Atherosclerosis Speeds Up in Older Men on Testosterone: T Trial

Marlene Busko

February 24, 2017

LOS ANGELES, CA — In a randomized trial of 138 older men with age-related low testosterone levels, those who received testosterone gel (AndroGel, AbbVie) for a year to attain youthful testosterone levels had a 20% greater buildup of noncalcified plaque in their coronary arteries than those who received a placebo gel[1].

These findings from the Cardiovascular Trial—one of the seven National Institutes of Health (NIH) Testosterone Trials (T Trials) examining different clinical outcomes in older men with age-related low testosterone levels who receive testosterone or placebo—were published in the February 21, 2017 issue of the Journal of the American Medical Association.

The men had a mean age of 71 and a high prevalence of cardiovascular risk factors, and half had severe atherosclerosis.

The findings "should at least strike some caution in people, to not be too laissez- faire" about testosterone therapy in similar men, Dr Matthew J Budoff (Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center) told heartwire from Medscape.

"Plaque progression is bad; there's no mechanism by which this could be helpful," he continued. When treating men with low testosterone, "I would be more cautious in patients who have already had a cardiovascular event or have significant atherosclerosis [and] tell these men that either we should forgo testosterone or use a much lower dose."

The study dose aimed to give 70-year-old men the testosterone levels of 30-year-old men, which may not be warranted. "Maybe once you're 70, you don't have to be 40 again," Budoff observed. "It didn't work out so well for women either in the hormone-replacement trial."

Perhaps "more modest doses of androgen or . . . forgoing it depending on their risk should be considered," he added. "Certainly a larger trial needs to be done with heart attack and stroke, but until we have more data I just think this should raise some caution."

An editorialist[2] goes even further, saying the findings are "unprecedented " and "ominous." Dr David J Handelsman (University of Sydney, Australia) writes that "the coronary luminal narrowing observed over 12 months in this study is an unprecedented drug effect and appears ominous in signifying accelerated atherosclerosis and is perhaps a harbinger of increased cardiac ischemic events."

Effect of Testosterone on Coronary Plaque

The trial aimed to test the hypothesis that testosterone therapy would slow the progression of noncalcified coronary artery plaque volume in older men with age-related low testosterone.

Since this was a 1-year study and it takes longer to see changes in calcified plaque, the researchers examined "noncalcified plaque, which represents the more active plaque in the coronaries" and is associated with myocardial ischemia and subsequent cardiovascular adverse events, Budoff explained.

Secondary outcomes included total plaque volume and coronary artery calcium score.

The researchers analyzed data from 138 men (73 men in the testosterone group and 65 in the placebo group) at nine sites who had coronary artery plaque volume assessed by coronary computed tomographic angiography (CCTA) at baseline and 12 months.

The men were 65 or older, with average serum testosterone below 275 ng/mL, and subjective complaints and objective evidence of sexual dysfunction, physical dysfunction, and/or reduced vitality.

Most were obese (mean body-mass index [BMI] 30), hypertensive (66%), or former smokers (66%), and close to a third had type 2 diabetes (30%). The men had an average coronary artery calcium score of 250 Agatston units, which is "pretty high but not an outrageous number; you would expect a 70-year-old man to have some coronary calcium," according to Budoff.

The men in the treatment group received an initial 5-g/day dose of testosterone gel, which was adjusted (based on regular testosterone determinations) to try to keep serum testosterone levels in the normal range for young men (280–873 ng/dL).

"Implausible Mechanism," "Dimmed Hopes for Rejuvenation"

From baseline to 12 months, the median volume of noncalcified plaque increased from 204 mm3 to 232 mm3 in the treatment group but only from 317 mm3 to 325 mm3 in the placebo group—a difference of 41 mm3 (P=0.003).

During the same time, the median total plaque volume increased from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm 3 to 541 mm3 in the placebo group (P=0.006).

The increased plaque progression in the testosterone group was similar after adjustment for higher baseline plaque values in the placebo group.

The median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (P=0.31).

