July 15, 2025
11 min learn
Key takeaways:
- The FDA eliminated a warning about CV danger from testosterone product labels after a randomized trial confirmed no hyperlink.
- Use of testosterone remedy could rise, however extra analysis is required about different potential dangers.
Outcomes from a randomized managed trial led the FDA to make a serious change to testosterone alternative remedy labeling in February.
The FDA introduced it will take away language about elevated danger for adversarial cardiovascular occasions from the label of all testosterone alternative merchandise. In keeping with the company, the choice adopted a evaluation of findings from the TRAVERSE trial, a research that enrolled males aged 45 to 80 years at excessive danger for heart problems with a low testosterone stage at baseline and was revealed in The New England Journal of Drugs in 2023. The trial, supported by producers of testosterone merchandise together with AbbVie, Acerus Prescribed drugs, Endo Prescribed drugs and Upsher-Smith Laboratories, discovered males receiving testosterone had related danger for CV loss of life, nonfatal myocardial infarction and nonfatal stroke in contrast with these receiving placebo.
The FDA requested that producers of testosterone alternative merchandise conduct a trial after a number of research in 2013 and 2014 discovered use of testosterone remedy could increase CV danger. Outcomes from these research prompted the FDA so as to add a boxed warning in 2015 about potential adversarial CV danger for all testosterone merchandise.
The TRAVERSE findings have been very impactful in establishing CV security for testosterone remedy, based on Abraham Morgentaler, MD, FACS, the Blavatnik College Fellow in Well being and Longevity at Harvard Medical Faculty and government secretary of the Androgen Society. Morgentaler mentioned he believes that the trial “settled” the argument of CV danger with testosterone remedy.
“We’re in what must be a brand new period for testosterone remedy,” Morgentaler advised Healio | Endocrine Right this moment. “The previous fears of prostate most cancers and CV danger are now not tenable. They’re not scientifically supportable anymore.”
Whereas the findings from TRAVERSE could have supplied stronger proof supporting CV security of testosterone, Steven E. Nissen, MD, MACC, chief tutorial officer on the Sydell and Arnold Miller Household Coronary heart, Vascular & Thoracic Institute, the Lewis and Patricia Dickey Chair in Cardiovascular Drugs at Cleveland Clinic and a TRAVERSE investigator, mentioned he believes that the research additionally raised extra security questions on different potential dangers, comparable to nonfatal arrhythmia and fractures. Nissen additionally famous that sufferers in TRAVERSE have been intently monitored, which differs from the best way many males use testosterone in a real-world setting.
“Whereas we confirmed that testosterone, when given rigorously, shouldn’t be dangerous, we did see some harms within the TRAVERSE trial, even when the drug was used rigorously,” Nissen advised Healio | Endocrine Right this moment.
’A one-two punch’
Considerations about potential elevated CV danger with testosterone remedy have been raised after the publication of two research in late 2013 and early 2014. A 2013 research revealed in JAMA assessed loss of life, MI and stroke in a gaggle of males within the Veterans Affairs system with testosterone ranges under 300 ng/dL. Testosterone alternative remedy was related to elevated danger for adversarial CV outcomes (HR = 1.29; 95% CI, 1.04-1.58).
A 2014 research revealed in PLOS One examined danger for nonfatal MI amongst males prescribed testosterone remedy within the Truven Well being MarketScan Industrial Claims and Encounters database. Contributors had a better MI danger after being prescribed testosterone remedy in contrast with baseline (HR = 1.36; 95% CI, 1.03-1.81). The elevated MI danger with testosterone remedy was extra elevated amongst males aged 65 years and older (RR = 2.19; 95% CI, 1.27-3.77).
“It felt like a one-two punch,” Morgentaler mentioned of the 2 research. “They each acquired a whole lot of publicity.”
Adrian S. Dobs, MD, MHS, director of Johns Hopkins Scientific Analysis Community and professor of drugs and oncology at Johns Hopkins College Faculty of Drugs, famous that whereas the research obtained a whole lot of publicity, that they had a number of key limitations.
“These research have been [based on] medical or epidemiological databases,” Dobs advised Healio | Endocrine Right this moment. “The issue is that they’re very onerous to interpret. It seems if you actually look deep into these databases, there have been many males the place you didn’t know what their dose of testosterone was. You didn’t know in the event that they have been even taking testosterone. It was incomplete information as to whether or not they had MI vs. another coronary heart illness.”
After publication of those research, The New York Occasions editorial board revealed an article criticizing the “overselling” of testosterone alternative remedy and calling for a big medical trial to be performed. Roughly 1 yr later, in March 2015, the FDA introduced label modifications for all prescription testosterone alternative merchandise. The modifications required producers to make clear authorized makes use of of testosterone alternative remedy and add details about potential elevated danger for MI and stroke.
