Off-label testosterone therapy in men with diabetes is associated with higher long-term cardiovascular and mortality risk than therapy in confirmed hypogonadism

Aims

Testosterone therapy (TT) is recommended for symptomatic men with biochemically confirmed hypogonadism. However, TT is frequently prescribed without clear diagnostic evidence. Men with diabetes represent a high-risk cardiometabolic population, yet the long-term cardiovascular safety of off-label TT in this group remains insufficiently defined. We therefore compared long-term cardiovascular outcomes in men with diabetes receiving off-label TT versus TT prescribed in the context of confirmed hypogonadism.

Methods

Using a global federated electronic health-record network (TriNetX; 169 healthcare organizations), we identified 75,717 men aged 30–75 years with diabetes initiating TT. Off-label TT was defined as TT exposure in the absence of a hypogonadism diagnosis, laboratory evidence of low testosterone, or documented sexual dysfunction. The comparator cohort included men with hypogonadism diagnosis and/or laboratory-confirmed low testosterone.

Patients with any testosterone prescription within 3 years before index (new users) as well as those with major cardiovascular or thromboembolic events during the same pre-index window were excluded to implement a strict new-user design. Cohorts were balanced using 1:1 propensity-score matching for demographics and comorbidities. Outcomes were assessed from day 1 to 10 years using Kaplan–Meier estimates and Cox proportional hazards models.

Results

After matching, 16,894 patients remained in each cohort.

Off-label TT was associated with a significantly higher risk of MACE (13.5% vs 12.1%; HR 1.54, 95% CI 1.44–1.65; log-rank p<0.001) and markedly increased all-cause mortality (7.3% vs 5.1%; HR 2.07, 95% CI 1.90–2.26; log-rank p<0.001).

Heart failure risk was elevated overall (HR 1.34, 95% CI 1.24–1.46; log-rank p<0.001), including acute HF (HR 1.30, 95% CI 1.14–1.48; p<0.001) and chronic HF (HR 1.37, 95% CI 1.23–1.51; p<0.001). Off-label TT was further associated with higher risk of cardiac arrest (HR 1.83, 95% CI 1.45–2.31; p<0.001) and stroke (HR 1.27, 95% CI 1.11–1.45; p=0.001).

No statistically robust differences were observed for myocardial infarction (HR 1.10, 95% CI 0.98–1.24; p=0.102) or pulmonary embolism (HR 1.16, 95% CI 0.97–1.39; p=0.105). The negative-control outcome (appendicitis) showed no significant association (HR 0.67, 95% CI 0.41–1.07; p=0.091).

Conclusions

In men with diabetes, TT prescribed without diagnostic evidence of hypogonadism was associated with excess long-term MACE and a pronounced increase in mortality compared with TT in confirmed hypogonadism. These real-world data support guideline-concordant prescribing and careful cardiovascular risk assessment when considering TT in high-risk metabolic populations.MACCE