At least 5 studies indicating that testosterone replacement therapy either has no effect on cardiovascular health -- or tends to improve it -- appeared during the 3-week period immediately after the US Food and Drug Administration's controversial decision to mandate warnings about the potential cardiovascular risks of such treatment.
At least 5 studies indicating that testosterone replacement therapy either has no effect on cardiovascular health — or tends to improve it —appeared during the 3-week period immediately after the US Food and Drug Administration’s controversial decision to mandate warnings about the potential cardiovascular risks of such treatment.
The new research comes on the heels of at least half a dozen other trials, analyses and meta-studies that have popped up over the last year to contradict the 2 studies that precipitated the FDA’s investigation of testosterone’s safety and underpinned its decision to mandate the new warnings.
The first of the new studies, which was presented at the American College of Cardiology’s (ACC’s) 2015 Scientific Sessions, analyzed the records of 7,245 men with testosterone levels <300 ng/dL.
The research team compared cardiovascular outcomes for men who did and did not treat their hypogonadism with testosterone replacement over an average follow-up of 1.78 years and found that testosterone therapy was associated with fewer cardiovascular events (unadjusted hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.51-0.98; p=0.038). When they adjusted for potential confounding factors, however, the statistical strength of the benefit was no longer significant (p=.54). The effects of testosterone supplements on cardiovascular outcomes were also non-significant when adjusted through 1:1 matching in 3,115 matched-pairs (adjusted HR, 0.86; 95% CI, 0.57-1.29).
The second of the new studies, which was also presented at the ACC’s 2015 Scientific Sessions, was actually a meta-study that included data from 122,889 men from 29 different studies and used the random-effect model to calculate that testosterone therapy does not cause statistically significant adverse cardiovascular events among men (relative risk [RR], 1.168; 95% CI, 0.794-1.718; p=.431).
The third of the new studies, which was presented at the Endocrine Society’s Annual Meeting, compared the cardiovascular outcomes of 102,650 hypogonadal men who received testosterone replacement with 102,650 similar men who did not. Retrospective cohort analysis revealed a hazard ratio for idiopathic venous thrombotic events that was 1.08 for all testosterone-treated patients, but the difference was not significant (95% CI, 0.91-1.27; p=0.378). Subgroup analysis that looked at different testosterone forms (gel vs. injection) and different patient ages found similarly insignificant results.
The fourth of the new studies, which was also presented at the Endocrine Society’s Annual Meeting, was a retrospective analysis of data on nearly 30,000 patients enrolled in 2 randomized trials that evaluated the effect of the lipoprotein phospholipase A2 inhibitor darapladib on ischemic events.
Researchers pulled the data on major adverse cardiovascular events in men who used testosterone replacement therapy and comparable men who did not. Men exposed to testosterone replacement 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 testosterone. Men who used testosterone replacement for more than 12 months had a hazard ratio of 0.47 (95% CI, 0.25-0.87; p=0.02) compared to those who did not.
The fifth study, which was also presented at the Endocrine Society’s Annual Meeting, was the only prospective trial of the lot, and,although it used mice rather than people, the findings were interesting enough to take home the Endocrine Society’s presidential award.
British researchers used testosterone-deficient mice to show that higher levels of testosterone allowed both the liver and the body’s muscles to absorb more sugar and to store fat relatively harmlessly under the skin. Testosterone deficiency forced the body to break down more sugar and thus contributed to diabetes. It also forced fat towards the liver and into the arteries, where it can cause cardiovascular events.
These findings not only gel with the observed association between low testosterone and cardiovascular disease in human men; they also indicate that lack of testosterone causes the problem (at least partially) and that appropriate testosterone replacement should mitigate it.
The 5 new studies, along with the many similar studies that preceded them, have convinced many researchers that the balance of evidence, at present, suggests that testosterone replacement therapy is more likely to protect the heart than harm it — and that the FDA’s new warnings are a mistake — but there is even more widespread agreement that only a major randomized trial will settle the matter definitively.