Nissen S, et al. SY-038. Presented at: ENDO Annual Meeting; June 15-18, 2023; Chicago.
Bhasin reports receiving consulting fees from Novartis; receiving grant funding from AbbVie, FPT, MIB, the NIH and Transition Therapeutics; and owning stock in FPT and Xyone. Lincoff reports serving on an advisory board for Novo Nordisk; receiving consultant fees from Akebia, Ardelyx, Becton Dixon, Eli Lilly, Endologix, Fibrogen, GlaxoSmithKline, Medtronic, Novo Nordisk, Provention Bio and Veralox; receiving grant funding from AbbVie, AstraZeneca, CSL Behring, Esperion and Novartis; and owning stock in Cadrenal. Nissen reports receiving grant funding from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion, Novartis and Silence Therapeutics. Snyder reports receiving grant funding from AbbVie. Please see the study for all other authors’ relevant financial disclosures.
- Men receiving testosterone in the TRAVERSE trial had a similar risk for major adverse CV events compared with placebo.
- An increased risk for fractures was observed with men receiving testosterone therapy.
CHICAGO — Older men with hypogonadism and high risk for cardiovascular disease who received testosterone therapy had similar rates of CV events as those who received placebo, according to findings from the TRAVERSE trial.
In data presented at ENDO 2023 and simultaneously published in The New England Journal of Medicine, the use of testosterone therapy among men aged 45 to 80 years with hypogonadism and preexisting CVD or high risk for CVD was considered noninferior to placebo, with CV events occurring in 7% of men receiving testosterone and 7.3% of men receiving placebo.
“These findings of CV safety should facilitate more informed consideration of potential benefits and risks of testosterone treatment for middle-aged and older men with hypogonadism,” A. Michael Lincoff, MD, vice chair for research, cardiovascular medicine and professor of medicine at Cleveland Clinic, said during the presentation. “But, these results apply only to men with hypogonadal symptoms and measured low testosterone levels and should not be used to justify treatment in other populations not studied in the trial.”
CV risk similar between testosterone, placebo groups
The TRAVERSE trial was an FDA-mandated trial to analyze the risk for myocardial infarction and stroke among men using testosterone therapy. The presenters said the trial followed concerns over an increased risk for CV events among men using testosterone in the early 2010s. Steven E. Nissen, MD, study chair of the TRAVERSE trial, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said previous studies found mixed results as to whether testosterone therapy increases CV risk among men with hypogonadism.
A. Michael Lincoff
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial in which 5,204 men aged 45 to 80 years with at least one symptom of hypogonadism, two fasting serum testosterone levels of less than 300 ng/dL and preexisting CVD or elevated CV risk were randomly assigned, 1:1, to transdermal 1.62% testosterone gel (AbbVie) or matching placebo gel daily. Gel was administered through metered-dose pumps. Blood samples were collected at 2, 4, 12 and 26 weeks, followed by 12, 18, 24, 36 and 48 months. The primary endpoint was first occurrence of a major adverse cardiac event, defined as a composite of death from CV causes, nonfatal MI or nonfatal stroke. A secondary endpoint was first occurrence of any death from CV causes, nonfatal MI, nonfatal stroke or coronary revascularization.
“This population of patients are those at highest risk, which was the concern of the FDA and many of the medical community,” Lincoff said.
The CV safety analysis included 2,601 men who received testosterone and 2,603 who received placebo included. Median testosterone was 227 ng/dL at baseline. The mean duration of treatment was 21.8 months in the testosterone group and 21.6 months with placebo. Mean follow-up was 33.1 months in the testosterone group and 32.9 months in the placebo group. The testosterone group had a 148 ng/dL increase in serum testosterone at 12 months.
Steven E. Nissen
There was no difference in major adverse CV events between the testosterone and placebo groups. The findings were similar in sensitivity analyses that censored events occurring more than 1 year after the last dose or events occurring more than 30 days after the last dose or interruption of treatment. No meaningful differences were found in any secondary endpoint events between the two groups, according to the researchers.
