New Testosterone Trial in Men (TRAVERSE) Promising for Cardiovascular Health

Krista Anderson Ross, ND | February 29, 2024

Conflicting evidence over the safety and efficacy of testosterone in men’s health led to a 2015 FDA mandate requiring testosterone manufacturers to conduct clinical trials to assess whether pharmaceutical testosterone products are associated with an increased risk for cardiovascular events. In response, a consortium of testosterone product manufacturers provided funding for the phase 4 Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial – a landmark randomized, placebo-controlled trial resulting in four published trials including primary findings related to cardiovascular disease, as well as secondary and tertiary findings related to prostate cancer, sexual function and anemia.  

The study randomized 5200+ men with mild to moderate hypogonadism (total testosterone <300 ng/dL) aged 45-80, to daily 1.62% testosterone gel, or matching placebo gel. All participants had pre-existing cardiovascular diagnoses (coronary artery disease, cerebrovascular disease or peripheral arterial disease); or at least three of the following cardiovascular risk factors: hypertension, dyslipidemia, current smoker, stage 3 chronic kidney disease, diabetes, elevated high sensitivity C- reactive protein level, age 65 or older, or a coronary calcium score above the 75th percentile for age and race. Additionally, participants had one or more of the following symptoms of hypogonadism: decreased sexual desire or libido; decreased spontaneous erections; fatigue or decreased energy; low or depressed mood; loss of axillary, pubic or body hair or decreased frequency of shaving; and hot flashes.  

“Among men with hypogonadism 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,” investigators concluded. In other words, for those who received testosterone replacement therapy (TRT) there was no increased risk for cardiovascular events or death from myocardial infarction (MI) or stroke. This is welcome news for doctors and patients - but not without a few caveats: 

  1. The primary safety endpoint was the first occurrence of a major cardiovascular event defined as a composite of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke. In the testosterone group, 182 patients (7%) experienced one primary endpoint over the course of the trial, compared to 190 patients (7.3%) in the placebo group (HR, 0.96; 95% confidence interval, 0.78-1.17; P < .001 for noninferiority).  
  2. Other observed non-primary outcomes in the testosterone group included nonfatal arrhythmias among 134 (5.2%) of the testosterone group versus 87 (3.3%) in the placebo group (P=.001); acute kidney injury in 2.3% of the testosterone group versus 1.5% of the placebo group (P=.04); and prostate cancer in 12 (0.5%) of the testosterone group versus 11 (0.4%) in the placebo group (P=.87) 
  3. While the trial treatment was shown to increase median serum levels by 148ng/dL in the treatment group, the starting median total T in both groups was quite low at 227 ng/dL with an end point of only 375 ng/dL, just above what’s considered hypogonadism (< 300 ng/dL). While a typical targeted supplementation range is between 400-700 ng/dL, these results suggest that though levels that started low did rise, they did not reach the targeted clinical supplementation range.  

These results are clearly promising for men with hypogonadism and cardiovascular risk; however, more research is needed to evaluate risk when serum levels fall within the supplementation range. Author and anti-aging researcher Peter Attia MD succinctly states, “…the finding that TRT was noninferior to (not more harmful than) placebo at a low level does not necessarily mean that it is noninferior with higher testosterone increases. So, as it stands, the cardiovascular effects at clinically relevant levels of testosterone replacement are still unknown.” He also points out that the study did not measure free testosterone or SHBG to measure if the amount of bioavailable testosterone was increased. Because the free portion of total hormone is only 2-5%, with such a small increase in total testosterone, one could only expect a trivial increase in free testosterone.  

Saliva testing enables direct measurement of the 2-5% free/unbound testosterone available to tissues because steroid based hormones are lipophilic and don’t require a carrier protein in saliva. In contrast, because serum is an aqueous environment, the carrier proteins SHBG and albumin enable fatty, steroid-based hormones like testosterone to exist in solution. A calculation is applied to total testosterone using SHBG and albumin standards to calculate the free portion. To learn more, click here.  

 

References

Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. doi:10.1056/NEJMoa2215025  

Antonio L, Wu FC, O'Neill TW, et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. J Clin Endocrinol Metab. 2016;101(7):2647-2657. doi:10.1210/jc.2015-4106 

Campbell, Patrick. TRAVERSE Trial: No Increased Cardiovascular Risk with Testosterone Replacement Therapy. June 18, 2024. Accessed 2/22/24 https://www.hcplive.com/view/traverse-trial-no-increased-cardiovascular-risk-with-testosterone-replacement-therapy 

Attia, Peter MD. Is testosterone replacement therapy both safe and effective in men with higher cardiovascular risk factors? October 25, 2023. Accessed 2/22/24 https://peterattiamd.com/traverse-trial-and-trt-in-men/ 

Rubin, Rachel, MD. The Most Exciting Time for Testosterone. January 18, 2024. Accessed 2/22/24. https://www.medscape.com/viewarticle/999636#vp_1 

 

Buy Now Pay Later: The True Cost of HPA Axis Dysfunction

Presented by Ruth Hobson, ND

March 13, 2024 at 9:30AM and 12 PM Pacific

Each session is approximately 60 minutes with Q&A

Learning Objectives:

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March 20, 2024 at 12 PM Pacific

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Today's patients often present with multiple confounding symptoms with several biological systems being simultaneously dysregulated. The challenge to the modern functional medicine practitioner often is where to start and how to go about effectively assessing and treating these individual who are suffering from fatigue, depression, anxiety, gut health issues, chronic pain, autoimmune initiation and progression, thyroid and other hormonal imbalances, and many more. Join Dr. Lundell as he progresses through a challenging case study showing which labs provide the best evidence for care, along with a proven treatment strategy that can be applied to most of your clinical cases.

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