Studies demonstrate testosterone’s CV safety, benefits

Two recently published studies significantly contribute to current knowledge regarding testosterone therapy and cardiovascular health, says one expert urologist.

Researchers led by Shalender Bhasin, MD, of Brigham and Women’s Hospital, Boston and co-authors reported that 3 years of testosterone replacement therapy (TRT) in older men with low or low-normal testosterone does not cause progression of subclinical atherosclerosis. The prospective, double-blind, placebo-controlled clinical trial was published in JAMA (2015; 314:570-81).

In addition, as reported online in a fast-track article in the European Heart Journal (Aug. 6, 2015), findings of a large observational study designed specifically to examine the effect of normalization of TRT on cardiovascular outcomes in men with low testosterone showed it significantly reduced risks of all-cause mortality, myocardial infarction, and stroke.

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The findings of both studies add another chapter to the ongoing discussion of TRT safety, cardiovascular safety in particular. In March 2015, the FDA issued a statement requiring makers of approved products to include revised labels indicating a possible risk of MI and stroke associated with the products. The FDA is also requiring manufacturers of the agents to conduct a controlled clinical trial to better determine the effects of TRT on cardiovascular outcomes.

In a recent development, FDA officials are now urging drug makers to collaborate on a single study. “We are encouraging companies to work together on a single trial,” Christine P. Nguyen, MD, and colleagues at the FDA wrote in the New England Journal of Medicine (2015; 373:689-91). “We believe the health of American men will be well served by the presence of accurate drug labels and reliable data to inform clinical decision making.”

The JAMA study (Testosterone’s Effects on Atherosclerosis Progression in Aging Men [TEAAM]) was conducted at three centers and included 308 men who were at least 60 years of age (mean 67.6 years) and had a total morning testosterone of 100 to 400 ng/dL. Fifteen percent of the cohort had cardiovascular disease, and many men had cardiovascular disease risk factors (hypertension, 42%; diabetes, 15%; obesity, 27%). Participants were randomized 1:1 to daily treatment with 7.5 grams of 1% testosterone or placebo gel; dose adjustments were made to achieve a testosterone level of 500 to 900 ng/dL.

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Rate of change in distal right common carotid artery intima-media thickness and coronary artery calcium were analyzed as co-primary endpoints, and there was no statistically significant difference for either parameter comparing the TRT and control groups. In addition, no association was found among TRT-treated men with respect to changes in intima-media thickness or coronary artery calcium scores and change in testosterone levels.

“It was importantly noted by the authors that the study was powered only to evaluate atherosclerosis progression and comprised a population averaging in the mid to late 60s in years of age,” commented Urology Times Editorial Council member Arthur L. Burnett, II, MD, MBA, of Johns Hopkins University, Baltimore, who was not involved with either study. “Thus, it did not directly measure cardiovascular events or allow inferences to be made about cardiovascular safety of testosterone use in somewhat older men. They also acknowledge that the therapy restored testosterone levels modestly at the mid-normal range and included men who were not symptomatically hypogonadal.

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“Accordingly, the interpretation of limited benefit drawn from an apparent lack of effect on sexual health and health-related quality of life (secondary outcomes of this study) may need to be restrained,” Dr. Burnett said.

For the European Heart Journal study, Rishi Sharma, MBBS, MS, of the VA Medical Center, Kansas City, MO, and colleagues conducted a retrospective review of 83,010 male veterans (median age, ~66 years) with documented low total testosterone levels who were further categorized as to whether they received TRT and achieved normalization of total testosterone (TT) levels (“normalized TRT,” n=43,931), received TRT but did not achieve normalization of TT (“non-normalized TRT,” n=25,701), or did not receive TRT (“no TRT,” n=13,378). Mean follow-up for the three groups ranged from 4.6 years to 6.2 years.

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In propensity score-weighted Cox proportional hazard models, pairwise comparisons showed men with normalized TRT had significantly lower risks than both their non-normalized TRT and no TRT counterparts for all-cause mortality (−56% and −47%), myocardial infarction (−24% and −18%), and stroke (−36% and −30%). Risk of myocardial infarction and stroke were similar in the non-normalized and no TRT groups, but mortality was significantly lower in men with non-normalized TRT than in those who were not treated.

Commenting on the strengths and limitations of the studies, Dr. Burnett said that TEAAM featured a rigorous design, well-defined, measurable clinical endpoints, and a reasonable duration of treatment. As noted by the authors, the study was powered only to evaluate atherosclerosis progression, not cardiovascular events, and comprised a population of men in their mid to late 60s.

Despite being retrospective and having possibly uncontrolled variables, the Kansas City VA study included a large, representatively healthy study population, used a strict definition and confirmation of therapeutic dosing, and featured long-term follow-up along with rigorous assessment of cardiovascular event outcomes, he said.

Describing the two studies as “impressive investigative work,” Dr. Burnett, said the reports are highly informative with respect to the possible safety and benefit of TRT in terms of cardiovascular health.

“These studies provide substantial confidence regarding the use of testosterone therapy when administered and monitored appropriately in well-selected individuals,” Dr. Burnett said.

Solvay Pharmaceuticals Inc. and Abbvie Pharmaceuticals Inc. supported the JAMA study.

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