Efficacy of Testosterone Replacement Therapy in Correcting Anemia in Men With Hypogonadism: A Randomized Clinical Trial

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 TRT on 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 end points included incidence of anemia among men who were not anemic. Binary end points 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; 247 Black [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 (143 of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24 months (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 level.

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.

Trial registration: ClinicalTrials.gov Identifier: NCT03518034.

Figure 1.. Study Flow Diagram

All randomized participants who could be classified as having anemia or not having anemia at baseline and met the eligibility criteria for the parent trial as well as the anemia study were included in the analysis. As this was an event-driven trial and the trial design required the participants to be followed up until the accrual of 256 adjudicated major adverse cardiovascular events. Participants were considered on study if their last visit date in the trial database fell within or after the defined visit window. All randomized participants were included in the primary and secondary analyses if they had at least 1 postbaseline hemoglobin value.

Figure 2.. Correction of Anemia Among Participants Who Had Anemia at Baseline

Frequencies and relative risks of correction of anemia in the testosterone replacement therapy (TRT) group relative to placebo group and 95% CIs at each visit in men who had anemia at baseline are shown by treatment group and time point. The omnibus test P value shown in the figure is a test of the null hypothesis of no difference between TRT and placebo groups across all time points.

Figure 3.. Men With Hemoglobin Increase in Participants Who Had Anemia at Baseline

Frequencies and relative risks of hemoglobin increase of more than 1.0 g/dL above baseline in the TRT group relative to the placebo group and the associated 95% CIs at each visit in men who had anemia at baseline are shown by treatment group and time point. The risk ratio of hemoglobin increase of more than 1.0 g/dL in the TRT vs placebo group was estimated by a repeated measures log-binomial regression with fixed effects for treatment, visit, treatment-visit interaction, preexisting cardiovascular disease, and a random per-subject repeated measures effect using an unstructured covariance matrix. The omnibus test P value shown in the figure is a test of the null hypothesis of no difference between TRT and placebo groups across all time points.

Figure 4.. Incidence of Anemia in Participants Who Did Not Have Anemia at Baseline

Frequencies and relative risks of incident anemia in the TRT group relative to placebo and 95% CIs at each visit in men who did not have anemia at baseline are shown by treatment group and time point. The risk ratio of incident anemia in the TRT vs placebo group was estimated by a repeated measures log-binomial regression with fixed effects for treatment, visit, treatment-visit interaction, preexisting cardiovascular disease, and a random per-subject repeated measures effect using an unstructured covariance matrix. The omnibus test P value shown in the figure is a test of the null hypothesis of no difference between TRT and placebo groups across all time points.