madman
Super Moderator
Abstract
IMPORTANCE
Testosterone deficiency causes mild anemia. Whether testosterone replacement therapy (TRT) can correct anemia or prevent the development of anemia in men with hypogonadism remains incompletely understood.
OBJECTIVE
To assess the efficacy of TRT in correcting anemia in men with hypogonadism and anemia, and reducing the risk of developing anemia in those without anemia.
DESIGN, SETTING, AND PARTICIPANTS
This randomized, placebo-controlled trial included men with hypogonadism at 316 US sites enrolled between May 2018 and February 2022. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study, which evaluated the effect of TRTon major adverse cardiovascular events in middle-aged and older men with hypogonadism. Eligible participants were aged 45 to 80 years, with 2 testosterone concentration results below 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. The last study visit took place in January 2023. Data were analyzed between March and August 2023.
INTERVENTION
Participants were randomized with stratification for preexisting CVD to 1.62%testosterone gel or placebo gel daily for the study duration.
MAIN OUTCOMES AND MEASURES
Proportion of participants with anemia (hemoglobin below 12.7 g/dL) whose anemia remitted (hemoglobin 12.7 g/dL or above) over the study duration. Secondary endpoints included the incidence of anemia among men who were not anemic. Binary endpoints were analyzed using repeated-measures log-binomial regression.
RESULTS
A total of 5204 men were included, 815 with anemia (mean [SD] age, 64.8 [7.7] years; 247Black [30.3%], 544 White [66.7%], 24 other [2.9%]) and 4379 without anemia (mean [SD] age, 63.0[7.9] years; 629 Black [14.4%], 3603 White [82.3%], 147 other [3.4%]). Anemia corrected in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (143of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24months (124 of 290 [42.8%] vs 95 of 307 [30.9%]), 36 months (94 of 216 [43.5%] vs 76 of 229[33.2%]), and 48 months (41 of 92 [44.6%] vs 38 of 97 [39.2%]) (P = .002). Among participants without anemia, a significantly smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Changes in hemoglobin were associated with changes in energy levels.
CONCLUSIONS AND RELEVANCE
In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. Among men who were not anemic, a smaller proportion of testosterone-treated men developed anemia than placebo-treated men.
Introduction
Anemia is prevalent in middle-aged and older adults and is associated with impaired quality of life, fatigue, mobility limitation, falls, and increased risk of mortality.6-10 Currently, there is no approved therapy for unexplained anemia that occurs during aging.
Testosterone deficiency causes mild normocytic anemia,11 and nearly 15% of older men with hypogonadism experience anemia.12,13 Testosterone treatment increases hemoglobin.14,15 Secondary analyses of a substudy of the Testosterone Trials (129 participants) reported that testosterone replacement therapy (TRT) increases hemoglobin in older men with hypogonadism and was associated with the correction of anemia.12 However, a large, randomized efficacy trial of TRT in men with hypogonadism and anemia, and with anemia as its primary outcome, has not been conducted. Furthermore, it is unknown whether TRT can prevent the development of anemia in men with hypogonadism.
In 2015, the US Food and Drug Administration directed testosterone manufacturers to conduct a randomized trial to determine whether TRT increases the risk of major adverse cardiovascular events (MACE). To address this regulatory requirement, the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE)Study evaluated the effect of TRT and placebo on MACE.16 The design and the MACE results of the TRAVERSE Study have been published previously.16 The TRAVERSE Anemia Study, nested within the parent TRAVERSE trial, sought to determine the effects of TRT on the correction of anemia in middle-aged and older men with hypogonadism. A secondary aim was to determine the effect of TRT on the development of anemia among participants without anemia at baseline. The study also evaluated whether changes in hemoglobin levels in testosterone-treated men were associated with improvements in energy and cognitive function and whether changes in hematocrit were associated with the risk of MACE and venous thromboembolism (VTE).
Limitations
This study had several limitations. These findings should not be applied to men who are not hypogonadal, women, transgender, and gender diverse people, or to men using supraphysiologic doses of testosterone. Although the TRAVERSE trial’s sample size is to our knowledge the largest of any randomized testosterone trials to date, the sample size of the Anemia Study was defined by the number of randomized participants who had anemia at baseline. The cause of anemia in the enrolled participants was not ascertained. As reported,17 the rates of study medication discontinuation were high although not dissimilar from those in hypogonadal men prescribed TRT in clinical practice.30Randomized trials in other chronic symptomatic conditions, such as menopausal women or chronic pain, tend to have high rates of study medication discontinuation.31,32 The trial was conducted during the SARS-CoV-2 pandemic, which affected retention. The rates of non-retention were similar in the 2 treatment arms, and drug discontinuation would only bias the results toward null. Furthermore, sensitivity analyses in which the endpoints were censored 30 days and 365 days after treatment discontinuation yielded similar results (eFigures 6 and 7 in Supplement 2).
Participants had high rates of obesity, diabetes, CAD, and other risk factors for CAD because eligibility criteria were designed to enroll men with CAD or increased risk of CAD in addition to meeting the criteria for hypogonadism. Surveys of men with hypogonadism33,34 and men receiving in the US,35 and most randomized testosterone trials, including the Testosterone Trials,36 have found high rates of obesity, diabetes, and other chronic conditions. The prevalence of anemia in study participants (15.7%) was similar to other studies of older men with hypogonadism.12
Conclusions
In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. TRT was also associated with a reduced incidence of anemia among men without anemia at baseline.
