[메디칼업저버 박선혜 기자] The cardiovascular safety debate surrounding testosterone replacement therapy is expected to be settled.
In a study of hypogonadal men with a history or high risk of cardiovascular disease, testosterone replacement therapy did not increase the risk of major cardiovascular events compared with placebo.
The study, called TRAVERSE, was conducted in 2015 when the US Food and Drug Administration (FDA) raised concerns about the cardiovascular safety of testosterone replacement therapy.
At the time, the FDA said that testosterone replacement therapy had not been proven safe, such as an increased risk of cardiovascular disease, and ordered manufacturers to add a warning warning of the risk of heart attack and stroke on the label of approved testosterone products. .
The results of this study were revealed at the annual meeting of the American Society of Endocrinology (ENDO 2023) held in Chicago, USA on the 15th and 18th, and were published simultaneously in the online edition of the New England Journal of Medicine on the 16th. . Based on the large number of participants in the clinical study and long follow-up, an efficacy assessment is expected to be published later this year.
Primary cardiovascular target frequency, 7.0% in the testosterone group versus 7.3% in the placebo group
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled study of 5246 men aged 45 to 80 years with a history or high risk of cardiovascular disease, hypogonadism, and two fasting testosterone levels <300 ng/dL.
The average age was 63 years, and more than half had a history of cardiovascular disease. Only 15 patients had previously received testosterone replacement therapy.
The entire patient group was randomly assigned to a once-daily treatment group (testosterone concentration maintained between 350 and 750 ng/dL, testosterone group) or a placebo group.
The primary cardiovascular safety endpoint was defined as the first event of cardiovascular death, nonfatal myocardial infarction, or fatal stroke. Secondary endpoints were death from cardiovascular disease, nonfatal myocardial infarction, first fatal stroke, or coronary revascularization.
Primary and secondary endpoints were assessed by time-to-event analysis. Non-inferiority was defined as an upper 95% confidence interval (CI) for the hazard ratio less than 1.5 in the group receiving at least one dose of testosterone or placebo. The average treatment period was 21.7 months, and the average follow-up period was 33.0 months.
As a result of the analysis, the incidence of the primary target point was 7.0% (182 patients) in the testosterone group and 7.3% (190 patients) in the placebo group. There was no significant difference in the risk of developing the primary endpoint between the two groups, and the testosterone group met the criteria for non-inferiority (HR 0.96; 95% CI 0.78 to 1.17; P < 0.001 at for noninferiority).
Results were similar in sensitivity analyzes evaluating data at different time points after discontinuation of testosterone or placebo. All primary target point evaluation factors or secondary target point incidence rates were also similar in the two groups.
There was also no increased risk of prostate cancer during follow-up. The incidence of prostate cancer was 0.5% in the testosterone group and 0.4% in the placebo group, showing no significant difference (P = 0.87).
In terms of effectiveness, the testosterone group significantly improved overall sexual activity (P = 0.011) and sexual symptoms (P < 0.001) for one year compared to the placebo group, and the effect was maintained for two years.
In addition, the incidence of anemia in the testosterone group was low, regardless of anemia at enrollment, and the effect of anemia correction and prevention was confirmed. However, there was no difference between the two groups in the rate of progression from pre-diabetes to diabetes, and glycemic control was not improved in the testosterone group who had diabetes at enrolment.
On the other hand, the incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was higher in the testosterone group. The incidence of pulmonary embolism was 0.9% in the testosterone group and 0.5% in the placebo group, supporting the current guideline for the cautious use of testosterone in men who have had thromboembolism.
The incidence of nonfatal arrhythmias requiring intervention was 5.2% in the testosterone group and 3.3% in the placebo group (P = 0.001), 3.5% and 2.4% (P = 0.02) for atrial fibrillation, and 2.3% and 1.5% ( P=0.02) for acute kidney injury, respectively 0.04), the testosterone group had a significantly higher number of cases.
However, this result only applies to men with testosterone deficiency and symptoms, and caution should be exercised in testosterone replacement therapy for men with normal levels.
“Testosterone deficiency is not life-threatening, so uncertainty about the cardiovascular safety of testosterone replacement therapy burdens medical staff and patient treatment decisions,” said Professor Michael Lincoff of the Cleveland Clinic, who presented the results of the study. “The therapy is not only cardiovascular safe, but also improves sexual function and corrects anemia in older men. Based on this, considering the benefits and possible risks of testosterone replacement therapy in middle-aged and elderly men with hypogonadism will facilitate treatment decisions. ”
“Testosterone deficiency affects quality of life. Many middle-aged and older men want help to improve these symptoms,” said co-author Shalender Bhasin, a professor at Brigham and Women’s Hospital in the United States. “It will change the risk-benefit discussion with patients about whether they should use testosterone replacement therapy for their patients.”
Unexpected result… Fracture risk in the testosterone group?
A notable result was an unexpected increase in fracture risk in the testosterone group. Previous studies have investigated testosterone replacement therapy improving factors related to bone quality in older men and patients with severe hypogonadism.
However, clinically confirmed fractures in this study were 91 in the testosterone group and 64 in the placebo group, and the risk of fracture in the testosterone group was significantly higher 1.43 times (HR 1.43; P = 0.03) .
Professor Peter J. Snyder of the University of Pennsylvania, who published the fracture-related results, said, “Previous studies on testosterone replacement therapy in hypogonadal men were not large enough to evaluate the effect or the follow-up period was not long.” We can speculate the mechanism of this elevation, but we did not conduct research to confirm the mechanism because we did not anticipate such a result. “
