madman
Super Moderator
* our meta-analysis stands as the most up to date analysis restricted to RCTs directed to men aged 40 or older.
* The main fndings were as follows: (1) there were no significant diferences between groups in all-cause mortality, cardiovascular mortality, MI, and stroke; (2) TRT signifcantly increased the incidence of cardiac arrhythmias; (3) TRT was associated with decreased levels of HDL-c; and (4) there was a marginal increase in SBP levels in the TRT group.
Long‑Term Cardiovascular Safety of Testosterone‑Replacement Therapy in Middle‑Aged and Older Men: A Meta‑analysisof Randomized Controlled Trials
Marcelo A. P. Braga1 · André Rivera2 · Gabriel Marinheiro3 · Nicole Felix4 · Pedro E. P. Carvalho5 ·Douglas Mesadri Gewehr6 · Larissa Teixeira4 · Mariana R. C. Clemente7 · Pedro C. Abrahão Reis1 ·Lucas G. C. R. de Amorim8 · Alice Deberaldini Marinho9 · Thiago Bosco Mendes10 · Francesco Costantini Mesquita11 ·Edoardo Pozzi12,13 · Ranjith Ramasamy14
4 Discussion
This systematic review and meta-analysis of 23 RCTs and 9280 patients assessed the long-term cardiovascular efects of TRT in middle-aged and older men with low to low-normal levels of serum testosterone. The main fndings were as follows: (1) there were no signifcant differences between groups in all-cause mortality, cardiovascular mortality, MI, and stroke; (2) TRT signifcantly increased the incidence of cardiac arrhythmias; (3) TRT was associated with decreased levels of HDL-c; and (4) there was a marginal increase in SBP levels in the TRT group.
Previous meta-analyses of observational studies including men with low testosterone levels receiving TRT reported a comparable risk of stroke, MI, and mortality between groups, which corroborates our fndings [53, 54]. However, these prior meta-analyses may have been subject to confounding factors and biases given the inclusion of non randomized data. Therefore, we restricted inclusion in our study to randomized data only.
Previous meta-analyses of RCTs in men with hypogonadism receiving TRT yielded cardiovascular safety results similar to ours [11, 12]. Nevertheless, our study difers from the above as these prior meta-analyses included younger men, who would be at lower risk of cardiovascular events. In contrast, our population was more homogeneous, restricting our inclusion criteria to middle-aged and older men with low to low-normal levels of serum testosterone, as we intended to analyze the impact of TRT among patients exhibiting a heightened cardiovascular risk profle [13, 14]. In addition, unlike prior meta-analyses, we only included studies with atleast 1 year of follow-up. Hence, our meta-analysis stands as the most up to date analysis restricted to RCTs directedto men aged 40 or older.
4.1 Study Limitations
This study has limitations. First, there was a slight variationin the defnition of low and low-normal testosterone levels, as well as in TRT protocols, including dosages, medications, and application methods across studies, which are detailed in the electronic supplementary material. To address these limitations, we performed subgroup analyses of the main outcomes according to serum total testosterone cutofs and TRT protocols in individual studies, with results similar to the overall analysis. This increases the generalizability of our analysis despite some diferences in the defnitions of low testosterone levels and TRT protocols. Second, the TRAVERSE trial exerted a substantial infuence in some analyses. However, we performed leave-one-out sensitivity analyses for all outcomes, which yielded consistent results to the pooled analysis of all trials. Third, we could not perform a dedicated analysis of diferent types of cardiac arrhythmias due to the absence of patient-level data and stratifed reporting of arrhythmia subtypes by individual studies. Finally, the lack of patient-level data also prevented a more robust assessment of factors potentially related to the safety of TRT versus placebo, such as age, diabetes, and established cardiovascular disease.
5 Conclusion
In men aged 40 and above with low to low-normal testosterone levels, TRT did not increase all-cause mortality, cardiovascular mortality, stroke, or MI, albeit with an increase in the incidence of cardiac arrhythmias as compared with placebo. Our fndings support TRT as an overall safe therapy from a cardiovascular perspective for middle-aged and older men with low to low-normal levels of testosterone who may otherwise beneft from androgen therapy.
