In the JournalsPerspective

Increase in noncalcified plaque associated with testosterone treatment in older men

Testosterone treatment in older men was linked to a significantly greater increase in coronary artery noncalcified plaque volume, according to a new study in JAMA.

“Although testosterone replacement is increasingly being used clinically, the [CV] benefits and risk of testosterone administration to older men with age-related decline in testosterone levels remain uncertain,” Matthew J. Budoff, MD, professor of medicine at David Geffen School of Medicine at UCLA and program director and director of cardiac CT at Harbor-UCLA Medical Center, and colleagues wrote. “Several observational studies show an inverse association between serum testosterone concentration and adverse [CV] outcomes, the metabolic syndrome, diabetes, and mortality, independent of traditional [CV] risk factors.”

In a double blind, placebo-controlled trial, Budoff and colleagues analyzed 170 men aged 65 years or older with an average of two serum testosterone levels lower than 275 ng/dL and symptoms suggestive of hypogonadism. Participants were enrolled between June 2010 and June 2014 and were randomly assigned testosterone gel (n = 82) or placebo gel (n = 88) for 12 months.

Matt Budoff
Matthew J. Budoff

Of those enrolled, data were available for 138 participants (73 receiving intervention, 65 receiving placebo; mean age, 71 years; 81% white). At baseline, 50.7% participants (n = 70) had a coronary artery calcification (CAC) score higher than 300 Agatston units.

The primary outcome was noncalcified plaque volume and was determined by coronary CTA.

From baseline to 12 months, participants in the testosterone arm had a significantly greater increase in noncalcified plaque volume (from median value 204 mm3 to 232 mm3) compared with placebo (from median value 317 mm3 to 325 mm3) with an estimated difference of 41 mm3 (95% CI, 14-67; P = .003).

The median total plaque volume increased in the testosterone group from 272 mm3 to 318 mm3, compared with 499 mm3 to 541 mm3 for placebo (estimated difference, 47 mm3; 95% CI, 13-80; P = .006). The median CAC score decreased in in the testosterone group (from 255 to 244 Agatston units) and increased in the placebo group (from 494 to 503 Agatston units) from baseline to 12 months (estimated difference, –27 Agatston units; 95% CI, –80 to 26 Agatston units), according to the researchers.

No one in either group had a major adverse CV event.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning because any limitation of the vascular lumen could be considered deleterious,” Budoff and colleagues wrote. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

The researchers concluded that larger studies are needed to understand the clinical implications. – by Cassie Homer

Disclosures: Budoff reports receiving a grant from General Electric. Please see the full study for a list of the other researchers’ relevant financial disclosures.

 

Testosterone treatment in older men was linked to a significantly greater increase in coronary artery noncalcified plaque volume, according to a new study in JAMA.

“Although testosterone replacement is increasingly being used clinically, the [CV] benefits and risk of testosterone administration to older men with age-related decline in testosterone levels remain uncertain,” Matthew J. Budoff, MD, professor of medicine at David Geffen School of Medicine at UCLA and program director and director of cardiac CT at Harbor-UCLA Medical Center, and colleagues wrote. “Several observational studies show an inverse association between serum testosterone concentration and adverse [CV] outcomes, the metabolic syndrome, diabetes, and mortality, independent of traditional [CV] risk factors.”

In a double blind, placebo-controlled trial, Budoff and colleagues analyzed 170 men aged 65 years or older with an average of two serum testosterone levels lower than 275 ng/dL and symptoms suggestive of hypogonadism. Participants were enrolled between June 2010 and June 2014 and were randomly assigned testosterone gel (n = 82) or placebo gel (n = 88) for 12 months.

Matt Budoff
Matthew J. Budoff

Of those enrolled, data were available for 138 participants (73 receiving intervention, 65 receiving placebo; mean age, 71 years; 81% white). At baseline, 50.7% participants (n = 70) had a coronary artery calcification (CAC) score higher than 300 Agatston units.

The primary outcome was noncalcified plaque volume and was determined by coronary CTA.

From baseline to 12 months, participants in the testosterone arm had a significantly greater increase in noncalcified plaque volume (from median value 204 mm3 to 232 mm3) compared with placebo (from median value 317 mm3 to 325 mm3) with an estimated difference of 41 mm3 (95% CI, 14-67; P = .003).

The median total plaque volume increased in the testosterone group from 272 mm3 to 318 mm3, compared with 499 mm3 to 541 mm3 for placebo (estimated difference, 47 mm3; 95% CI, 13-80; P = .006). The median CAC score decreased in in the testosterone group (from 255 to 244 Agatston units) and increased in the placebo group (from 494 to 503 Agatston units) from baseline to 12 months (estimated difference, –27 Agatston units; 95% CI, –80 to 26 Agatston units), according to the researchers.

