Testosterone Replacement Therapy Not Associated with Increased Risk of Cardiovascular Events in Men

Prior studies have reached mixed conclusions regarding the cardiovascular (CV) safety profile of testosterone replacement therapy in men. According to the authors of a study presented at ENDO 2015, this uncertainty particularly holds true for older men with preexisting coronary heart disease. This has been “heightened by recent retrospective analyses of observational data. Prior studies, including relatively small prospective clinical trials of hypogonadal men, have yielded conflicting results.”

For the study, Salim Janmohamed, BSc, MB BS, FRCP, and colleagues examined data from two large, international, double-blind, placebo-controlled randomized clinical trials that evaluated the effect of the lipoprotein phospholipase A2 inhibitor darapladib on ischemic events. The trials enrolled men and women with a history of stable coronary heart disease (n=15,828; the STABILITY trial) or recent acute coronary syndrome (n=13,026; the SOLID-TIMI 52 trial).

Participants received treatment that met the ‘standard of care’ for cardiovascular risk factors. Researchers monitored participants for major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarct and non-fatal stroke). Patients in the STABILITY and SOID-TIMI 52 trials were followed for a median period of 3.7 and 2.5 years, respectively, after the conclusion of the studies.

Analysis of study data showed that darapladib “did not significantly reduce the risk of CV events.” Researchers assessed the risk of MACE in men who received testosterone replacement therapy (TRT) for less than one year and in men who received TRT for 12 months or longer and compared this to men who did not receive TRT, using combined data from both trials. Calculations were adjusted for a variety of factors, including treatment group, age, BMI, HDL/Total Cholesterol ratio, systolic blood pressure, GFR, diabetes, aspirin use, statin use, smoking status, and geographic region.

Janmohamed pointed out that TRT use among male trial subjects was low (n=217, 1%) and that most (83%) usage was by US men. The majority of MACE events (n=1412, 57%) were myocardial infarctions. Men exposed to TRT for less than or equal to 12 months had a hazard ratio of 0.48 (95% CI: 0.15, 1.49) (p=0.21) compared to those not exposed to TRT. Men exposed to TRT for greater than 12 months had a hazard ratio of 0.47 (95% CI: 0.25, 0.87) (p=0.02) compared to those not exposed to TRT.

Based on their analysis, the authors concluded these data “suggest that TRT is not associated with an increased risk of MACE in men with well-characterized coronary heart disease. The incidence of MACE was 11.1% in non-testosterone treated males and 7.9% in males on TRT.”

This retrospective analysis had several limitations, particularly the small numbers of male subjects exposed to TRT in each trial and the lack of ascertainment of gonadal status. However, the authors wrote that “these data do not corroborate recent observational reports that testosterone therapy is associated with increased CV risk.”

Discussion during the question and answer session was focused around the ages and the overall health of the subjects; particularly those men receiving TRT. Janmohamed said the latter tended to be overweight and diabetic.

There were also questions and comments about participants’ baseline characteristics. TRT patients were likely to have adverse baseline parameters and therefore an increased risk of disease. One audience member opined that testosterone deficiency is associated with poor health.

Disclosure: the authors of this study were all GlaxoSmithKline employees.