Study of the Week: Cardiovascular Safety of Testosterone Replacement Therapy

Cosmetic medicine and a study that tells us nothing

Dr. Mandrola and I are trading beats this week. I am posting the “Study of the Week” today and John will be publishing a “My Favorite Article” piece later in the week.

Over time, I have realized the type of medicine I enjoy practicing. I love evaluating symptoms, making diagnoses, and curing (or more commonly managing) diseases. I appreciate the worth, and challenge, of controlling chronic diseases in parsimonious and tolerable ways. I enjoy counseling people on how to stay healthy, on appropriate screening, on lifestyle modification, and on behavioral change.

An aspect of primary care medicine that never excites me is what I (disparagingly) call cosmetic medicine. For me this is the type of medicine practiced when a doctor gives a name to a symptom that is part of the human condition (fatigue, achy muscles, grief, loss of libido, dysthymia…) and medicalizes it, offering a treatment, usually without evidence that the treatment even helps. Of course, sometimes fatigue can be a symptoms of a serious medical condition that needs to be treated – I refer you to chapter 18 of Symptom to Diagnosis: Fatigue. This is not what I am talking about, I am talking pharmacologic therapy for just plain old, “I wish I had more energy, I felt better when I was 26 than I do now at 56.”

Enter testosterone replacement therapy. Androgen deficiency is a real problem that needs to be evaluated and treated. It can be caused by failure of the testes to produce testosterone or by a problem higher up in the “pituitary-hypothalamic axis.” It has a defined differential diagnosis and evaluation. This is not what I am writing about.

Over the last couple of decades testosterone has been aggressively marketed. You have almost certainly seen an ad encouraging me to “Ask your doctor about low T.” These commercials are aimed at an array of non-specific symptoms – fatigue, decreased libido, decreased energy, fewer spontaneous erections, low or depressed mood who turn out to have slightly low testosterone with no clear cause. If you understand the normal distribution, and thus how we define what is a normal blood test result, and are, or know, a man over 45, you realize this is an ENORMOUS market.

Now you might say, “Whatever, what’s the harm? If the guy’s testosterone is a little low, replete it. Maybe he feels a bit better, even if it is just the placebo effect.” Well, this might sound OK, if you are OK with over-treatment and mild ethical lapses but what if testosterone repletion is associated with harm? There is reason to be concerned that testosterone repletion might be harmful, associated with cardiovascular events and prostate cancer.[i]

That long introduction brings us to an article published in the NEJM last week, Cardiovascular Safety of Testosterone-Replacement Therapy. This study was the result of the FDA demanding safety data from the companies who were making money selling testosterone (and no doubt funding all those damn low-T ads).

Patients

The study enrolled men, 45 to 80 years old, with cardiovascular disease or elevated cardiovascular risk. The men had at least one symptom of testosterone deficiency (decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood, loss of axillary or pubic hair or decreased frequency of shaving, or hot flashes)[ii] and had two fasting serum testosterone levels of less than 300 ng per deciliter – just below the lower limit of normal. Patients with very low testosterone levels (< 100) were excluded as were men with prostate cancer of an elevated PSA.

Intervention and Endpoints

The participants were randomized to testosterone gel or a placebo and a system to allow for dose adjustments without causing unblinding was established. This was designed as a non-inferiority study. The primary end point was the first occurrence of a component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Results and Limitations

Over 5000 men were randomized. The headline of this study was that testosterone treatment was not associated with an increase in cardiovascular events. A primary endpoint occurred 7.0% of the people in the testosterone group and 7.3% of people in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for non-inferiority).

These banal results are not the whole story. There is at least signal (a term I generally hate) for injury associated with testosterone therapy. There was about a 1% increase in afib and acute kidney injury in the treated group, in a study with a mean follow-up of less than 3 years.

What was so interesting about this study, and a fact that was well covered in some lay media, is that details about the study make the results meaningless. First, the increase in testosterone levels in the treated group was remarkably small. While the placebo group maintained levels of about 250, the treatment group peaked at a mean of about 350. The design of the study had the testosterone dose titrated to levels of 350-750. Underlining the fact that patients were under-treated, 61.4% of patients in the testosterone group stopped therapy, almost identical to the 61.7% of patients who stopped placebo.

Conclusion

So, what does this study tell us? Nothing. It tells us that homeopathic doses of testosterone -- ones that barely change blood levels of testosterone (the process measure) and have so little effect on how people feel that 60% of them stop the medicine -- are sort of safe. These results do nothing to reassure anyone that using testosterone for “cosmetic medicine” is safe. In practice, when we (I use the first person plural pronoun liberally here) treat low testosterone, we titrate the dose up every 2-4 weeks until there has been a response in target symptoms, elevated testosterone levels, or other abnormal blood tests. This is clearly not what was done in this study.

It is tempting to hypothesize that this study was designed to satisfy the FDA while minimizing the chance that any adverse effects were discovered. I, however, cannot imagine that a for profit company would manipulate a study design to limit the likelihood of finding that their product is dangerous.

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[i] Leave aside the fact that treating older men with low testosterone attributed to the “andropause” (or the more maddeningly termed menopause) is analogous to giving estrogen to every woman in menopause. You might remember that we once did that.

[ii] I shaved less during the pandemic since I had to wear a mask at work. I am not sure if this would have qualified me for the study.