New Veteran Study Further Complicates Testosterone Replacement Issue

VA Researchers Find Normalizing ‘T’ Levels Lowers Heart Risks

By Brenda L. Mooney

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KANSAS CITY, MO — The question over how testosterone replacement therapy (TRT) affects cardiovascular health became even more contentious with a new U.S. veterans study finding that some patients using TRT could be at lower risk of cardiovascular events, not higher.

That study, which appeared recently in the European Heart Journal, was conducted by researchers from the Kansas City VAMC. Examining the effect of TRT on cardiovascular outcomes by comparing incidents of heart attack, stroke and all-cause mortality among different sub-populations of treated and untreated patients, the study was touted as using the largest cohort of patients and the longest follow-up for TRT to date.1

Last year, with two major studies showing increased risk of cardiovascular events among men using TRT, the Food and Drug Administration announced that it was reassessing the safety of those products. The agency said it was investigating the risk of stroke, heart attack and death in men taking FDA-approved products for low testosterone.

“We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy,” the agency reported in a safety alert.

In January 2014, a study appearing in PLOS ONE, an online open-access journal, found that the risk of myocardial infarction following initiation of testosterone therapy was substantially increased in older men and in younger men with pre-existing diagnosed heart disease.2

The FDA also cited a VA study published in 2013. It found that TRT increased risks of death, heart attack or ischemic stroke in veterans who had undergone coronary angiography and low serum testosterone levels.3

In March, the FDA reiterated that testosterone is approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland or brain that cause hypogonadism.

The most recent study from the Kansas City VAMC involved 83,010 male veterans, all without history of myocardial infarction (MI) or stroke, for which data was reviewed between December 1999 and May 2014. While only 63% of patients achieved normal testosterone levels after TRT use, that group was found to have had significantly fewer deaths and cardiovascular events than those whose testosterone levels were not normalized.

“With such widespread and ever-increasing use of TRT, there has been growing concern regarding its effect on mortality, as well as conflicting results,” explained co-author Rajat S. Barua, MD, PhD. “Our aim was to address the knowledge gap.”

For the study, the veterans were divided into three groups: the first receiving TRT and achieving normal levels; the second receiving TRT but failing to achieve normal levels, and a third receiving no replacement therapy.

According to the results, the greatest difference was between the first and the last group — the men who were successfully treated with TRT were 56% less likely to die during the follow-up period, 24% less likely to suffer a heart attack and 36% less likely to have a stroke than those who received no treatment at all.

A less significant difference was detected between patients in which testosterone levels were normalized by TRT compared to those who used TRT but failed to achieve normalization.In fact, the second and third groups showed little difference when it came to risk for cardiovascular events, although those who received TRT had a slight survival advantage, according to the study.

“In this study of men, without previous history MI or stroke, with low testosterone levels, normalization of testosterone levels using TRT is associated with lower mortality, fewer MIs, and strokes,” Barua said in a journal press release. “This is the first study to demonstrate that significant benefit is observed only if the dose is adequate to normalize the testosterone levels.”

Study authors call for more research, especially randomized controlled trials with long-term follow-up, to reach a definitive conclusion on how TRT affects cardiovascular outcomes. Several other recent studies, many of them industry sponsored, have shown little cardiovascular effect from TRT use.

The researchers also caution against “off-label” use, emphasizing, “None of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition.”

1 Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, Sharma R, Parashara D, Savin VJ, Ambrose JA, Barua RS. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015 Aug 6. pii: ehv346. [Epub ahead of print] PubMed PMID: 26248567.

2 Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014 Jan 29;9(1):e85805. doi:10.1371/journal.pone.0085805. eCollection 2014. PubMed PMID: 24489673; PubMedCentral PMCID: PMC3905977.3 Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36. doi: 10.1001/jama.2013.280386. PubMed PMID: 24193080.

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