Revisiting Death by Testosterone? We think not!

Abdul M. Traish and Abraham Morgentaler

In July 2023 the cardiovascular results of the TRAVERSE trial were published in the New England Journal of Medicine, demonstrating conclusively that the use of testosterone therapy (TTh) in T-deficient men was associated with no increased risk of major adverse cardiovascular events (MACE), consisting of myocardial infarction, stroke, or cardiovascular death [ 1]. These results confirm the findings of other large randomized controlled trials (RCT) and observational studies and should finally lay to rest the purported concern that TTh is associated with increased cardiovascular (CV) risks.

The story of how CV risks became associated with TTh is illuminating. To refresh our memories, it began with publication in 2010 of a study by Basaria et al. [2] designed to investigate the effects of T therapy on muscle strength in men 65 years or older with mobility limitations (inability to climb 10 stairs or walk 2 blocks). Before completion of the study, the data safety monitoring board became aware of greater number of cardiovascular events in the T arm (23 events) compared with the placebo arm (5 events), and they terminated the study early.

However, most of these reported events were of uncertain clinical significance, such as pedal edema, palpitations, and nonspecific EKG changes. Nonetheless, 4 major adverse cardiovascular events (MACE) did occur (2 myocardial infarction, 1 stroke, 1 death), and all of these were in the group that received TTh. While this was obviously concerning, the authors reasonably noted, “The lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.” Moreover, a similar RCT in a similar population published in the same year had reported two MACE, both of which had occurred in the placebo group. This study by itself presented no compelling evidence of grave concern with TTh, yet the early termination of the study coupled with the greater number of events CV-related events in the testosterone arm caught the eye of the medical community and the public.

All was then quiet until late 2013 when Vigen et al [3] published a provocative observational study in the Journal of the American Medical Association that reported greater cumulative risk of MACE among men with low T levels that received a prescription for TTh compared with men that did not receive a prescription. Another study by Finkle et al [4] published just two months appeared to confirm that TTh was associated with serious CV risks, and the story of increased CV risks with TTh became the hottest medical media story in years.

The publicity led the New York Times to write an editorial titled, “Overselling Testosterone, dangerously.” Law firms advertised on television for patients who had experienced an adverse event while taking TTh, and the FDA added a CV warning label to T products. Suddenly and out of the blue there was a public and medical belief that T is a poison that kills men.

However, on the scientific front, it immediately became apparent that there were serious problems with the paper by Vigen et al [3]. Although the authors reported there was a greater absolute rate of MACE events among those who received a testosterone prescription, their own numbers revealed this was incorrect- the absolute rate of events was lower by half for those that received a T prescription compared with those that did not!

The authors eventually published two corrections [5,6] due to mis-reporting of results, mis-categorization of >1000 individuals, and the inclusion of substantial numbers of women in their all-male study population. Numerous articles eventually challenged the credibility of this study, and the FDA itself acknowledged its serious limitations [7-25], even as it relied upon it to determine there was enough concern to investigate further. The article by Finkle et al [4] was subsequently shown to suffer from such a serious design flaw that it also could not be reasonably offered as evidence of increased CV risk with TTh.

What also had gone almost unnoticed in the discussions of CV risk prompted by the papers mentioned above was that there was an existing literature accumulated over several decades that had demonstrated CV benefits of TTh. In fact, there were multiple reports from the 1930s and 1940s that TTh could alleviate angina. More recent evidence had indicated reduced mortality and reduced prevalence of atherosclerosis and coronary artery disease for men with normal endogenous T levels as compared to those with subnormal levels; RCTs had shown greater exercise tolerance in men with angina and improvements in men and women with heart failure; and two observational studies had shown substantially reduced mortality among men with low T levels that had received TTh compared with those who did not.

It was therefore a dizzying and bewildering experience for us to find our previously quiet area of interest thrust so prominently into the public spotlight, and in such a distorted fashion. It was distressing when patients discontinued treatment on the basis of this negative publicity despite excellent clinical benefits over many years. Some called to complain of mistreatment, saying, “How could you have given me such a dangerous medication?” Another said he’d been called by his cardiologist to tell him he needed to stop taking TTh because “testosterone is going to kill you.”

We believed that as experienced scientists and clinicians in the field with expertise in this area, we had an ethical obligation to correct the record and explain what was true about testosterone and the relevant scientific literature. With various colleagues we wrote to the FDA and made a presentation at its 2015 scientific advisory board meeting. We spoke with the editor of the Journal of the American Medical Association soon after the article by Vigen et al [3] appeared, alerting him to their incorrect values that resulted in one of the published corrections, and later wrote a letter to the editor that prompted a second correction. We worked with colleagues and medical organizations around the world to educate them on the broader scientific literature regarding TTh and CV risk, and the issues with the new articles that had raised concerns. And we published an article entitled, “Death by Testosterone? We think Not!” (7).

It is gratifying to see how well that paper has held up over the past decade, written in 2014 at the start of the media frenzy about CV risks with TTh and prior to any of the large randomized controlled trials in the field. We reviewed the studies that had caused the alarm, pointing out their errors and limitations, and contrasted these with the existing literature at the time that pointed to promising CV and mortality benefits of TTh in T-deficient men. We authored the paper together with our dear late colleague, Andre Guay, and it was published together with endorsements from 15 international figures in the field, many of whom are actively involved in the Androgen Society, including Geoffrey Hackett, Hugh Jones, Martin Miner, Mohit Khera, and Michael Zitzmann.

In the ensuing years numerous studies have confirmed the thrust of our conclusions in Death By Testosterone? We Think Not!, in which we argued that the studies suggesting increased CV risk provided no real evidence and were contradicted by a substantial literature. Indeed, among dozens of studies, including observational studies, large RCTs, and meta-analyses, we are unaware of a single one that provides compelling evidence of increased CV risk with TTh.

The results of the TRAVERSE trial argue this concern need no longer be seriously considered.

While it is gratifying to see our assessment from a decade ago proven correct, what is more important is to recognize several lessons from this chapter in medical history. One is that the media can powerfully shape and distort scientific issues. A second is that the media particularly finds appealing health stories that suggest there is unexpected risk in a commonly used health treatment, which we have previously described as, “If it bleeds, it leads.” A third is that once a risk has been raised as a serious concern, it can be challenging to “prove” it may be without scientific foundation, regardless of how strong the subsequent evidence may be.

We believe the evidence is now clear that clinicians may offer T therapy to men without any concern that treatment may entail CV risks. We also believe that in light of the reassuring results from the TRAVERSE trial, the FDA should now remove the warning language regarding CV risk that it added to testosterone labels in 2015 when it first required testosterone manufacturers to perform the TRAVERSE trial to investigate this issue. Finally, in light of the safety and efficacy demonstrated by TRAVERSE as well as the Testosterone Trials, both of which were performed in populations of men with age-related hypogonadism, that the FDA should expand the indications for T products to include men with age-related testosterone deficiency.

References

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