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Int J Clin Pract, 2016. 70(10): p. 843-852.

15.          Dohle, G.R., et al. 2016 EAU Guidelines on Male Hypogonadism, available at http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Hypogonadism-2016.pdf (accessed July 26, 2016).

16.          Dean, J.D., et al., The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. J Sex Med, 2015. 12(8): p. 1660-86.

17.          Dimopoulou, C., et al., EMAS position statement: Testosterone replacement therapy in the aging male. Maturitas, 2016. 84: p. 94-9.

18.          Morales, A., 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): p. 1369-77.

19.          Goodman, N., et al., American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of Testosterone and Cardiovascular Risk. Endocr Pract, 2015. 21(9): p. 1066-73.

20.          Snyder, P.J., et al., Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374(7): p. 611-24.

21.          Sharma, R., et al., Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J, 2015. 36(40): p. 2706-15.

22.          Anderson, J.L., et al., Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol, 2016. 117(5): p. 794-9.

23.          Wallis, C.J., et al., Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol, 2016.

24.          Sharma, R., et al., Association Between Testosterone Replacement Therapy and the Incidence of DVT and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database. Chest, 2016. 150(3): p. 563-71.

25.          Bhattacharya, R.K., et al., Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS). Clin Interv Aging, 2012. 7: p. 321-30.

26.          Miner, M.M., et al., 12-month observation of testosterone replacement effectiveness in a general population of men. Postgrad Med, 2013. 125(2): p. 8-18.

27.          Corona, G., E. Maseroli, and M. Maggi, Injectable testosterone undecanoate for the treatment of hypogonadism. Expert Opin Pharmacother, 2014: p. 1-24.

28.          Corona, G., et al., Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf, 2014. 13(10): p. 1327-51.

29.          Rosen, R.C., et al., Registry of Hypogonadism in Men (RHYME): design of a multi-national longitudinal, observational registry of exogenous testosterone use in hypogonadal men. Aging Male, 2013. 16(1): p. 1-7.

30.          Basaria, S., et al., Adverse events associated with testosterone administration. N Engl J Med, 2010. 363(2): p. 109-22.

31.          Haider, A., et al., 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): p. e339-49.

32.          Yassin, A.A., et al., 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: p. Jan 14. doi: 10.1111/and.12514. [Epub ahead of print].

33.          Haider, A., et al., Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vasc Health Risk Manag, 2016. 12: p. 251-61.

34.          FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use 2015. Available at http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm (assessed December 8, 2016).

Last modified on Tuesday, 13 December 2016 04:26
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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