IMPORTANCE
Testosterone deficiency causes mild anemia. Whether testosterone replacement therapy (TRT) can correct anemia or prevent the development of anemia in men with hypogonadism remains incompletely understood.
OBJECTIVE
To assess the efficacy of TRT in correcting anemia in men with hypogonadism and anemia, and reducing the risk of developing anemia in those without anemia.
DESIGN, SETTING, AND PARTICIPANTS
This randomized, placebo-controlled trial included men with hypogonadism at 316 US sites enrolled between May 2018 and February 2022. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study, which evaluated the effect of TRTon major adverse cardiovascular events in middle-aged and older men with hypogonadism. Eligible participants were aged 45 to 80 years, with 2 testosterone concentration results below 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. The last study visit took place in January 2023. Data were analyzed between March and August 2023.
INTERVENTION
Participants were randomized with stratification for preexisting CVD to 1.62%testosterone gel or placebo gel daily for the study duration.
MAIN OUTCOMES AND MEASURES
Proportion of participants with anemia (hemoglobin below 12.7 g/dL) whose anemia remitted (hemoglobin 12.7 g/dL or above) over the study duration. Secondary endpoints included the incidence of anemia among men who were not anemic. Binary endpoints were analyzed using repeated-measures log-binomial regression.
RESULTS
A total of 5204 men were included, 815 with anemia (mean [SD] age, 64.8 [7.7] years; 247Black [30.3%], 544 White [66.7%], 24 other [2.9%]) and 4379 without anemia (mean [SD] age, 63.0[7.9] years; 629 Black [14.4%], 3603 White [82.3%], 147 other [3.4%]). Anemia corrected in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (143of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24months (124 of 290 [42.8%] vs 95 of 307 [30.9%]), 36 months (94 of 216 [43.5%] vs 76 of 229[33.2%]), and 48 months (41 of 92 [44.6%] vs 38 of 97 [39.2%]) (P = .002). Among participants without anemia, a significantly smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Changes in hemoglobin were associated with changes in energy levels.
CONCLUSIONS AND RELEVANCE
In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. Among men who were not anemic, a smaller proportion of testosterone-treated men developed anemia than placebo-treated men.
Introduction
Anemia is prevalent in middle-aged and older adults and is associated with impaired quality of life, fatigue, mobility limitation, falls, and increased risk of mortality.6-10 Currently, there is no approved therapy for unexplained anemia that occurs during aging.
Testosterone deficiency causes mild normocytic anemia,11 and nearly 15% of older men with hypogonadism experience anemia.12,13 Testosterone treatment increases hemoglobin.14,15 Secondary analyses of a substudy of the Testosterone Trials (129 participants) reported that testosterone replacement therapy (TRT) increases hemoglobin in older men with hypogonadism and was associated with the correction of anemia.12 However, a large, randomized efficacy trial of TRT in men with hypogonadism and anemia, and with anemia as its primary outcome, has not been conducted. Furthermore, it is unknown whether TRT can prevent the development of anemia in men with hypogonadism.
In 2015, the US Food and Drug Administration directed testosterone manufacturers to conduct a randomized trial to determine whether TRT increases the risk of major adverse cardiovascular events (MACE). To address this regulatory requirement, the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE)Study evaluated the effect of TRT and placebo on MACE.16 The design and the MACE results of the TRAVERSE Study have been published previously.16 The TRAVERSE Anemia Study, nested within the parent TRAVERSE trial, sought to determine the effects of TRT on the correction of anemia in middle-aged and older men with hypogonadism. A secondary aim was to determine the effect of TRT on the development of anemia among participants without anemia at baseline. The study also evaluated whether changes in hemoglobin levels in testosterone-treated men were associated with improvements in energy and cognitive function and whether changes in hematocrit were associated with the risk of MACE and venous thromboembolism (VTE).
Limitations
This study had several limitations. These findings should not be applied to men who are not hypogonadal, women, transgender, and gender diverse people, or to men using supraphysiologic doses of testosterone. Although the TRAVERSE trial’s sample size is to our knowledge the largest of any randomized testosterone trials to date, the sample size of the Anemia Study was defined by the number of randomized participants who had anemia at baseline. The cause of anemia in the enrolled participants was not ascertained. As reported,17 the rates of study medication discontinuation were high although not dissimilar from those in hypogonadal men prescribed TRT in clinical practice.30Randomized trials in other chronic symptomatic conditions, such as menopausal women or chronic pain, tend to have high rates of study medication discontinuation.31,32 The trial was conducted during the SARS-CoV-2 pandemic, which affected retention. The rates of non-retention were similar in the 2 treatment arms, and drug discontinuation would only bias the results toward null. Furthermore, sensitivity analyses in which the endpoints were censored 30 days and 365 days after treatment discontinuation yielded similar results (eFigures 6 and 7 in Supplement 2).
Participants had high rates of obesity, diabetes, CAD, and other risk factors for CAD because eligibility criteria were designed to enroll men with CAD or increased risk of CAD in addition to meeting the criteria for hypogonadism. Surveys of men with hypogonadism33,34 and men receiving in the US,35 and most randomized testosterone trials, including the Testosterone Trials,36 have found high rates of obesity, diabetes, and other chronic conditions. The prevalence of anemia in study participants (15.7%) was similar to other studies of older men with hypogonadism.12
Conclusions
In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. TRT was also associated with a reduced incidence of anemia among men without anemia at baseline.
