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Rachel S. Rubin, MD: I am Dr Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. I am so blessed to have with me one of my favorite sexual medicine doctors on earth, Dr Mo Khera, professor of urology at Baylor College of Medicine. He's the president of the Sexual Medicine Society of North America and has been a part of a very big trial — the results of which just came out — all about testosterone, which is what we're going to talk about today.

Mohit Khera, MD, MBA, MPH: Thank you, Rachel, for having me on.

Rubin: We have some big news. We're talking about testosterone. Tell us about the very exciting findings that have just come out.

Khera: This is probably the most exciting time for testosterone. We've published the largest randomized, placebo-controlled trial on testosterone and cardiovascular and prostate safety — a landmark trial. The genesis of this trial was cardiovascular concerns. Before 2010, the available studies suggested that testosterone may be protective against cardiovascular disease, with no increased risk for cardiovascular events. Then from 2010 to 2014, four studies came out suggesting an increased risk for cardiovascular events. There are a lot of limitations with these studies; they weren't randomized or placebo controlled. Still, in September of 2014, the FDA said they wanted to further investigate this. They convened, and two big things came out of that meeting. In 2015, they made a label change on all testosterone products saying that long-term clinical safety of testosterone cannot be assessed. We need larger trials, and it's inconclusive whether testosterone is safe against cardiovascular disease.

The second big thing was that the FDA required that manufacturers of testosterone products conduct a large clinical trial to show that testosterone is safe. That's why the TRAVERSE trial started, in 2015. The placebo-controlled study involved more than 5200 men who were randomized to get testosterone gel or placebo. They had to have a low testosterone level (< 300 ng/dL), and they had to be symptomatic. The key point was that all of these men either had preexisting cardiovascular disease or at least three out of eight cardiovascular risk factors such as hypertension, diabetes, and metabolic syndrome. The study started in May 2018 and finished in February 2022. I'm very excited today to show you the results of four trials that have already been published.

Rubin: Let's hear it. Start with the big one in The New England Journal of Medicine.

Khera: The "big one" was about cardiovascular risk. The primary endpoint was time to cardiovascular events (myocardial infarction [MI] or stroke). The secondary outcome was risk for high-grade prostate cancer, and the tertiary outcome was any prostate cancer or intervention (medical or surgical) for BPH. All patients received an International Prostate Symptom Score (IPSS) to look for urinary symptoms. The benefit of this study was the other secondary outcomes, such as sexual activity and erectile dysfunction, anemia, diabetes, and bone fracture. Many of these study findings are yet to come out.

Among the men who received testosterone gel, testosterone levels went up by about 148 ng/dL to about 400 ng/dL. Levels in the placebo group went up by about 14 ng/dL at the end — a small increase. The key message is that there was no increased risk in cardiovascular events.

But three things surprised me. One, there was a slight increase in pulmonary embolism (PE) (0.5% in the placebo group vs 0.9% in the testosterone group). Two, men treated with testosterone had an increased risk for atrial fibrillation (2.54% with placebo vs 3.5% in the testosterone group). And three, an increased risk for acute kidney injury was seen (1.5% with placebo vs 2.3% with testosterone treatment). Remember, only the PE was adjudicated; the other outcomes were just self-reported. But it is what it is.

That's the cardiovascular safety study. The second study was the sexual function study, with 1000 patients randomized to testosterone gel or placebo. The primary outcome was increase in sexual activity. Secondary outcomes were an increase in erectile function and libido. They found that testosterone as monotherapy did not improve erectile function. We already knew that; it's in the American Urological Association (AUA) guidelines.

Testosterone as monotherapy does not improve erectile function, but it did significantly improve sexual activity and libido. What is very nice about the study is that testosterone improved libido, and it was sustained up to 24 months.

The prostate cancer trial came out last week. With 5200 men randomized to testosterone gel or placebo, the primary outcome was high-grade prostate cancer. The secondary outcome was whether their urinary symptoms get worse, meaning their IPSS, need for surgery (eg, TURP) or the need for a medication. They found no increased risk in high-grade prostate cancer — no increased risk in any type of prostate cancer. In fact, there were only 23 cancers out of 5200 men (11 in the placebo group and 12 in the treatment group). No significant difference whatsoever. And for the first time, a large study showed no increased risk for worsening of urinary symptoms. Right now, it's on the package insert to be careful if you give someone testosterone because their urinary symptoms may get worse. This study suggests that isn't true at all.