No one in either group had a major adverse CV event.

“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning because any limitation of the vascular lumen could be considered deleterious,” Budoff and colleagues wrote. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”

The researchers concluded that larger studies are needed to understand the clinical implications. – by Cassie Homer

Disclosures: Budoff reports receiving a grant from General Electric. Please see the full study for a list of the other researchers’ relevant financial disclosures.

 

    Perspective
    Adrian Dobs

    Adrian Dobs

    The results of the present study are concerning. Previous studies that were more pharma-epidemiological received a lot of press about 2 years ago for concluding that people who received testosterone had a greater risk of developing some cardiac event. All those studies were vastly criticized, rightly so, since large databases suffer from incomplete information on patients. One doesn’t know the circumstances behind why a patient was or was not placed on testosterone. Were they too sick to be treated, or too healthy? Were they truly taking the hormone or did they discontinue? They were nonrandomized in these clinical databases and in fact, about a third of those patients didn’t even have testosterone levels drawn before they were treated. Those studies using large pharmacy-oriented databases were interesting, but did not produce firm conclusions. The controversy has raged on since other non-randomized studies showed metabolic benefits in treated men.

    The difference here is that this is a randomized study, in which elderly men were treated with testosterone vs. placebo. Since it was a relatively short 12-month study, clinical outcomes did not change, rather they used a surrogate marker of CAD, ie, coronary artery noncalcified plaque volume on coronary CTA, as an indicator of coronary atherosclerosis. This measure has been associated with myocardial ischemia and subsequent CV adverse events. The investigators reported an increase in their primary outcome, as well as total plaque volume on coronary CTA in the testosterone-treated group.

    There are several issues to consider before making any changes in clinical practice based on these findings. Firstly, can these findings be generalized to all men? The patients in this study, by design, were older (more than 65 years of age), many of whom were found to have significant heart disease already with elevated coronary artery calcium scores. This population varies from the group of men who are most likely to be treated in clinical practice, ie, the middle-aged, 45-to-65-year-olds. The results may thus not apply to the younger, larger populations who are taking the medication.

    Secondly, how well do we trust the change in coronary CTA, as a surrogate marker of CAD progression? There was a statistical change over the period of observation, but it remains questionable whether we trust this information enough to make clinical decisions based on it. This is not a `real’ angiogram and these are people who didn’t have any kind of real events. How sure are we that if someone has a change in plaque, it’s going to be associated with a clinical event, and in what amount of time? It may suggest that a patient may have a clinical cardiac event 10 years from now, but patients could stay relatively healthy with a high calcium score for a long time.

    Thirdly, what is the total risk-benefit ratio? The JAMA journals also published two other investigations from this study, although the data may not have been for the exact same patients. The authors found that testosterone treatment was associated with a statistically significant increase in bone density as measured by DEXA scan (Snyder PJ, et al. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2016.9539), and an improvement in anemia (Roy CN, et al. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2016.9540). Bone density is also an intermediate marker, in this case a surrogate for fracture risk. The increased bone density thus is an important finding for men who are at increased risk of osteoporosis and fractures. Similarly, improvements in hematocrit could also be beneficial. Previously in this same study, testosterone treatment was linked to slight improvements in sexual function (Snyder PJ, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1506119). Thus, clinicians need to balance the risks and benefits.

    There are clear indications for testosterone treatment, eg, when there is no question that the patient must be treated because of extremely low levels. Examples include pituitary disease, or congenital or acquired testicular damage. In those situations, we commonly understand the mechanism to explain the hypogonadism, and the men are symptomatic. Treatment in these situations would be recommended, even if the man has known heart disease, assuming there is careful monitoring afterwards.

    A study to evaluate the effect of testosterone on clinical CV outcomes is being planned, but it will take a large sample size and many years of observation. Unfortunately, we will need to wait a long time for this. Until then, treating men with testosterone should, like all medications, come only after careful thought and discussions with the patient. Clinicians should offer testosterone therapy to men with low serum testosterone levels, who are symptomatic and have an underlying mechanism to explain their hypogonadism. Physicians should always emphasize lifestyle intervention and direct treatment for CV risk factors. Also, depending on the circumstances, testosterone therapy need not be continued forever if there is no symptomatic improvement or physiological benefit. 

    • Adrian Dobs, MD, MHS
    • Professor of Medicine and Oncology Johns Hopkins Medicine

    Disclosures: Dobs reports no relevant financial disclosures.