Testosterone Therapy Paradox? CV Events Up in Older Men, but Mortality Down

Patrice Wendling

July 24, 2019

After years of studying the twists and turns of hormone replacement therapy among women, Montreal-based epidemiologist Christel Renoux, MD, PhD, shifted her focus to its use in aging men — a path that's proving no less controversial.

"There is a passionate debate around testosterone replacement therapy; you have strong, strong believers it is really having a benefit and others say the benefit is modest and not worth the risk. You can see that it is really dividing even the scientific community," she told theheart.org | Medscape Cardiology.

Following the publication of two articles linking testosterone replacement therapy with an increased risk for myocardial infarction (MI) and stroke, the US Food and Drug Administration and Health Canada issued warnings about using testosterone products for age-related low testosterone and required a warning on product labels. The European Medicines Agency, however, found no consistent evidence for such risks.

Prescribing patterns appear equally conflicted, with one recent study showing testosterone prescriptions plunging in 2013 after publications of the cardiovascular safety concerns, while another report found spending on testosterone nearly quadrupled from $108 million in 2007 to $402 million in 2016.

Rates of hypogonadism, however, have remained stable, suggesting that aging but otherwise healthy men with low testosterone may be turning to testosterone replacement therapy (TRT) as an elixir for aging and dwindling sexual function, the investigators note.

"We are at the early stage of the debate. We need much more work to clearly delineate is there a place, possibly, for testosterone replacement therapy and in which clinical scenario and at which age," said Renoux, from Jewish General Hospital and McGill University, both in Montreal, Canada.

Renoux and colleagues' latest work provides no easy answers, despite a large cohort of 15,401 men, aged 45 years or older (mean 60.4 years), diagnosed with low testosterone without evidence of hypogonadotropic or testicular disease in the UK Clinical Practice Research Datalink database between 1995 and 2017.

Most patients received testosterone gels or creams (56.8%) and 33.6% received injections.

The results show a 21% increased risk for the composite of MI and ischemic stroke/transient ischemic attack (TIA) in current TRT users vs nonusers after adjusting for more than 20 potential confounders (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.00 - 1.46).

This corresponds to an adjusted risk difference of 2.4 events per 1000 persons per year, the authors reported July 18 in the American Journal of Medicine.

MI and stroke risk was highest in the first 6 months to 2 years of continuous use and mostly driven by an increased risk among men aged 45 to 59 years. Risk was also increased in men with and without prior cardiovascular disease (CVD), but the results did not reach statistical significance.

Surprisingly, current TRT use was associated with a lower risk for all-cause mortality (HR, 0.64; 95% CI, 0.52 - 0.78) and past use with an increased risk when compared with nonuse (HR, 1.72; 95% CI, 1.21 - 2.45).

"It's difficult to reconcile on one hand an increased risk of cardiovascular disease, which is one of the leading causes of mortality in older men, and at the same time finding a strong predictive effect on all-cause mortality," Renoux said.

"What we think is happening is that when these people become less healthy, because hormone therapy is not a vital treatment, they will stop it."

She noted that additional analyses using 5α-reductase inhibitors or finasteride as control exposures showed a similar but statistically nonsignificant protective effect of TRT on all-cause mortality.

"When you see such a strong protective effect on all-cause mortality, you have to begin to wonder because if it's too good to be true, it probably is," she said. "Because how many drugs can you claim have a 75% decrease risk in all-cause mortality?"

Reached for comment, Bradley Anawalt, an endocrinologist and chief of medicine at the University of Washington Medical Center in Seattle, said he was surprised the authors dismissed the all-cause mortality findings and highlighted a 2012 study he coauthored with "equally stringent statistical analyses," in which the risk for death was lower among men aged 40 years or older treated with testosterone (adjusted HR, 0.61; 95% CI, 0.42 - 0.88). 

"There are plausible mechanisms; testosterone increases strength, which means perhaps these men didn't fall and break their hips or die from fractures," he said.

"To a priori say it couldn't be a drug effect that has the same biases and errors in logic someone might have if they say it couldn't have been the testosterone causing the heart attacks and strokes," Anawalt said.

As for the effect of testosterone on the composite of MI/stroke/TIA, Anawalt said that the absolute risk difference for just 2.4 events/1000 persons/year was very small. Exactly how TRT imparts CVD risks remains unclear, but the authors note it may enhance platelet aggregation.

They also highlight the Testosterone Trials, in which coronary artery plaque volume increased significantly among elderly hypogonadal men after 1 year of testosterone treatment. What they fail to mention, however, is that the trials failed to find evidence of increased CVD risk, Anawalt observed.

Anawalt, a coauthor on the Endocrine Society's recent clinical guideline on testosterone therapy in men with hypogonadism, underlined that the present results only apply to aging men with low testosterone without an identifiable pathology.

Although these patients outnumber those with known pathology, he said research suggests that somewhere around 2% to 2.5% of middle-aged and older men have bona fide testosterone deficiency.

"What this study raises questions about is whether testosterone might infer risk of stroke in administration in men that don't have a known identifiable cause of testosterone insufficiency," he said.

"I think that this is important because I see patients that come in with a borderline low testosterone level and I can't identify a cause. I use this uncertainty as an important part of my conversation with them."

Renoux sounded a similar note: "At the end of the day, I think our main message is that it's an individual decision to balance the risks and benefits of whether or not to prescribe this treatment in the context of the potential cardiovascular risks and potential expected benefits."

While more research is needed into what testosterone does mechanistically to the organs it affects, the long-awaited TRAVERSE trial is expected to shed some light on the long-term vascular risks and benefits of TRT.

"If not quite the equivalent of the Women's Health Initiative, but we will have something that will begin to answer these questions," Anawalt said.

"The Women's Health Initiative initially made it sound like estrogen was poison to postmenopausal women and then as time has unfolded 20 years later it's now 'well, maybe we shouldn't start late but starting it very early is actually a very good thing.' I predict we're going to see something similar unfold with the testosterone story in men. I don't know what it's going to be, precisely, but it's going to be neither panacea nor is it going to be diabolically evil. There will be subtleties."

The study was supported in part by funding from the Canadian Institutes of Health Research. The authors and Anawalt have declared no relevant financial relationships.

Am J Med. 2019;DOI:10.1016/j.amjmed.2019.03.022. Abstract

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