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. 2025 Jul 22.
doi: 10.1007/s40256-025-00737-w. Online ahead of print.

Long-Term Cardiovascular Safety of Testosterone-Replacement Therapy in Middle-Aged and Older Men: A Meta-analysis of Randomized Controlled Trials

Marcelo A P Braga #  1 , André Rivera #  2 , Gabriel Marinheiro  3 , Nicole Felix  4 , Pedro E P Carvalho  5 , Douglas Mesadri Gewehr  6 , Larissa Teixeira  4 , Mariana R C Clemente  7 , Pedro C Abrahão Reis  8 , Lucas G C R de Amorim  9 , Alice Deberaldini Marinho  10 , Thiago Bosco Mendes  11 , Francesco Costantini Mesquita  12 , Edoardo Pozzi  13   14 , Ranjith Ramasamy  15
Affiliations

Long-Term Cardiovascular Safety of Testosterone-Replacement Therapy in Middle-Aged and Older Men: A Meta-analysis of Randomized Controlled Trials

Marcelo A P Braga et al. Am J Cardiovasc Drugs. .

Abstract

Introduction: The cardiovascular safety of testosterone-replacement therapy (TRT) for middle-aged and older men with low to low-normal levels of testosterone remains unclear.

Methods: We systematically searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing TRT versus placebo for men aged ≥ 40 years old with hypogonadism or low to low-normal testosterone levels (≤ 14 nmol/L), and at least 12 months of follow-up. We pooled risk ratios (RRs) with 95% confidence intervals (CIs) applying a random-effects model and using R version 4.3.1 for statistical analyses.

Results: We included 23 RCTs comprising 9280 men with testosterone deficiency, of whom 4800 (51.7%) were randomized to TRT. The mean age was 64.6 years, and the baseline total testosterone was 9.17 nmol/L. Placebo and TRT had similar rates of all-cause mortality (RR 0.85; 95% CI 0.60-1.19; p = 0.33). There was a significant increase in the incidence of cardiac arrhythmias (RR 1.53; 95% CI 1.20-1.97; p < 0.01). There was no significant difference between groups in cardiovascular mortality (RR 0.85; 95% CI 0.65-1.12; p = 0.25), stroke (RR 1.00; 95% CI 0.67-1.50; p = 0.99), and myocardial infarction (RR 0.94; 95% CI 0.69-1.28; p = 0.70).

Conclusion: In men with low to low-normal testosterone, aged 40 and above, TRT did not increase all-cause mortality, cardiovascular mortality, stroke, or myocardial infarction, but increased the incidence of cardiac arrhythmias.

Registration: PROSPERO identifier number CRD42024502421.

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Conflict of interest statement

Declarations. Funding: No external funding was used in the preparation of this manuscript. Conflict of Interest: Marcelo A.P. Braga, André Rivera, Gabriel Marinheiro, Nicole Felix, Pedro E.P. Carvalho, Douglas Mesadri Gewehr, Larissa Teixeira, Mariana R. C. Clemente, Pedro C. Abrahão Reis, Lucas G. C. R. de Amorim, Alice Deberaldini Marinho, Thiago Bosco Mendes, Francesco Constantini Mesquita, Edoardo Pozzi, and Ranjith Ramasamy declare that they have no potential conflicts of interest that might be relevant to the contents of this article. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. There were no external funding sources for this study. Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics Approval: Not applicable. Code Availability: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Authors’ Contributions: Concept and design: Braga, Rivera, Felix, Mendes. Systematic Review and study selection: Braga, Rivera, Felix, Marinheiro. Data Curation: Braga, Rivera, Felix, Marinheiro, Carvalho, Gewehr, Teixeira, Clemente, Reis, de Amorim, Marinho. Drafting of the manuscript: Braga, Rivera, Mendes. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Braga, Rivera. Supervision: Mesquita, Pozzi, Ramasamy.

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