Testosterone and Cardiovascular Risk: The TRAVERSE Trial and Results from the New FDA Label Change

madman · Apr 25, 2025

Mohit Khera, MD, MBA, MPH, Professor of Urology and F. Brantley Scott Chair of Urology, Baylor College of Medicine, Houston, Texas, discusses evolving understanding of testosterone therapy and cardiovascular risk. In this 13-minute presentation, Dr. Khera focuses on the pivotal TRAVERSE trial and the recent announcement regarding class-wide labeling changes for testosterone products.

History of CV Events and Testosterone Therapy

Dr. Khera traces the history of concern of cardiovascular risks with testosterone therapy. He details that early studies—such as Molly Shores’ 2006 work—showed that low testosterone was associated with higher mortality, particularly due to cardiovascular events. However, between 2010 and 2014, several flawed studies suggested that testosterone therapy could increase cardiovascular risk. These studies prompted the FDA to issue a warning in 2015 restricting labeled indications to men with specific medical conditions, excluding age-related hypogonadism.

The TRAVERSE Trial

The TRAVERSE trial launched out of these concerns. This large, randomized, placebo-controlled trial enrolled over 5,200 men aged 45 to 80 with low testosterone levels and existing cardiovascular risk. Over a mean follow-up of 33 months, the trial found no increase in cardiovascular events among men treated with testosterone compared to placebo. Importantly, no increased risk of prostate cancer or worsening of lower urinary tract symptoms was observed.

TRAVERSE Trial Update in 2025

As a result, in February 2025, the FDA updated the labeling for testosterone products. While maintaining existing restrictions around age-related use, the FDA removed language from the Black Box related to increased risk of cardiovascular outcomes. The FDA now requires inclusion of TRAVERSE results in labeling. Following Ambulatory Blood Pressure Monitoring (ABPM) studies, the FDA requires product-specific information on increased blood pressure for testosterone products with completed ABPM studies. This is in addition to warnings about increased blood pressure across all testosterone products that currently lack such warnings.

Dr. Khera emphasizes the clinical impact of these changes. He notes that previous warnings led many high-risk men to avoid testosterone therapy despite potential benefits. He advocates for further research into the role of testosterone normalization in reducing cardiovascular risk. He also encourages a reevaluation of lingering concerns around prostate health.

madman · Apr 25, 2025

Thread 'FDA issues class-wide labeling changes for testosterone products'

Feb 28, 2025

FDA issues class-wide labeling changes for testosterone products

www.fda.gov

[2/28/2025] Today, FDA informed sponsors of testosterone products about new labeling changes following the agency’s review of the findings from the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) clinical trial External Link Disclaimer and the results from required postmarket ambulatory blood pressure (ABPM) studies.

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madman · Apr 25, 2025

Thread 'Is it the TRAVERSE Trial or a Travesty?'

Jul 16, 2024

There is a paper published that did not put its limitations into perspective and may lead to false reassurance about the safety of testosterone, recently published in the New England Journal of Medicine.1 This trial was done to demonstrate cardiovascular safety of testosterone repletement in men with low testosterone and symptoms. The authors concluded “Among 5,198 patients who received testosterone or placebo fora mean duration of 22 months, testosterone replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events”.1...

madman · Apr 26, 2025

Thread 'TRT and cardiovascular risk: TRAVERSE with caution'

Jul 25, 2024

The relationship between testosterone replacement therapy (TRT) and cardiovascular(CV) disease (CVD) risk in older, hypogonadal men has been debated for years. Observational studies have variably linked low endogenous testosterone levels with adverse cardio metabolic effects and increased CVD risk in men. However, the causality of this association is unclear, and low testosterone may simply be a biomarker of aging and poor health status rather than a direct contributor to CVD1. Given this association, TRT has been utilized to improve the symptoms of older, hypogonadal men such as...

*We bring attention to the limitations of the TRAVERSE trial due to the potential for misleading reassurance of the safety of TRT at physiologic or supraphysiologic levels. The long term CV effects and the safety of such regimens have yet to be studied. We certainly advocate for further research to explore the long-term CV impact of TRT, especially at these higher dosing levels.

*The debate surrounding TRT and CVD risk thus far can be summarized as follows: current evidence suggests TRT does not increase CVD risk in older, hypogonadal men when administered over a short duration and at low-normal levels of replacement. The question remains open when considering the effects of TRT at physiologic or supraphysiologic levels.

madman · 2025-05-23T10:18:15-0500

* Interpretation of the TRAVERSE findings is limited by several factors. Over 60 % of participants discontinued treatment prior to trial completion, resulting in a median exposure of less than 22 months. Additionally, outcome data were only available for approximately 80 % of the potential follow-up period. The trial's exclusive use of transdermal testosterone also limits generalisability to other formulations, particularly intramuscular injections, which may have differing cardiovascular profiles. These caveats necessitate cautious interpretation, though TRAVERSE remains the most definitive trial to date assessing cardiovascular safety in this population.

* Taken together, the current evidence suggests that while low endogenous testosterone is associated with adverse cardio metabolic profiles and increased all-cause mortality, its direct role in cardiovascular disease remains uncertain. Exogenous testosterone therapy, particularly when administered transdermally in men with established or elevated cardiovascular risk, does not appear to increase the risk of major adverse cardiovascular events in the short to medium term. However, observed increases in non-atherothrombotic events such as arrhythmias and thromboembolism underscore the need for careful patient selection, ongoing surveillance, and further investigation into formulation-specific effects and long-term outcomes.

Thread 'Cardiometabolic outcomes of early onset hypogonadism in males'

Today at 10:10 AM

* Interpretation of the TRAVERSE findings is limited by several factors. Over 60 % of participants discontinued treatment prior to trial completion, resulting in a median exposure of less than 22 months. Additionally, outcome data were only available for approximately 80 % of the potential follow-up period. The trial's exclusive use of transdermal testosterone also limits generalisability to other formulations, particularly intramuscular injections, which may have differing cardiovascular profiles. These caveats necessitate cautious interpretation, though TRAVERSE...

madman · 2025-05-23T10:32:29-0500

Summary Points

• Testosterone, the main endogenous active androgen, is used to treat many clinical conditions

• Testosterone and other androgens are also used by athletes, non athlete weightlifters or bodybuilders to enhance muscle development, strength, and performance and endurance

• Testosterone at supraphysiological levels increases cardiovascular disease risk, causes myocardial infarction, stroke, high blood pressure, blood clots, and heart failure

• Testosterone affects the cardiovascular system by changing lipid profile, insulin sensitivity, hemostatic mechanisms, sympathetic nervous system, and renin angiotensin-aldosterone system

• Testosterone activates proinflammatory and redox processes, decreases nitric oxide bioavailability, and stimulates vasoconstrictor signaling pathways

• Testosterone affects the vasculature by interfering with all mechanisms that control vascular function

• In the endothelium, testosterone modulates NO, COX-derived metabolites and EDHF release and signaling

• In VSMCs, testosterone modulates ROS generation, expression, and activity of receptors and ion channels

Thread 'High Testosterone Levels: Impact on the Heart'

Mar 9, 2024

Abstract

Testosterone, the main endogenous active androgen, is used to treat many clinical conditions, such as hypogonadism, infertility, erectile dysfunction, osteoporosis, anemia, and in transgender therapy (female-to-male transsexuals). Androgens are also used by athletes to enhance performance and endurance, and by non athlete weightlifters or bodybuilders to enhance muscle development and strength. Accordingly, testosterone and other anabolic-androgenic steroids are the main class of appearance and performance enhancing drugs (APEDs), i.e., substances used to improve...