Testosterone and Cardiovascular Risk: TRAVERSE Trial and New FDA Label Change
Mohit Khera, MD, MBA, MPH, discusses testosterone therapy and cardiovascular risk, focusing on the TRAVERSE trial and FDA label changes.
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testosterone therapy
TRAVERSE: Meaning of the Testosterone Safety Trials
Martin M. Miner, MD, reviews testosterone safety trials and recent data on the cardiometabolic effects of testosterone, addressing concerns from the FDA about off-label testosterone use among aging men. The TRAVERSE trial, conducted in response to these concerns, examines whether testosterone therapy increases the risk of myocardial infarction or stroke.
In this 12-minute presentation, Dr. Miner provides a comprehensive review of studies from 1940 to 2014, which found minimal evidence suggesting cardiovascular risks associated with testosterone. However, key studies released in 2013-2014 raised concerns about testosterone therapy, indicating a potential increased risk of non-fatal myocardial infarctions. In response, the FDA issued a directive in 2015, leading to the large-scale TRAVERSE trial, a double-blind, placebo-controlled trial that assessed testosterone gel effects over five years.
The TRAVERSE study is notable as the longest randomized, controlled trial on testosterone safety among hypogonadal men to date. Findings indicate that testosterone therapy poses low cardiovascular risk, improves sexual health, and has no significant impact on prostate cancer risk or progression. This suggests that normalized testosterone levels may reduce risks of mortality and adverse cardiovascular events, without elevating prostate cancer concerns.
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The Association Between Testosterone Treatment and Incident of Cardiovascular Events among Testosterone Deficient U.S. Veterans
Thomas J. Walsh, MD, MBA, MS, provides a detailed examination of the relationship between testosterone treatment and the incidence of cardiovascular events among testosterone-deficient U.S. veterans.
In this 19-minute presentation, Dr. Walsh outlines the background of testosterone deficiency, noting ongoing concerns regarding its safety, particularly its potential to increase the risk of heart attacks, strokes, and other heart-related issues.
Drawing on data from a large cohort of U.S. veterans, Dr. Walsh discusses the incidence of cardiovascular events in patients undergoing testosterone therapy compared to those who do not receive such treatment. He discusses the methodology used in the study, including the selection of participants, the duration of follow-up, and the statistical analyses employed to control for confounding variables.
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TRAVERSE Trial Update
Mohit Khera, MD, MBA, MPH, presents the latest updates from the TRAVERSE Trial, examining the cardiovascular effects of testosterone therapy. This presentation is an update to Dr. Khera’s “Results from the TRAVERSE Trial” lecture, which was presented to the Grand Rounds in Urology audience in August 2023.
Dr. Khera begins by reviewing the history of the TRAVERSE Trial and its initial results regarding the impact of testosterone therapy on cardiovascular health. He outlines the design of the TRAVERSE Trial, which concluded in January 2024 with a final enrollment count of 5,246 men.
In addition to the original secondary and tertiary endpoints regarding cardiovascular safety and prostate safety, Dr. Khera discusses other secondary endpoints in the trial. These endpoints were sexual function, depression, bone fractures, diabetes, and anemia.
Dr. Khera concludes by delving into the final results of testosterone therapy on all endpoints in the trial. He notes that the results indicate that testosterone therapy does not significantly worsen BPH symptoms and may protect against the development of anemia. However, he notes that testosterone therapy may raise the risk of bone fractures and pulmonary embolisms.
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Deciphering Options for Testosterone Replacement Therapy and Managing Withdrawal
Jesse N. Mills, MD, discusses the importance of testosterone replacement therapy and presents an algorithm for determining treatment and managing withdrawal. He begins with an overview of the history of the study of testosterone, from the first recorded effects of castration to the warning against the over-prescription of testosterone therapy issued in 2015 by the FDA.
Dr. Mills discusses the AUA guidelines for testosterone replacement therapy and the lack of on-label options for treatment. He presents options for on-and-off-label testosterone replacement therapy.
Dr. Mills then presents an algorithm for determining the best treatment option for the patient, beginning by addressing male fertility concerns. He addresses questions of lab work, transference, insurance, administration, and other patient and physician concerns.
Dr. Mills concludes with the discontinuation of testosterone replacement therapy and when it is indicated. He discusses the available options for weaning patients off of testosterone, cautioning strongly against abrupt discontinuation.
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The Association Between Testosterone Treatment and Incident of Cardiovascular Events among Testosterone Deficient U.S. Veterans
In this 19-minute presentation, Thomas J. Walsh, MD, MBA, MS, University of Washington, Seattle, Washington, highlights the need for further research to clarify the long-term effects of testosterone therapy on cardiovascular health, advocating for a balanced approach that weighs the potential benefits against the risks. Dr. Walsh’s presentation underscores the importance of personalized medicine in managing testosterone deficiency.
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Results from the TRAVERSE Trial
Mohit Khera, MD, MBA, MPH, provides an update on the results of the landmark TRAVERSE Trial, which examined the potential cardiovascular effects of testosterone therapy in men. After reviewing the complex recent history and controversies surrounding testosterone therapy, Dr. Khera walks through the TRAVERSE Trial, a randomized, double-blind, placebo-controlled study of over 5,000 hypogonadal men who either had cardiovascular disease (CVD), or were at increased risk for CVD over 5 years.
