Testosterone-Replacement Therapy and Cardiovascular Safety

The cardiovascular effects of testosterone-replacement therapy in middle-aged and older men with below normal testosterone levels have not been determined. Recent studies involving men receiving testosterone-replacement therapy demonstrate conflicting results. Some have shown increased and others decreased cardiovascular risk⁽¹⁾. 

In addition, there are numerous studies that were not designed to systematically assess cardiovascular outcomes, were inadequately powered and had a short duration⁽²⁾.

Due to the concerns and conflicting data regarding the cardiovascular safety of testosterone-replacement therapy, the Food and Drug Administration (FDA) issued a guidance on March 3, 2015, requiring manufacturers of approved testosterone products to conduct clinical trials to ascertain whether testosterone-replacement therapy is associated with an increased risk of cardiovascular events⁽³⁾.

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to clarify the impact of testosterone-replacement therapy on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism (the reduction or absence of hormone secretion) and either preexisting or a high risk of cardiovascular disease⁽⁴⁾.

This research was a phase 4, randomized, double-blind, placebo-controlled, noninferiority, event-driven trial conducted at 316 clinical-trial sites in the United States.

Inclusion criteria were:

• - Men, 45-80 years old, with preexisting cardiovascular disease or an elevated cardiovascular risk
• - Reported one or more symptoms of hypogonadism, including decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood, loss of axillary or pubic body hair or decreased frequency of shaving, or hot flashes
• - Had two fasting serum testosterone levels of less than 300 ng per deciliter in blood samples obtained between 5:00 a.m. and 11:00 a.m. and measured by gold standard LC-MS⁽⁵⁾.

Cardiovascular disease was defined as clinical or angiographic evidence of coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

Increased cardiovascular risk was defined as the presence of three or more of the following risk factors: hypertension, dyslipidemia, current smoking, stage 3 chronic kidney disease, diabetes, elevated high-sensitivity C-reactive protein level, age of 65 years or older, or an Agatston coronary calcium score that was above the 75th percentile for age and race.

Exclusion criteria included:

• - Congenital or acquired severe hypogonadism (testosterone level, <100 ng per deciliter)
• - History of prostate cancer or prostate nodules
• - Elevated screening prostate-specific antigen (PSA) level
• - Thrombophilia, and uncontrolled heart failure.

In addition, patients could not be enrolled within 4 months after an acute coronary syndrome, stroke, or coronary or peripheral revascularization or within 6 months after treatment with testosterone or androgenic steroids⁽⁵⁾.

Major Findings

As mentioned, this randomized, placebo-controlled trial was conducted to address the uncertainty to whether testosterone-replacement therapy in middle-ages and older men with hypogonadism enhances the risk of cardiovascular events.  Men with established cardiovascular disease or multiple cardiac risk factors were included. These men were the most vulnerable to an increased risk of adverse cardiovascular outcomes. Testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events⁽⁵⁾.

Essentially, 'noninferior' means that taking testosterone replacement therapy is not worse than the placebo.

Figure: No apparent clinically meaningful differences in the incidence of secondary cardiovascular end-point events were observed between the trial groups⁽⁵⁾ 

The incidence of pulmonary embolism was higher with testosterone than with placebo. Evidence indicates that most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia⁽⁶⁾. 

A meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations⁽⁷⁾.

Findings in this current study support current guidelines that testosterone should be used with caution in men who have preceding thromboembolic events⁽⁸⁾.  

An unexpected finding revealed in patients receiving testosterone had more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury. A cohort study suggested that normalization of low testosterone levels by testosterone-replacement therapy was associated with a decrease in the incidence of atrial fibrillation⁽⁹⁾.

Essentially, when men’s low testosterone levels were increased and normalized, they showed less incidence of atrial fibrillation.

Previous well-controlled research indicates that the use of testosterone in older men improves sexual function, increases bone mineral density, corrects unexplained anemia, and moderately reduces depressive symptoms.

Because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has influenced whether clinicians choose to treat patients.  

These current findings regarding the cardiovascular safety of testosterone may enable a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with low testosterone levels.

Summary

Among men with low testosterone levels and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone-replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low.

To learn more about declining test levels and what you can do to optimize your hormone profile, read this.

References:
1.    Baillargeon, J., Urban, R. J., Kuo, Y. F., Ottenbacher, K. J., Raji, M. A., Du, F. et al. (2014) Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy Ann Pharmacother 48, 1138-1144 10.1177/1060028014539918
2.    Alexander, G. C., Iyer, G., Lucas, E., Lin, D., andSingh, S. (2017) Cardiovascular Risks of Exogenous Testosterone Use Among Men: A Systematic Review and Meta-Analysis Am J Med 130, 293-305 10.1016/j.amjmed.2016.09.017
3.    Administration., F. a. D. (2018) 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. In FDA drug safety communication, Food and Drug Administration.,
4.    Bhasin, S., Lincoff, A. M., Basaria, S., Bauer, D. C., Boden, W. E., Cunningham, G. R. et al. (2022) Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study Am Heart J 245, 41-50 10.1016/j.ahj.2021.11.016
5.    Lincoff, A. M., Bhasin, S., Flevaris, P., Mitchell, L. M., Basaria, S., Boden, W. E. et al. (2023) Cardiovascular Safety of Testosterone-Replacement Therapy N Engl J Med 389, 107-117 10.1056/NEJMoa2215025
6.    Glueck, C. J., andWang, P. (2014) Testosterone therapy, thrombosis, thrombophilia, cardiovascular events Metabolism 63, 989-994 10.1016/j.metabol.2014.05.005
7.    Hudson, J., Cruickshank, M., Quinton, R., Aucott, L., Aceves-Martins, M., Gillies, K. et al. (2022) Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis Lancet Healthy Longev 3, e381-e393 10.1016/S2666-7568(22)00096-4
8.    Bhasin, S., Brito, J. P., Cunningham, G. R., Hayes, F. J., Hodis, H. N., Matsumoto, A. M. et al. (2018) Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab 103, 1715-1744 10.1210/jc.2018-00229
9.    Sharma, R., Oni, O. A., Gupta, K., Sharma, M., Sharma, R., Singh, V. et al. (2017) Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation J Am Heart Assoc 6, 10.1161/JAHA.116.004880