The last study was a small study about anemia, with 815 patients. The primary outcome was whether giving testosterone supplementation, would the anemia improve? At 6 months, they found a significant improvement: 41% in the testosterone patients and 27% in the placebo arm. This is not a novel study. It's been shown in the T trials that if you give testosterone, it can cause erythrocytosis. But in this case, we're actually using this as a beneficial effect. We're trying to help those who have anemia, defined as a hemoglobin level < 12.7 g/dL.

These are the results of the four studies have come out. We still have three more studies coming out: bone fracture, diabetes, and depression. I'm excited about those. These are very exciting times for testosterone research.

Rubin: Well, there you have it, folks. You've heard huge news. This is groundbreaking research in testosterone therapy. We want to get the word out to the everyday primary care doctors who are seeing these patients all the time with symptoms. What do you think primary care doctors should take away from this data?

Khera: They should realize that testosterone does not increase the risk for heart attack or stroke. In 2015, many clinicians stopped prescribing testosterone when the label changed. If you ask them, they say, I'm concerned that testosterone may cause a heart attack in my patient. Now we know that is not true. We also know that many clinicians are scared that if they give testosterone, it may cause prostate cancer. Now with this large clinical trial, no data suggest that testosterone increases risk for prostate cancer. This is very consistent with the AUA guidelines. In 2018, they came out suggesting there was no increased risk for prostate cancer in men receiving testosterone. This study only confirms it.

Another important point is that testosterone is not the best treatment for erectile dysfunction as monotherapy. We know it helps if you are giving a PDE-5 inhibitor in conjunction with testosterone. Testosterone does help libido. So in men with low libido, using testosterone as monotherapy may be beneficial.

Finally, testosterone increases the risk for erythrocytosis. In some patients with anemia, this may be beneficial. It's what we saw in the trial as well.

Rubin: You alluded to this, but primary care physicians are always considering risks vs benefits. What do you see as the benefits of testosterone therapy? And what are your patients telling you?

Khera: Great question. The key is that patients who do not have a low testosterone value do not benefit. They have to have a low serum testosterone value. The typical symptoms that improve are energy, sex drive, erectile function, muscle mass, fat deposition, some types of depression, and sleep. Those are the main symptoms that we see in patients. Typically, the lower the testosterone level the patient starts at, the greater the improvement. Not all patients will see improvement in all of these variables, but many patients do.

Rubin: What do you tell the doctor who says, "We'll just work on lifestyle issues first. If we start with lifestyle issues, then maybe if it's bad enough, we can address the testosterone issue"? It's kind of a chicken-or-egg situation. Where do you stand on that?

Khera: I think lifestyle is extremely important. I tell patients that it's not one or the other. We must do both at the same time. What I expect from the patient are four pillars: diet, exercise, sleep, and stress reduction. I don't have a pill on the planet stronger than diet, exercise, sleep, and stress reduction. Nothing. Even if they choose to do one of those and focus on that one, it changes their entire life. So I tell them, you meet me halfway. You focus on diet, exercise, sleep, and stress reduction, and I will focus on optimizing you so that you can change your diet, exercise, sleep and stress reduction. Together we're a team, but it really works best when both are optimized.

Rubin: Are there any patient populations that make you nervous or contraindications where you say, "I really don't think this is a safe option for you"?

Khera: First of all, testosterone is a natural contraceptive. So if a person is trying to conceive or have a child, you absolutely do not want to give them testosterone because it will shut down the sperm count. So that's one population. But based on the TRAVERSE trial, we should at least acknowledge the fact that there was a very slight increased risk for PE. That should be mentioned to patients who have a history of PE. It's also important to let patients know that we still don't have a lot of data on patients with a history of prostate cancer — those who have undergone radical prostatectomy or radiation. With proper counseling, most clinicians feel comfortable prescribing a bit of testosterone to men who have had a history of radical prostatectomy. You still want to do the appropriate counseling.

