Off-label testosterone therapy is associated with higher long-term cardiovascular risk in men

Background: Testosterone therapy (TT) is increasingly initiated outside classical hypogonadism, but long-term cardiovascular safety in this context remains uncertain. We assessed whether TT initiation without evidence of hypogonadism is associated with higher long-term cardiovascular risk than TT initiation with evidence of hypogonadism. Methods: In this global retrospective real-world cohort study, men aged 30–75 years initiating TT were identified from secondary, de-identified structured EHR data from 123 healthcare organisations. A prespecified 3-year pre-index washout excluded prior TT and major cardiovascular/thromboembolic events. Men initiating TT without evidence of hypogonadism were compared with those with evidence of hypogonadism using 1:1 propensity-score matching. The primary outcome was major adverse cardiovascular events (MACE); secondary outcomes included separately all-cause mortality, myocardial infarction, ischaemic stroke, cardiac arrest, and heart failure. Acute appendicitis served as a negative-control outcome. Findings: Among 358,957 TT initiators, 127,152 (35.4%) had no evidence of hypogonadism. After matching, 113,554 pairs were followed for up to 10 years. TT without evidence of hypogonadism was associated with higher risk of MACE (16.53% vs 11.83%; HR 1.51, 1.45–1.56) and all-cause mortality (HR 1.90, 1.79–2.00), with higher risks of ischaemic stroke (HR 1.23, 1.14–1.33), cardiac arrest (HR 1.41, 1.23–1.61), and heart failure (HR 1.32, 1.26–1.39). Race-stratified estimates were directionally consistent but varied in magnitude. Interpretation: The cardiovascular safety of TT appears context-dependent and less favourable when treatment is initiated without evidence of hypogonadism, with clinically relevant heterogeneity across race/ethnicity, supporting biologically informed prescribing and cardiovascular risk surveillance. Funding: Deutsche Forschungsgemeinschaft, Schleswig-Holstein Excellence-Chair Program, and Region Stockholm.