Sandeep Dhindsa, MD, professor of drugs, the Clara A. Drefs Chair in Inner Drugs and chief of the division of endocrinology and metabolism at Saint Louis College, mentioned regardless of the findings of the JAMA and PLOS One research, different analysis revealed on the subject was inconclusive. The FDA acknowledged this in its 2015 announcement and known as on testosterone alternative producers to conduct a medical trial to higher assess CV danger with remedy.
“FDA, being a physique that’s supposed to observe security, didn’t need to ignore this doable sign,” Dhindsa advised Healio | Endocrine Right this moment. “I really feel including a boxed warning was somewhat untimely, however asking for a research to be finished on CV security of testosterone was the appropriate choice.”
TRAVERSE offers perception
The FDA’s name led to TRAVERSE, a randomized, double-blind, placebo-controlled trial that enrolled 5,246 males aged 45 to 80 years with a fasting whole testosterone of lower than 300 mg/dL and with or at excessive danger for CVD. Contributors have been randomly assigned to once-daily transdermal 1.62% testosterone gel (AndroGel, AbbVie) or placebo. Incidence of a serious adversarial CV occasion, outlined as CV loss of life, nonfatal MI or nonfatal stroke, was the trial’s main endpoint.
Seven p.c of the testosterone group and seven.3% of the placebo group skilled a CV endpoint. Throughout a imply follow-up of 33 months, danger for a serious adversarial CV occasion was related for males receiving testosterone alternative in contrast with these receiving placebo (HR = 0.96; 95% CI, 0.78-1.17; P < .001). Dangers have been additionally related between the 2 teams when every endpoint was analyzed individually.
In 2024, the Androgen Society launched a place paper stating that the shortage of connection between testosterone and CV loss of life/MI/stroke danger is “conclusively decided” and the dialogue of CV danger with testosterone remedy is “settled science.” Morgentaler was the lead writer of the assertion and Dhindsa and Dobs have been co-authors.
The FDA eliminated the CV danger warning from testosterone merchandise based mostly on TRAVERSE, however Nissen mentioned the trial solely assessed a testosterone gel and never injectable merchandise.
Questions concerning the real-world applicability of the trial outcomes have been raised in a associated editorial revealed in NEJM. Eric Orwoll, MD, professor of drugs at Oregon Well being & Science College, wrote that the findings won’t be generalizable as a result of the research inhabitants was in danger or had preexisting CVD, and the bulk had weight problems and diabetes. Moreover, Orwoll famous that the research inhabitants was adopted for a brief interval and the long-term danger for CV occasions stays unknown. Orwoll additionally acknowledged that the research inhabitants’s median testosterone stage ranged from 226 ng/dL to 386 ng/dL, which was under the traditional stage of 450 mg/dL to 600 ng/dL really helpful by the American Urological Affiliation.
“No less than over a 2-year therapy interval, testosterone alternative remedy appeared to impart no further danger of main adversarial cardiac occasions,” Orwoll wrote. “Nevertheless, the security of longer-term remedy, the implications of supplementation to achieve larger testosterone ranges and the adversarial results that gave the impression to be related to this remedy should be higher understood.”
Different security questions
Nissen mentioned TRAVERSE’s outcomes is probably not relevant in a real-world setting because of the trial’s strict protocols relating to dose titration and follow-up.
“It’s actually essential to know how nicely managed the trial was,” Nissen mentioned. “Males needed to have two morning ranges drawn of testosterone that have been under 300 ng/dL and needed to have signs [to participate]. … Males then acquired both placebo or testosterone gel, and it was titrated. The dose was adjusted to get these males into the traditional vary. If their stage was above the traditional vary, then that they had their dose diminished.”
Nissen mentioned the strict oversight that occurred in TRAVERSE shouldn’t be occurring in the actual world for all males utilizing testosterone remedy. Dobs added that real-world information can be troublesome to interpret resulting from many inconsistencies within the affected person inhabitants and laboratory testing. She mentioned well being care professionals have to completely consider and monitor sufferers present process therapy.
Dhindsa cautioned that some males could also be utilizing testosterone remedy for signs for which it’s not indicated.
“[The label change] doesn’t give a clear slate to [health care professionals] who’re giving testosterone therapy to individuals who should not have low testosterone,” Dhindsa mentioned. “[Some clinics] are overtreating males, after which they [need] a phlebotomy to take care of the results of extreme testosterone on hemoglobin. We don’t know whether or not [overtreatment] is CV-safe or not.”
