Off-label testosterone use linked to higher long-term cardiovascular risk

Clinical takeaway: Reserve testosterone therapy for men with documented hypogonadism in accordance with current guidelines, and carefully assess baseline cardiovascular risk and monitor patients throughout treatment.

Testosterone prescribing has expanded beyond guideline-supported indications. These findings reinforce the importance of confirming hypogonadism before starting therapy and monitoring cardiovascular risk over time.

In this global retrospective cohort study, investigators analyzed electronic health record data from 358,957 men aged 30-75 years who initiated testosterone therapy across 123 healthcare organizations. More than one-third (35%) had no documented evidence of hypogonadism before treatment. After propensity-score matching, 113,554 pairs were followed for up to 10 years.

Men treated without evidence of hypogonadism experienced a 40%-50% higher relative risk of major adverse cardiovascular events, with a 10-year event rate of 16.5% versus 11.8% among men treated for documented hypogonadism. All-cause mortality was nearly doubled (10.7% vs 6.0%), while risks of ischemic stroke, cardiac arrest, and heart failure were increased by about 20%-40%. Myocardial infarction showed only a small increase in the primary analysis and was not elevated in a prespecified sensitivity analysis. Results remained generally consistent across multiple sensitivity analyses, including a laboratory-based analysis and exclusion of patients with diabetes.

Risk increases were observed across racial and ethnic groups, although the magnitude varied. As the authors noted, “The central message is clear—approximately one third of men receiving testosterone therapy lacked evidence of hypogonadism, and this prescribing pattern was associated with a clinically meaningful excess risk of major adverse cardiovascular and cerebrovascular events over long-term follow-up.” They conclude that testosterone’s cardiovascular safety appears to be context-dependent and is more favorable when treatment is initiated for confirmed hypogonadism under guideline-based care.

Source: Kerniss H, et al. (2026 July 9) EBioMedicine. Off-label testosterone therapy is associated with higher long-term cardiovascular risk in men