Testosterone-Replacement Therapy in Men With Hypogonadism Does Not Increase Risk of Cardiovascular Events

In middle-aged men who have hypogonadism and preexisting or high risk of cardiovascular disease (CVD), testosterone-replacement therapy does not lead to a higher risk of cardiovascular events, results of a study published in The New England Journal of Medicine showed.

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The randomized, double-blind, placebo-controlled trial featured 5204 patients in the full-analysis population. Men were eligible for the study if they were between 45 and 80 years of age, reported 1 or more symptoms of hypogonadism, including decreased sexual desire, decreased energy, or a depressed mood, and had 2 fasting serum testosterone levels of less than 300 ng per deciliter, the study authors wrote.

CVD was defined as clinical or angiographic evidence of cerebrovascular disease, peripheral arterial disease, or coronary artery disease. The risk of CVD was seen as the presence of 3 or more risk factors, including dyslipidemia, hypertension, current smoking, stage III chronic kidney disease, age 65 years of older, or diabetes, the investigators explained.

Individuals in the study were randomly assigned in a 1:1 ratio to either receive daily transdermal 1.62% testosterone gel or a matching placebo, with randomization stratified based on the presence of preexisting CVD, according to the study authors.

The primary safety endpoint in the time-to-event analysis was the first occurrence of any component of major adverse cardiac events, a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stoke.

For the secondary cardiovascular endpoint in the time-to-event analysis, investigators included first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Tertiary cardiovascular endpoints were death from any cause, hospitalization or an urgent visit, peripheral arterial revascularization, and venous thromboembolic events, the authors continued.

Of the analyzed trial population, 2601 men were assigned to receive testosterone and 2603 were to receive the placebo. A primary safety endpoint, which was the first major adverse cardiovascular event, happened in 182 patients (7.0%) in the testosterone-receiving group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% CI, 0.78 to 1.17; P<0.001), the results of the trial showed.

In the principal sensitivity analysis, which censors data on any events that occurred after 365 days after the last dose, a primary safety endpoint occurred in 154 patients (5.9%) in the testosterone-receiving group and in 152 patients (5.8%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.81 to 1.27; P<0.001). Similar results were found when doing a sensitivity analysis that excluded events more than 30 days after the last dose, the investigators wrote.

There were no apparent clinically meaningful differences between the 2 groups in the appearance of tertiary cardiovascular endpoints, the researchers explained.

The investigators noted that, after analyzing the first batch of individuals enrolled in April 2019 and seeing a pooled primary event rate below the projected 1.5%, they made the decision to discontinue enrollment for individuals with cardiovascular risk factors and only enrolled those with preexisting CVD thereafter.

Up until this study, the cardiovascular effects of testosterone-replacement therapy on middle-aged men with hypogonadism were undetermined, as previous studies showed conflicting results and were generally inconsistent, the investigators explained.

“Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism,” the study authors concluded.

Reference

Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;10.1056/NEJMoa2215025. doi:10.1056/NEJMoa2215025