Testosterone therapy may be associated with increased risk of mortality and cardiovascular events

Testosterone therapy was associated with increased risk of mortality, myocardial infarction (MI) or ischemic stroke among men in the Veterans Administration (VA) health care system, a study found.

To assess the association between testosterone therapy and all-cause mortality, MI, or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease, researchers conducted a retrospective national cohort study of all men (n=23,173) who underwent coronary angiography in the VA system between 2005 and 2011 and who had testosterone levels less than 300 ng/dL.

Results appeared in the Nov. 6 Journal of the American Medical Association.

There was a high rate of comorbidities among the 8,709 men with low testosterone levels. About 20% had a prior MI, 50% had diabetes, and more than 80% had CAD. In the low testosterone group, 748 men died, 443 had MIs, and 519 had strokes. Of 7,486 patients who did not receive testosterone therapy, 681 died, 420 had MIs, and 486 had strokes.

There were 1,223 patients who started testosterone therapy following coronary angiography. Among this group, 67 died, 23 had MIs, and 33 had strokes. The absolute rate of events was 19.9% among those who didn't receive testosterone versus 25.7% in those who did. The absolute risk difference for events was 5.8% (95% CI, −1.4% to 13.1%) at 3 years after coronary angiography with absolute risk differences of 1.3% (95% CI, −7.1% to 9.7%) at 1 year and 3.1% (95% CI, −4.9% to 11.0%) at 2 years.

Cox proportional hazards models showed that testosterone therapy as a time-varying covariate was associated with increased risk of adverse outcomes (HR, 1.29; 95% CI, 1.04 to 1.58) but that there was no significant difference in the effect size of testosterone therapy between patients with and without CAD (test for interaction, P=0.41). These findings from this observational study may raise concerns about the potential safety of testosterone therapy, the authors said.

“Although physicians should continue to discuss the symptomatic benefits of testosterone therapy with patients, it is also important to inform patients that long-term risks are unknown and there is a possibility that testosterone therapy might be harmful,” they wrote. “Randomized clinical trials and observational studies in other populations are needed to help inform whether long-term testosterone therapy use is safe or if it is associated with adverse cardiovascular events.”

An editorialist pointed out that the VA study population had more comorbidities than men enrolled in most randomized clinical trials. In addition, there was little information about whether testosterone was prescribed according to guidelines. This brings into question the generalizability of the results to the broader population of men taking testosterone, whether for “low T,” antiaging purposes or physical enhancement.

The editorialist wrote, “In light of the high volume of prescriptions and aggressive marketing by testosterone manufacturers, prescribers and patients should be wary. There is mounting evidence of a signal of cardiovascular risk, to which [this study] contributes. This signal warrants both cautious testosterone prescribing and additional investigation.”