Rubin: I find that a lot of primary care doctors are fearful. They think testosterone is controversial, and they don't like to talk about it — even some endocrinologists. Why do you think it's so controversial as opposed to, say, thyroid hormone or insulin?

Khera: Clinicians don't get much training on testosterone in medical school. I know I didn't get it until my late in my residency or my fellowship. So, there's the discomfort zone. Many of us were ingrained that testosterone causes prostate cancer. In 2000, when I started my residency, we were told that if you give it to a man who has a history of radical prostatectomy, it's like putting fuel on the fire. We were just ingrained that it carried risk for prostate cancer. Then the cardiovascular risk came up. There were many unknowns. And when there are unknowns, there is controversy. But I think a lot of that controversy has been put to rest with the TRAVERSE trial.

Rubin: The TRAVERSE trial was done with topical testosterone. Do you think the type of testosterone matters, whether it's the injectable or some of the newer oral agents?

Khera: I think it could matter. When it comes to prostate safety, I believe in the prostate saturation model. In patients who are below 250 ng/dL of testosterone, as you raise them above the saturation level, some adverse action can occur. You'll see a rise in PSA. You can see a transient worsening of BPH. But once you have patients above the saturation tipping point, raising them to higher levels doesn't make a difference. So it doesn't matter if they're on a gel or injectable; it's not going to make much of a difference. It could make a difference to cardiovascular health, because higher levels could induce erythrocytosis. Some studies have suggested that the injectable may have be associated with a higher rate of erythrocytosis and cardiovascular concerns than the gel. I'm not saying that it couldn't, but it may not be as transferable when we're talking about cardiovascular risk.

Rubin: Why is testosterone a controlled substance? Why does it make me feel like an opioid-prescribing doctor, that I need to give two factor authentication and sign my life away every time I prescribe it?

Khera: Because there's a potential for abuse, and it's actually not stated in the package insert. Any product with abuse potential has to be more regulated.

Rubin: Do you think that the label change will happen now that the TRAVERSE trial is out?

Khera: Well, I think it should. It's only fair, because this trial was initiated because of concerns that came out in 2010-2014. That's why the label changed. The FDA required a large clinical trial to show that there was no increased cardiovascular risk. So, it makes sense to make that label change at this time.

Rubin: Finally, Dr Khera: Paint a picture for us. We both have many stories of patients who benefit so much from testosterone therapy. Not your classic bodybuilding patient who comes in wanting to abuse testosterone. But tell us the story of that guy who comes in and his life is transformed — his relationships, everything, is better.

Khera: There's a profound effect on quality of life for many men who initiate testosterone therapy. The typical man is older; remember that roughly 60% of patients who come in who have low testosterone levels will have metabolic syndrome, diabetes, or obesity. That syndrome is there. He now has erectile dysfunction, low libido, and some depression. He has increased fat deposition, and decreased muscle mass. He's now having some difficulty in his relationship with his partner because he cannot engage in sexual activity, so he is stressed. When you put these patients on testosterone, many of them could see a significant improvement in their energy. Fat deposition declines and muscle mass improves. They work out, and their erectile function can improve, particularly if they are using a PDE-5 inhibitor in combination therapy. If you watch them over time, these patients are extremely appreciative when they come in, thanking you for making a profound impact on their quality of life.

Rubin: That's why you and I keep showing up to work. This is just been an absolute honor. I am your number-one fan, and we're very excited. Can you give us any hints about the next stage of the TRAVERSE trial? What is it going to show us? Are there any abstracts yet?

Khera: The next one's coming out next month, I believe, and within the next 6 months, we'll have the next three out. Then hopefully we can start taking a deeper dive in some substudies at the dataset to look at other questions. It's a huge, amazing dataset, and there are so many questions that we can answer just by going through those data.

Rubin: Big congratulations. We will be looking for the next data to come out. Thank you so much for joining us today.

Transcript ends.

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Original article found here: https://www.medscape.com/viewarticle/999636

Cite: The Most Exciting Time for Testosterone - Medscape - Jan 18, 2024.

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