Dobs mentioned well being care professionals ought to study a person’s complete hormone profile and well being standing to find out the etiology of low testosterone ranges earlier than contemplating prescribing testosterone.
“We’d like whole testosterone, free testosterone, follicle-stimulating hormone and luteinizing hormone [levels],” Dobs mentioned. “That offers us a extra complete image of the underlying etiology of hypogonadism.”
Even with strict follow-up protocols, Nissen mentioned there have been a number of adversarial occasions in TRAVERSE that occurred in a better proportion of males within the testosterone group than the placebo group, together with nonfatal arrhythmias (5.2% vs. 3.3%; P = .001), atrial fibrillation (3.5% vs. 2.4; P = .02) and acute kidney damage (2.3% vs. 1.5%; P = .04).
“This isn’t a benign remedy,” Nissen mentioned. “It must be given by specialists rigorously.”
Elevated blood strain can be a priority with testosterone remedy. In TRAVERSE, imply systolic BP elevated by 0.3 mm Hg at 6 months with testosterone in contrast with a 1.5 mm Hg lower for the placebo group (P < .001).
As a part of its testosterone label modifications introduced in February, the FDA mentioned merchandise which have accomplished ambulatory BP monitoring research could have info on elevated BP added to their labels. For merchandise that haven’t accomplished a BP monitoring research, a brand new warning about elevated BP might be added.
Dhindsa mentioned extra information are wanted on systolic BP change with testosterone remedy, as a few of the ambulatory BP research have proven extensive variation amongst people.
“Some folks improve loads and others really lower,” Dhindsa mentioned. “It both doesn’t meet significance or, if it does, it is vitally small. As a clinician, I inform sufferers that there’s a chance testosterone alternative could improve your BP, and that is one thing we’ll keep watch over.”
There have been a couple of considerably elevated adversarial occasion dangers with testosterone, however Morgentaler famous that whereas potential elevated danger for prostate most cancers was one of many largest fears of well being care professionals about testosterone remedy prior to now, in TRAVERSE, the incidence of prostate most cancers was related within the testosterone group in contrast with the placebo group (0.5% vs. 0.4%, respectively; P = .87).
TRAVERSE substudies
TRAVERSE’s main focus was on CV danger with testosterone remedy, however researchers additionally performed a number of substudies to research different outcomes. Among the substudies have raised new questions, comparable to whether or not testosterone will increase fracture danger. In a research revealed in January 2024 in NEJM, males receiving testosterone had larger danger for medical fractures (HR = 1.43; 95% CI, 1.04-1.97; P = .03) and all fractures (HR = 1.52; 95% CI, 1.13-2.05; P = .006) in contrast with males receiving placebo. Dhindsa mentioned the information have been stunning.
“We’ve got a whole lot of research displaying elevated bone density after testosterone therapy,” Dhindsa mentioned. “Everybody anticipated that possibly that testosterone will result in a lower in fracture charges. For some purpose testosterone tended to extend the fracture charges. Nobody is aware of why. The authors don’t know why. This was fully sudden, however one thing that we actually want to research additional.”
Findings have been combined in different analyses. A substudy revealed in The Journal of Scientific Endocrinology & Metabolism in 2023 discovered males receiving testosterone remedy in TRAVERSE had better enhancements in sexual exercise and libido than these within the placebo group, however no enhancements in erectile operate. One other substudy revealed in The Journal of Scientific Endocrinology & Metabolism in 2024 examined testosterone remedy’s impact on melancholy signs. Males receiving testosterone had better enhancements in temper and power than the placebo group. Nevertheless, amongst these with low-grade persistent depressive dysfunction, researchers noticed no distinction in any outcomes, although just one.5% of members in TRAVERSE have been outlined as having persistent depressive dysfunction.
A substudy revealed in JAMA Inner Drugs discovered testosterone remedy was not related to a decrease development from prediabetes to diabetes. Moreover, glucose and HbA1c amongst males with prediabetes and diabetes didn’t differ between the testosterone and placebo teams.
Nissen mentioned the TRAVERSE trial revealed testosterone remedy could not present as many advantages for males as some well being care professionals realized earlier than the trial.
“I’m pleased with the truth that we dominated out CV hurt with one among these merchandise,” Nissen mentioned. “I’m additionally practical about what [testosterone] didn’t do.”
Shifting ahead
With the CV danger warning faraway from testosterone labels, Dhindsa mentioned he believes that testosterone remedy analysis will start to shift. With the TRAVERSE substudies elevating a number of new questions on testosterone alternative, extra trials analyzing the remedy’s impact on a variety of outcomes and circumstances must be pursued, Dhindsa mentioned.