Dr. Khera highlights the thoroughness of the trial’s design, giving special focus to the primary, secondary, and tertiary endpoints relating to any MACE events for the trial participants. He concludes by presenting the results of the trial; testosterone therapy, for a mean duration of 22 months, did not increase the risk of major cardiovascular events in hypogonadal men over 40 years old with previous CVD or elevated risk for CVD.
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Update on Testosterone and Treatment for Diabetes Mellitus: T2DM Australian Study
T. Mike Hsieh, MD, MBA, provides an update on a study examining the use of testosterone therapy (TT) to treat type 2 diabetes mellitus (T2DM) in men. He describes the Testosterone Trials and summarizes findings in men treated with TT, including a significant increase in testosterone (T) levels and subsequent improvement of symptoms.
Dr. Hsieh discusses T and diabetes, and explains that obesity with or without diabetes is associated with lower T and an increased risk of T2DM. He explains that lifestyle intervention and metformin were shown to prevent progression of prediabetes to T2DM without TT. He discusses TT and cardiovascular disease (CVD), explaining T deficiency is associated with CVD. Though there is conflicting data on the benefit of TT on CVD, the 2018 American Urological Association (AUA) Testosterone Deficiency guideline cites no definitive evidence linking TT to a higher incidence of venous thromboembolism (VTE).
Dr. Hsieh discusses an Australian double-blind, randomized, controlled trial that aimed to determine whether TT combined with lifestyle intervention vs. lifestyle intervention alone reduced T2DM incidence and improved glucose tolerance at two years, while closely monitoring for signs of CVD. The study supported that, while TT plus lifestyle modification can prevent or revert T2DM in men without hypogonadism, hematocrit (HCT) levels must be closely monitored in men undergoing TT, and long-term safety and cardiovascular outcomes of TT remains to be determined. Finally, Dr. Hsieh cites the ongoing TRAVERSE study, examining the complications of TT in older men.
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Challenging Case Discussion Panel: Men’s Health
Martin M. Miner, MD, discusses a challenging case involving testosterone therapy, cardiovascular risk, and prostate cancer. He begins by providing information about a case study patient, highlighting obesity, low testosterone levels, and diminished libido. Dr. Miner then discusses data that find a connection between testosterone therapy and increased cardiovascular risk.
He notes a review of all articles from 1940 to 2014 researching this connection, finding only four studies indicating a connection and uncovering major flaws in their procedures. This leads him to question the link between testosterone therapy and increased cardiovascular risk while also describing the case study patient’s testosterone therapy treatment. Dr. Miner then reviews guidelines from the American Urological Association and the Endocrine Society. He references the case study patient once again, noting the patient’s development of cardiac events and questions whether the patient should return to testosterone therapy.
After reviewing additional data on this topic, Dr. Miner concludes that testosterone therapy has at least neutral effects on cardiovascular risk factors, although additional studies are needed. He transitions the discussion back to the case study patient, noting his new development of prostate cancer and reviewing data on testosterone therapy’s effects on prostate cancer. Dr. Miner opens the discussion up to panelists, who discuss testosterone levels, obesity management, and individualized urologic treatment.
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Testosterone Update on Oral Products
T. Mike Hsieh, MD, MBA, provides an update on available oral testosterone treatments, beginning by explaining that oral testosterone is a large and growing market and outlining the development testosterone therapy over recent decades. Dr. Hsieh hones in on the three therapies most recently approved by the U.S. Food and Drug Administration (FDA), all of which are oral testosterone therapies (Jatenzo, Tlando, and Kyzatrex).
He cites a study of Oral Testosterone Undecanoate in Hypogonadal Men, which led to the approval of Jatenzo. Dr. Hsieh then addresses Tlando, and explains the study behind its approval, which found the treatment’s efficacy was 80 percent, exceeding the FDA threshold of 75 percent. He then addresses Kyzatrex, a gelatin capsule that uses a SEDDS formulation (phytosterol esters that form microemulsions in gastrointestinal fluids, allowing oral dosing of poorly-soluble drugs). As far as clinical efficacy, Kyzatrex well exceeded the FDA threshold, with 96 percent of patients achieving testosterone levels in the therapeutic range after 90 days of treatment.
Dr. Hsieh explains that, unlike Jatenzo, Tlando and Kyzatrex do not need to be taken with a high-fat meal. With all three medications, blood pressure increase is a possible side effect (though the data on hypertension was more favorable in the Kyzatrex study), and all these treatments carry FDA warnings to that effect.
Dr. Hsieh concludes that there is a wide variety of commercially available testosterone options on the market, with new oral formulations with favorable safety profiles representing exciting new options for patients. He reiterates that blood pressure should always be monitored in patients on oral testosterone.
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Male Mortality and Men’s Health Issues: Barriers, Testosterone, PDE5 Therapy and GLP1 Agonist Therapy
Martin M. Miner, MD, discusses the role of testosterone therapy in improving men’s health outcomes, including in prostate cancer.
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Interviews with Icons: Abraham Morgentaler, MD, FACS, and Testosterone Therapy in Clinical Medicine
Neil H. Baum, MD, interviews Abraham Morgentaler, MD, FACS, on his clinical research treating men using testosterone therapy.
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