November 5th, 2013

Should You Be Worried About the Treatment for Low-T?

The ubiquitous ads ask: “Should I be worried about Low-T”? But now there’s a good chance there’s a more important question: “Should I be worried about the treatment for low-T?”

A new study published in JAMA raises the distinct possibility that testosterone therapy may increase the risk for death, heart attack, and stroke. The findings are hardly definitive, but they may raise significant questions about the enormous increase in testosterone use in recent years, especially given the absence of any evidence demonstrating the safety of testosterone therapy.

Rebecca Vigen and colleagues performed a retrospective analysis of 8709 male veterans with low testosterone levels (300 ng/mL) who underwent coronary angiography; 1223 of the men went on to start testosterone therapy sometime after their angiogram. At 3 years, the absolute rate of death, MI, or stroke was 25.7% in the testosterone group versus 19.9% in the no testosterone group. (The 95% confidence interval for the difference was −1.4% to 13.1%).

After adjustment for baseline differences between the groups, there was a significant, 29% increase in risk associated with testosterone (CI 1.05-1.58, p = 0.02). The effect size was the same in the groups of people who had coronary artery disease and those who did not. One important finding was that the testosterone group was at increased risk for events despite having a generally lower risk profile at baseline.

The authors acknowledge the limitations of observational studies and that their study does not prove that testosterone therapy is harmful. But, they write, it is important for physicians “to inform patients that long-term risks are unknown and there is a possibility that testosterone therapy might be harmful.”

In an accompanying editorial, Anne Cappola writes that “in light of the high volume of prescriptions and aggressive marketing by testosterone manufacturers, prescribers and patients should be wary.” She also considers whether or not the results are applicable to the larger patient population taking testosterone:

Perhaps the most important question is the generalizability of the results of this study to the broader population of men taking testosterone: men of this age group who are taking testosterone for “low T syndrome” or for antiaging purposes and younger men taking it for physical enhancement. Does the 29% increased risk of myocardial infarction, ischemic stroke, or mortality apply to these groups? Are the benefits—real or perceived—for these groups of men worth any increase in risk? These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men.

Joe Ross sent the following comment:

I think this is a critical study that helps to enhance our understanding of the risks of testosterone therapy. Experience with this drug illustrates the challenge of understanding benefits and risks for therapy, particularly for drugs that are approved on the basis of surrogate outcomes, made all the more complicated when drugs, like testosterone, are increasingly used and seemingly promoted for off-label uses. No drug is without risk. We need better methods of post-market surveillance to estimate these risks of therapy once the drugs are approved for use in the wider population. While many adults may perceive the risks of therapy to be outweighed by the benefits, patients are best served by ensuring that this information is available and can be used to inform decision making. Although the authors suggest that an RCT is needed to accurately estimate the risks associated with testosterone therapy, such a trial would not be completed for years. In the meantime, this study provides key information that patients should be considering when making a decision to use testosterone therapy.

One Response to “Should You Be Worried About the Treatment for Low-T?”

  1. I asked David Herrington, a well-known researcher who played a key role in the HERS and WHI trials more than a decade ago, to comment on this topic.

    Herrington first responded:

    “Important topic. More RCT (randomized controlled trial) data are urgently needed in relevant populations with sufficient numbers of subjects and duration of follow-up to determine if there are adverse CV effects and how frequent and severe they are relative to any benefits. These observational data provide the kind of worrisome, but not definitive, information that further justify the need for a definitive RCT.”

    I then asked Herrington whether the situation with testosterone was similar to the earlier situation with HRT:

    “There are some similarities. They both are sex-steroid hormones (which involve very complex biology), they both are used for relief of non-life threatening symptoms (although technically testosterone replacement is approved for use for “hypogonadism”), but with potential life threatening but under-appreciated adverse effects. However, the magnitude of the problem is not as great as it was for HRT and there are not as many advocates promoting testosterone. Remember that Premarin was perhaps the first billion $ drug (or one of the first) and HRT was actually recommended to prevent heart disease in numerous professional society guidelines prior to HERS and WHI.”