* The main fndings were as follows: (1) there were no significant diferences between groups in all-cause mortality, cardiovascular mortality, MI, and stroke; (2) TRT signifcantly increased the incidence of cardiac arrhythmias; (3) TRT was associated with decreased levels of HDL-c; and (4) there was a marginal increase in SBP levels in the TRT group.
Long‑Term Cardiovascular Safety of Testosterone‑Replacement Therapy in Middle‑Aged and Older Men: A Meta‑analysisof Randomized Controlled Trials
Marcelo A. P. Braga1 · André Rivera2 · Gabriel Marinheiro3 · Nicole Felix4 · Pedro E. P. Carvalho5 ·Douglas Mesadri Gewehr6 · Larissa Teixeira4 · Mariana R. C. Clemente7 · Pedro C. Abrahão Reis1 ·Lucas G. C. R. de Amorim8 · Alice Deberaldini Marinho9 · Thiago Bosco Mendes10 · Francesco Costantini Mesquita11 ·Edoardo Pozzi12,13 · Ranjith Ramasamy14
4 Discussion
This systematic review and meta-analysis of 23 RCTs and 9280 patients assessed the long-term cardiovascular efects of TRT in middle-aged and older men with low to low-normal levels of serum testosterone. The main fndings were as follows: (1) there were no signifcant differences between groups in all-cause mortality, cardiovascular mortality, MI, and stroke; (2) TRT signifcantly increased the incidence of cardiac arrhythmias; (3) TRT was associated with decreased levels of HDL-c; and (4) there was a marginal increase in SBP levels in the TRT group.
Previous meta-analyses of observational studies including men with low testosterone levels receiving TRT reported a comparable risk of stroke, MI, and mortality between groups, which corroborates our fndings [53, 54]. However, these prior meta-analyses may have been subject to confounding factors and biases given the inclusion of non randomized data. Therefore, we restricted inclusion in our study to randomized data only.
Previous meta-analyses of RCTs in men with hypogonadism receiving TRT yielded cardiovascular safety results similar to ours [11, 12]. Nevertheless, our study difers from the above as these prior meta-analyses included younger men, who would be at lower risk of cardiovascular events. In contrast, our population was more homogeneous, restricting our inclusion criteria to middle-aged and older men with low to low-normal levels of serum testosterone, as we intended to analyze the impact of TRT among patients exhibiting a heightened cardiovascular risk profle [13, 14]. In addition, unlike prior meta-analyses, we only included studies with atleast 1 year of follow-up. Hence, our meta-analysis stands as the most up to date analysis restricted to RCTs directedto men aged 40 or older.
4.1 Study Limitations
This study has limitations. First, there was a slight variationin the defnition of low and low-normal testosterone levels, as well as in TRT protocols, including dosages, medications, and application methods across studies, which are detailed in the electronic supplementary material. To address these limitations, we performed subgroup analyses of the main outcomes according to serum total testosterone cutofs and TRT protocols in individual studies, with results similar to the overall analysis. This increases the generalizability of our analysis despite some diferences in the defnitions of low testosterone levels and TRT protocols. Second, the TRAVERSE trial exerted a substantial infuence in some analyses. However, we performed leave-one-out sensitivity analyses for all outcomes, which yielded consistent results to the pooled analysis of all trials. Third, we could not perform a dedicated analysis of diferent types of cardiac arrhythmias due to the absence of patient-level data and stratifed reporting of arrhythmia subtypes by individual studies. Finally, the lack of patient-level data also prevented a more robust assessment of factors potentially related to the safety of TRT versus placebo, such as age, diabetes, and established cardiovascular disease.
5 Conclusion
In men aged 40 and above with low to low-normal testosterone levels, TRT did not increase all-cause mortality, cardiovascular mortality, stroke, or MI, albeit with an increase in the incidence of cardiac arrhythmias as compared with placebo. Our fndings support TRT as an overall safe therapy from a cardiovascular perspective for middle-aged and older men with low to low-normal levels of testosterone who may otherwise beneft from androgen therapy.
