The possibility that testosterone replacement for men with hypogonadism increases cardiovascular risk has been a controversial topic, and the data are inconsistent. Many studies have been retrospective, and the few randomized trials were not designed to evaluate cardiovascular outcomes and were underpowered. In 2015, the Food and Drug Administration issued a guidance that required that manufacturers of approved testosterone medications conduct clinical trials to determine whether testosterone replacement therapy increases cardiovascular risk.
At the Endocrine Society annual meeting held June 15–18, 2023, in Chicago, the study design and cardiovascular safety results of TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men), a prospective randomized placebo-controlled trial of testosterone replacement was presented by Drs. Nissen, Lincoff, Bhasin, and Snyder. TRAVERSE enrolled 5,246 hypogonadal men, mean age 63 years, with either a high cardiovascular risk or a previous cardiovascular event. Participants were included if they had one sign or symptom of testosterone deficiency, and two blood samples taken between 5 and 11 a.m. showed total testosterone concentrations below 300 ng/dL. They were randomized 1:1 to testosterone gel 1.6% or placebo, and testosterone was titrated to levels between 350 and 700 ng/dL. Median testosterone at baseline was 227 ng/dL in each group. At 12 months, the mean increase in serum testosterone 24 hours after receiving a dose was 148 ng/dL. A large proportion of participants in both groups were taking lipid-lowering therapy.
The primary safety endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease (CVD) death. A non-inferiority analysis of the time to the first event of the composite endpoint found that during a mean treatment duration of 21.7 months, 182 and 190 primary safety endpoints occurred in the testosterone and placebo groups, respectively, showing that in middle age and elderly men with hypogonadism and CVD or high risk of CVD, testosterone replacement therapy was non-inferior to placebo with regard to major cardiac events. Although there was a high rate of study dropout, intention-to-treat analyses and on-treatment sensitivity analyses found similar results. These data support the cardiac safety of testosterone treatment of hypogonadal men of middle age or older, treated for about two years.
Venous thromboembolic events, a tertiary endpoint, did not significantly differ in both groups. However, pulmonary embolism was higher in the testosterone group, 24 (0.9%), compared to the placebo group, 12 (0.5%). Deep vein thrombosis was reported in 16 (0.5%) participants in the testosterone group and 13 (0.5%) participants in the placebo group. There was no difference in prostate cancer among testosterone and placebo randomized participants. The increase in PSA levels from baseline was significantly greater in the testosterone group versus the placebo group (0.20 vs. 0.08 ng/ml.
The cardiovascular safety results were published in the New England Journal of Medicine on June 16, 2023, the same day as the ENDO presentation.
Also presented at ENDO were TRAVERSE data on bone fracture, which surprisingly showed more fractures in participants allocated testosterone compared to placebo: 91 vs. 64 clinical bone fractures. The bone sub-study will be the subject of another publication.
Dr. Newman has no conflicts of interest to report.
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