There were no major adverse cardiovascular events in either group, but the trial was not powered or long enough to detect this.

These results make sense, since it's "implausible" that testosterone is good for the coronaries, according to Budoff. "Men have more heart disease than women, and men have more testosterone than women. So how could testosterone be protective? . . . If testosterone were so good for the coronaries, wouldn't women have more heart attacks?"

A larger, longer trial is needed to investigate the risk of cardiovascular events, but "it is unlikely that the limited efficacy shown by the T Trials meets the mandate of the 2004 Institute of Medicine report to warrant public funding for a powerful, long-term, large randomized clinical trial for evaluating testosterone," according to Handelsman.

In the meantime, "rejuvenation fantasies thrive on hope without needing facts," he observes, so "professional societies should revise guidelines that provide tacit, uncritical endorsement, which is too readily used for boosting testosterone as a panacea for male aging." The current study findings support the cardiovascular safety warnings about off-label testosterone prescribing.

With the latest results from the T Trials, "the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed," he concludes.

A Look at the Seven T Trials and an Eighth Related Trial

The National Institutes of Health funded seven T Trials to each test the short-term efficacy of testosterone on a clinical end point—sexual function, physical function, vitality, cognition, anemia, bone health, and cardiovascular health—after a 2004 review from the US Institute of Medicine (now the National Academy of Medicine) concluded that there was not enough evidence for benefits of testosterone therapy in older men to justify a large-scale trial like the Women's Health Initiative for estrogen replacement, Handelsman explained.

The results of the three main T Trials of sexual function, physical function, and vitality that were published a year ago showed "a modest increase in sexual function (a 42% relative increase compared with baseline) early in the study before waning by the end of the study, but there was no objective benefit for physical function or vitality," Handelsman noted.

Two other T Trials examining anemia and bone health were published February 21, 2017 in JAMA Internal Medicine and showed that "hormone treatment improved bone density and corrected anemia of both known and unknown causes," according to an NIH statement.[3]

The T Trial looking at testosterone and cognition investigated 493 older men with age-associated memory impairment at baseline, by Dr Susan M Resnick (National Institute on Aging, National Institutes of Health, Baltimore, MD) and colleagues, was published in the same issue of JAMA as the cardiovascular trial by Budoff and colleagues[4]. It provides "convincing" evidence that testosterone does not improve cognition; however, this does not preclude other mood-elevating effects, according to Handelsman.

A study by Dr T Craig Cheetham (Kaiser Permanante Southern California), which was not part of the seven T Trials and which was also published February 21 in JAMA Internal Medicine, did not find an increased risk of cardiovascular events in men taking testosterone therapy, but this was an observational study with inherent weaknesses, Dr Budoff stressed.

The study compared cardiovascular outcomes in men who were 40 and older (mean age 59), treated at a Kaiser Permanente medical center in California and diagnosed with androgen deficiency. A total of 8808 men had received testosterone-replacement therapy and 35,527 men had not received it.

During a median follow-up of 3.4 years, 17 per 1000 men per year in the testosterone-treated group vs 24 per 1000 men per year in the placebo group had a cardiovascular event (MI, coronary revascularization, unstable angina, stroke, transient ischemic attack, or sudden cardiac death).

However, in observational studies of hormones such as testosterone or estrogen, "people who take the therapies tend to be healthier," Budoff warned. Randomized trials, such as the current study or the Testosterone in Older Men With Sarcopenia (TOM) trial[5], which showed that patients on testosterone therapy had more heart attacks, provide stronger data, he noted.

The Testosterone Trials were supported by the Heart, Lung, and Blood Institute and additional funding was provided by the National Institute of Neurological Diseases and Stroke and the National Institute of Child Health and Human Development. AbbVie provided funding, AndroGel, and placebo gel. Budoff reported receiving a grant from General Electric. Disclosures for the coauthors are listed in the paper. Handelsman reported receiving grants from Lawley Pharmaceuticals and Besins Healthcare and serving as a medical expert in testosterone litigation.


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