During a Q&A session following the presentation, Nissen noted one of the study’s limitations was a short duration of treatment and mean follow-up time. However, he said he believes that the trial fulfilled the mandate set by the FDA.
“The study does provide information that practitioners can use to have informed discussions with their patients,” Nissen said.
Increased risk for fractures observed with testosterone
In addition to CV safety data, researchers presented findings from five substudies to analyze the effects of testosterone therapy on prostate safety, anemia, diabetes, sexual function and fractures.
Participants in TRAVERSE were asked if they had a fracture during each trial visit. Reported fractures were adjudicated before being labeled as confirmed, unconfirmed or uncertain.
There were 154 confirmed fractures in the testosterone group compared with 97 in the placebo group. Men receiving testosterone had a higher risk for sustaining a clinical fracture compared with men receiving placebo (HR = 1.43; 95% CI, 1.04-1.97; P = .03). The risk for all fractures was also higher in the testosterone group compared with placebo (HR = 1.52; 95% CI, 1.13-2.05; P = .006).
Findings from the fracture substudy were surprising, according to Peter J. Snyder, MD, professor of medicine at the University of Pennsylvania and medical director of the Penn Pituitary Center.
“If testosterone improves bone quality, why does it increase the risk for fracture?” Snyder said. “We can speculate about the possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism.”
No differences in prostate cancer risk, progression to diabetes
In the prostate safety substudy, researchers analyzed the incidence of high-grade prostate cancer among men receiving testosterone vs. placebo. Men were considered for a urological referral and possible biopsy if they had a confirmed prostate-specific antigen test increase of more than 1.4 ng/mL above baseline in the first year of treatment, a confirmed test of more than 4 ng/mL at any time, or a prostate nodule or induration.
The researchers found no difference in prostate cancer or prostate event rates compared with placebo. The overall incidence of prostate cancer was low in the full cohort, with 12 men in the testosterone group and 11 in the placebo group diagnosed with prostate cancer. There was no difference in lower urinary tract symptoms between the groups.
“It is possible that the viewing of video and shared decision-making played a role in low rates of prostate biopsy and overall low rates of cancer detection,” Shalender Bhasin, MD, professor of medicine at Harvard Medical School, director of the research program in Men’s Health: Aging and Metabolism and director of the Boston Claude D. Pepper Older Americans Independence Center at Brigham and Women’s Hospital, said during the presentation.
Another substudy analyzed the rate of progression from prediabetes to diabetes in TRAVERSE participants. The substudy included 607 men in the testosterone group and 568 in the placebo group who had prediabetes at baseline. In the study, there was no difference in the rate of men who progressed to diabetes between the two groups at any timepoint. There was slightly lower HbA1c among men with prediabetes receiving testosterone compared with placebo at 48 months, but the difference was not deemed to be clinically meaningful, according to Bhasin.
In an analysis of data from 1,917 men in the testosterone group and 1,963 men in the placebo group with diabetes at baseline, the percentage of men who had diabetes remission was similar between the two groups.
Testosterone corrects anemia, improves sexual function
In the anemia substudy, researchers collected data from men who had anemia at baseline to analyze the prevalence of anemia correction. There were 390 men receiving testosterone and 425 men receiving placebo with anemia at baseline. Men in the testosterone group were more likely to have anemia correction at 6, 12, 24 and 36 months compared with placebo.
In an analysis of men who did not have anemia at baseline, the testosterone group had a lower risk for incident anemia at 6, 12 and 24 months compared with placebo.
Researchers also analyzed the effect of testosterone on sexual activity and hypogonadism symptoms. Using the Psychosexual Daily Questionnaire – Question 4 survey, men receiving testosterone reported more sexual activities than those receiving placebo (P = .011). Men in the testosterone group who completed the Hypogonadism Impact of Symptoms Questionnaire reported fewer hypogonadism symptoms than men receiving placebo (P < .001).
“Testosterone treatment was more efficacious than placebo in improving overall sexual activity in middle-aged and older men with hypogonadism who had low libido,” Bhasin said. “The improvements in sexual activity over 1 year were maintained over 2 years of treatment.”
- Lincoff AM, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215025.