TRT and heart health: Conflicting findings published

Five recently published studies, including four from the National Institutes of Health-supported large-scale Testosterone Trials, provide new insight on testosterone replacement therapy’s effect on cardiovascular health, as well as anemia, cognitive function, and volumetric bone density and strength.

The effect of TRT on cardiovascular health in men with hypogonadism has been an unresolved issue considering the conflicting findings and design limitations of available research. Two of the new studies generated differing results, and while both studies had notable strengths, they had important weaknesses as well.

The Cardiovascular Trial of the Testosterone Trials (TTrials) was a prospective, randomized, double-blind, placebo-controlled study that included 170 men aged 65 years and older with hypogonadal symptoms and low testosterone (<275 ng/dL) appearing to be age-related. Participants were randomized to use testosterone gel or placebo gel for 1 year.

Noncalcified coronary artery plaque volume determined by coronary computed tomographic angiography, a surrogate for coronary atherosclerosis, was investigated as the primary endpoint. Data from 138 men who completed the study showed the median plaque volume increased significantly more in the TRT-treated men compared with the control group (204 mm³ to 232 mm³ vs 317 mm³ to 325 mm³; estimated difference, 41 mm³, p=.003) (JAMA 2017; 317:708-16). Compared with controls, the TRT-treated group also had a significantly greater increase in total plaque volume, but there was no difference between groups in the change in coronary artery calcium score.

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“The strengths of the trial include its prospective, randomized design, selection of men with unequivocally low testosterone, and high retention rate. However, it used surrogate outcomes for cardiovascular events and was not of sufficient size or duration to investigate risk of major adverse cardiovascular events,” said J. Kellogg Parsons, MD, MHS, of the University of California, San Diego, an investigator for the TTrials and a coauthor for previously published TTrials research. “Larger studies are needed to understand the clinical implications of the radiologic findings.”

Separately, researchers from Kaiser Permanente California analyzed cardiovascular event rates in a cohort of men age ≥40 years who had documented androgen deficiency (coded diagnosis or morning serum total testosterone <300 ng/dL). They compared men who had been dispensed a prescription for any form of TRT (n=8,808) and those who were never dispensed TRT (n=35,527). In the TRT group, men had a mean age of 58.4 years, 1.4% had a history of a cardiovascular event, and median follow-up was 4.2 years. Men who never received TRT had a mean age of 59.8 years, 2.0% had a prior cardiovascular event, and median follow-up was 3.2 years.

Multivariable Cox proportional hazard analysis using propensity score methodology to balance baseline characteristics found a 33% significantly reduced risk (p<.001) for the primary outcome (composite cardiovascular endpoint including acute myocardial infarction, coronary revascularization, unstable angina, stroke, transient ischemic attack, and sudden cardiac death) in the TRT group compared with controls (JAMA Intern Med, epub., Feb. 21, 2017). The result was similar in additional analyses comparing risks for all but one of the individual events and in subgroups of men <65 years, ≥65 years, with a cardiovascular event history, without a cardiovascular event history, and looking at defined follow-up intervals.

T. Craig Cheetham, PharmD, MS, of Southern California Permanente Medical Group’s department of research and evaluation, Pasadena, is lead author of the paper, which was not part of the TTrials. He told Urology Times, “Our findings suggest that TRT is safe in androgen-deficient males. However, based on findings from previous studies, we believe caution is warranted when treating frail elderly males and those with high cardiovascular risk.”

Commenting on the study design, Dr. Cheetham noted that its relatively large cohort of androgen-deficient men treated with TRT represents its major strength. In addition, the TRT-treated group was well matched to the control group, and the results were robust in the planned stratified and sensitivity analyses.

However, he acknowledged that because it was an observational study, the reported data only identify associations and cannot determine cause and effect. In addition, the study could not control for potential bias from unmeasured confounding.

Next: Dr. Burnett discusses findings

Commenting on the data, Urology Times Editorial Council member Arthur L. Burnett, II, MD, MBA, noted that the TTrials are definitely a positive step forward in understanding the benefits and risks of TRT because they address the need for evidence from rigorous studies. Nevertheless, while the finding of increased coronary artery plaque in the cardiovascular TTrial is a potentially concerning signal, it needs to be considered in the context that it is not known whether it predicts a subsequent clinical cardiovascular endpoint, said Dr. Burnett, of Johns Hopkins University, Baltimore.

“Certainly, a longer study investigating clinical endpoints of cardiovascular health is needed before deciding that TRT adversely affects cardiovascular health,” Dr. Burnett told Urology Times.

Results from TTrials investigating TRT effects on anemia, cognitive function in men with age-associated memory impairment, and volumetric bone density and strength were published in February 2017 in JAMA (cognitive function) and JAMA Internal Medicine (anemia, bone).

The anemia trial included 126 men who were anemic, including 62 whose anemia had no known cause. It found that the hemoglobin level increased by 1.0 g/dL in a significantly greater percentage of men in the TRT group compared with placebo-treated controls whether looking at men with unexplained anemia (54% vs 15%) or those with anemia of known cause (52% vs. 19%) (JAMA Intern Med, epub. Feb 21, 2017).

The investigators suggested considering measurement of testosterone levels in men 65 years of age or older with unexplained anemia and symptoms of low testosterone, but noted that the overall health benefits of testosterone treatment remain to be established.

Read: What is driving younger men to seek treatment for ED?

The cognitive function TTrial included 493 men who met criteria for age-associated memory impairment at study entry. Neither TRT-treated men nor controls experienced any significant changes from baseline when tests of delayed paragraph recall, visual memory, executive function, or spatial ability were repeated at 6 and 12 months. The authors concluded that the study does not support using TRT to treat age-associated memory decline in older men with symptomatic hypogonadism (JAMA 2017; 317:717-27).

“The lack of any changes is not surprising considering the short duration of the study and the many factors that can affect cognitive function. Furthermore, it seems more likely that a benefit of TRT might be observed in terms of preventing decline rather than suddenly improving cognition,” Dr. Burnett said.

The study investigating effects of TRT on bone included 211 men, most of whom did not have osteoporosis. Its results showed significantly greater increases in mean volumetric bone mineral density and estimated strength in the TRT group compared with controls (JAMA Intern Med, epub. Feb 21, 2017). The benefits of TRT were greater in the spine than the hip and in trabecular bone versus cortical-rich peripheral bone.

The investigators suggested the need for a larger and longer trial to investigate whether TRT in older men with low testosterone reduces fracture risk.

Dr. Parsons has received grant support from Actavis.

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