“We must always make investments extra in learning results of testosterone on bone, irritation and our capacity to take care of infections,” Dhindsa mentioned.
Nissen mentioned he want to see one other trial analyzing CV danger with an injectable testosterone product to validate TRAVERSE’s findings, however acknowledged it’s unlikely one other trial will happen.
“Firms won’t ever do a research to find out if there are harms,” Nissen mentioned. “This was finished as a result of FDA demanded it, and I don’t assume they’re going to demand a giant CV end result trial with injectable merchandise.”
Dobs agreed that randomized managed trials stay the “gold commonplace” in analysis, however conducting such trials by which a big pattern dimension is required is difficult with testosterone remedy.
“As digital well being information turn into higher, we would have the ability to get hold of extra registry-oriented information,” Dobs mentioned. “I believe there are different methods we will nonetheless be taking a look at these [questions].”
Dhindsa mentioned he’s unsure whether or not testosterone remedy use will change after the removing of the field warning. A analysis letter revealed in JAMA in 2018 estimated that the proportion of males aged 30 years and older utilizing testosterone remedy within the U.S. elevated from 0.52% in 2002 to three.2% in 2013 earlier than dropping to 1.67% in 2016. Dhindsa mentioned prescription charges by no means returned to the degrees seen earlier than the CV danger warning was added and mentioned he believes that some sufferers will proceed to have considerations even with the warning eliminated.
“I believe there could be a small improve [in testosterone therapy use],” Dhindsa mentioned. “I don’t assume it should end in an awesome change.”
Morgentaler is unsure whether or not well being care professionals might be extra wanting to prescribe testosterone remedy even after the FDA’s labeling modifications. He mentioned testosterone remedy has not been accepted by some physicians resulting from security considerations and well being care professionals must be open to studying extra concerning the remedy.
“I’d encourage physicians, particularly in main care and endocrinology, who’ve been unsure about this matter, based mostly on their prior coaching and their very own perceptions, to be open to [testosterone therapy],” Morgentaler mentioned. “Attempt treating a couple of sufferers. Most of us who’re on this area tried it in a couple of sufferers and we discovered from our sufferers concerning the varieties of advantages it will possibly have of their lives.”
- References:
- Baillargeon J, et al. JAMA. 2018;doi:10.1001/jama.2018.7999.
- Bhasin S, et al. JAMA Intern Med. 2024;doi:10.1001/jamainternmed.2023.7862.
- Bhasin S, et al. J Clin Endocrinol Metab. 2024;doi:10.1210/clinem/dgae026.
- FDA Drug Security Communication: FDA cautions about utilizing testosterone merchandise for low testosterone resulting from growing older; requires labeling change to tell of doable elevated danger of coronary heart assault and stroke with use. https://www.fda.gov/medicine/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due. Printed March 3, 2015. Accessed Might 13, 2025.
- FDA points class-wide labeling modifications for testosterone merchandise. https://www.fda.gov/medicine/drug-safety-and-availability/fda-issues-class-wide-labeling-changes-testosterone-products. Printed Feb. 28, 2025. Accessed Might 13, 2025.
- Finkle WD, et al. PLoS One. 2014;doi:10.1371/journal.pone.0085805.
- Lincoff AM, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215025.
- Morgentaler A, et al. Mayo Clin Proc. 2024;doi:10.1016/j.mayocp.2024.08.008.
- Orwoll E, et al. N Engl J Med. 2023;doi:10.1056/NEJMe2305946.
- Overselling testosterone, dangerously. The New York Occasions editorial board. https://www.nytimes.com/2014/02/05/opinion/overselling-testosterone-dangerously.html. Printed Feb. 4, 2014. Accessed Might 13, 2025.
- Pencina KM, et al. J Clin Endocrinol Metab. 2023;doi:10.1210/clinem/dgad484.
- Snyder PJ, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2308836.
- Vigen R, et al. JAMA. 2013;doi:10.1001/jama.2013.280386.
- For extra info:
- Sandeep Dhindsa, MD, may be reached at sandeep.dhindsa@well being.slu.edu.
- Adrian S. Dobs, MD, MHS, may be reached at adobs@jhmi.edu.
- Abraham Morgentaler, MD, FACS, may be reached at amorgent@bidmc.harvard.edu and on X @drmorgentaler.
- Steven E. Nissen, MD, MACC, may be reached at nissens@ccf.org.
Sources/Disclosures
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Supply:
Healio Interviews
Disclosures:
Dhindsa studies advising for Tolmar and Verity Pharma and talking for Tolmar. Morgentaler studies talking for Besins Healthcare. Dobs and Nissen report no related monetary disclosures.
