TRT: Review finds no evidence of cardiovascular risk

A review of literature published online in Mayo Clinic Proceedings (Jan. 26, 2015) has found no evidence that testosterone therapy increases cardiovascular risk, although one men’s health expert cautions that thorough patient counseling is necessary and that only a “well-controlled prospective study” will definitively answer questions surrounding testosterone and cardiovascular risk.

The review’s lead author, Abraham Morgentaler, MD, of Men’s Health Boston and Beth Israel Deaconess Medical Center, Boston, called it “the most comprehensive and definitive review to date.” 

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Dr. Morgentaler and colleagues found four journal articles since 1940 that suggest increased cardiovascular risk with testosterone use. Two of the four articles (JAMA 2013; 310:1829-36,PLOS One 2014; 9:e85805), which drew media coverage questioning testosterone therapy’s safety during the last 15 months, had “serious methodological limitations,” according to a Beth Israel Deaconess Medical Center press release.

The other two studies were flawed as well, the authors say. One was a placebo-controlled trial with “few major adverse cardiac events” (J Gerontol A Biol Sci Med Sci 2013; 68:153-60), and the other was a meta-analysis that included “questionable studies and [cardiovascular] events” (BMC Med 2013; 11:108).

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The abundance of evidence is quite to the contrary, the authors say. Dr. Morgentaler and co-authors identified dozens of studies looking at a possible link between testosterone and cardiovascular issues, many of which found a positive correlation between “low testosterone levels and increased mortality… as well as atherosclerosis, incident coronary artery disease, and the severity of coronary artery disease,” according to the Beth Israel release.

For example, two observational studies suggest men with low testosterone who did not receive testosterone replacement therapy died at double the rate of men who did receive TRT. A small number of randomized controlled studies have shown that men with angina or congestive heart failure function better when they receive testosterone compared with placebo. In addition, numerous studies suggest cardiovascular disease risk factors, including waist circumference, improve with testosterone therapy, and the authors say “promising new data” suggest that testosterone therapy might improve insulin sensitivity and reduces blood glucose and hemoglobin A1C levels in men with Type 2 diabetes or obesity.

“There’s no good evidence that we could find that testosterone therapy increases cardiovascular risk,” Dr. Morgentaler said. “That’s not to say it’s perfectly safe. But we cannot find evidence, and the headlines that jumped out on recent retrospective studies appear to be too strong.”

The testosterone story “has been turned upside-down by trumpeting studies providing remarkably weak evidence of risk, and ignoring a substantial literature with reassuring or beneficial results,” added Dr. Morgentaler.

Despite the review’s findings, questions remain about the safety of testosterone therapy on cardiovascular health, Steven A. Kaplan, MD, of Weill Cornell Medical College, and the Iris Cantor Men’s Health Center, New York Presbyterian Hospital, New York, wrote in an email to Urology Times.

“The bottom line is that for those of us prescribing testosterone supplementation, we need to engage in thorough discussion with our patients of risks: real, imagined, or poorly studied. Only a well-controlled prospective study will answer these questions definitively,” said Dr. Kaplan, who was not involved with the study.

Dr. Morgentaler has been on the scientific advisory board or worked as a consultant for AbbeVie, Inc., Auxilium Pharmaceuticals, Inc., Clarus Therapeutics, Endo Pharmaceuticals, and TesoRx, and has received research funding from Antares Pharma, Auxilium Pharmaceuticals, Inc., Lipocine Inc., and Eli Lilly and Co. Three co-authors of the review have also worked as consultants to pharmaceutical companies.

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