When used to normalize a man's testosterone levels, testosterone supplementation can reduce the risk of myocardial infarction (MI), stroke, and all-cause mortality, a large new retrospective study of a Veterans Affairs (VA) population indicates.

"The risks [and] benefits depend on the profile of the patient rather than the therapy itself," principal investigator Rajat Barua, MD, PhD, emphasized to Medscape Medical News.

Dr Barua, an assistant professor of medicine at the University of Kansas School of Medicine, and his colleagues published their findings online August 6 in the European Heart Journal.

The results contradict other recent studies that have suggested increased cardiovascular risk from testosterone-replacement therapy. These spurred a warning from the US Food and Drug Administration (FDA) earlier this year.

But the European Medicines Agency last year concluded that there is "no consistent evidence" of an increased risk for cardiovascular problems with testosterone products, and other research has even indicated that testosterone might have a protective effect against cardiovascular disease.

"Our study was born out of our own dilemma of what to say to our patients, because there was conflicting news in the past few years," Dr Barua said.

A Search for Answers

In hopes of providing some answers, the study team retrospectively examined national data on 83,010 men with documented low testosterone, all age 50 or above, who received care from the Veteran's Administration between 1999 and 2014.

Dr Barua and his colleagues divided the men into three groups: 43,931 who were treated to the point where their total testosterone levels returned to normal, 25,701 who were treated but without reaching normal, and 13,378 who were untreated and remained at low levels.

The researchers matched the groups so there were no significant differences in age, body mass index, various chronic diseases, LDL- cholesterol levels, or the use of aspirin, beta-blockers, or statins.

The average follow-up across the groups ranged from 4.6 to 6.2 years.

The sharpest contrast emerged between those who were treated and attained normal levels and those whose low testosterone went untreated. The treated men were 56% less likely to die during the follow-up period (P < .001), 24% less likely to suffer an MI (P = .005), and 36% less likely to have a stroke (P = .031).

The difference between those who were treated and attained normal levels and those who were treated but did not attain normal levels was similar but less pronounced — the former were 37% less likely to die (P < .001), 18% less likely to suffer an MI (P = .008), and 30% less likely to suffer a stroke (P = .028) than the latter.

No statistically significant difference emerged between the two groups whose testosterone did not reach normal levels, except that the treated men were 16% less likely to die than the untreated men.

Dr Barua said the reasons for testosterone's benefits remain unclear. Possible explanations could involve effects of the hormone on body-fat composition, insulin sensitivity, lipids, blood platelets, inflammation, or other biological pathways.

Previous studies that showed an increased risk of cardiovascular events may have done so because their study populations were not well controlled or because the patients did not have normalized testosterone levels, he suggested.

For example, one of the first studies to raise concerns, published in 2013, included only hypogonadal men who had undergone coronary angiography, a population at higher risk of cardiovascular events (JAMA. 2013;310:1829-1836). Also, 40% of the men in the study did not have repeat checks of their testosterone levels.

Many of these men may not have achieved normalization of testosterone following therapy, Dr Barua said.

Likewise, another study, reported in 2014 (PLoS One. 2014;9:e85805), did not account for testosterone levels, so it is unclear whether the patients achieved normalization, said Dr Barua.

Although his study's results support testosterone-replacement therapy, Dr Barua emphasized the importance of carefully selecting patients before prescribing testosterone and of following them up afterward.

"Physicians should not prescribe testosterone just because the patient is complaining of low energy or low sex drive," he said.

In fact, another trial just published this week found that testosterone gel administration did not improve overall sexual function or health-related quality of life (JAMA. 2015;314:570-581). On the other hand, it had no adverse effect on atherosclerosis.

Dr Barua advised clinicians to check patients with low testosterone for systemic illness or recreational drug use, since either can transiently lower test levels.

Pinpointing Correct Dose Is Important, Too

"Patients should go through appropriate screening, which includes a regular physical checkup," he said. "You should not only have symptoms, you should also have signs of testosterone deficiency, with low testosterone levels checked at two different times."

Dr Barua and his colleagues excluded from their study patients whose testosterone level was low on a first test but normal on a second test. About 30% of patients with low testosterone regain normal levels without supplementation, he explained.

And finding the correct dose is also important, as is checking testosterone levels once therapy has begun, he stressed.

In addition, he advised clinicians to watch for side effects. Testosterone supplementation has been associated with prostate and breast cancer and sleep apnea, he pointed out.

The study was funded by the Kansas City Veterans Administration Medical Center and the Midwest Biomedical Foundation. The authors have no relevant financial interests.

Eur Heart J. Published online August 6, 2015. Article