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The issue of cardiovascular safety of testosterone replacement has been raised over the years, with both the US Food and Drug Administration and the European Medicines Agency previously determining that there was insufficient evidence to conclude whether testosterone therapy was associated with an increased risk of stroke or cardiovascular disease (CVD).

In this randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial, Lincoff and colleagues enrolled over 5,000 male participants aged 45–80 with hypogonadism (defined as having 2x fasting testosterone values of <10.4nmol/l, and symptoms consistent with the condition), who were deemed to be at high risk of CVD. Participants were randomised at a 1:1 ratio to daily 1.62% daily testosterone gel or matched placebo.

Over a mean±SD duration of treatment of 21.7±14.1 months, with mean follow up of 33.0±12.1 months, testosterone replacement was non-inferior to placebo for major adverse cardiovascular events (MACE: testosterone group 182 patients (7.0%) versus placebo group 190 patients (7.3%)). Interestingly, there was a higher incidence of pulmonary embolism, acute kidney injury and atrial fibrillation in patients on testosterone replacement compared with placebo.

These data demonstrate that, even in men at high risk of CVD, transdermal testosterone replacement was non-inferior to placebo for major cardiovascular events.

Read the full article in New England Journal of Medicine 389 107–117