madman
Super Moderator
Cardiovascular Morbidity and Mortality in Men − Findings From a Meta-analysis on the Time-related Measure of Risk of Exogenous Testosterone (2022)
Giuseppe Fallara, MD, Edoardo Pozzi, MD, Federico Belladelli, MD, Christian Corsini, MD, Luca Boeri, MD, Paolo Capogrosso, MD, Francesco Montorsi, MD, and Andrea Salonia, MD, PhD, FECSM
Abstract
Background: In the context of established male hypogonadism, testosterone therapy (TTh) has been employed to regain physiologic levels of circulating testosterone and improve sexual function and overall quality of life.
Aim: To assess the risk of cardiovascular disease and mortality as time-dependent outcomes in treated vs TTh untreated hypogonadal men.
Methods: A meta-analysis using weighted time-related measures of risk (hazard ratios (HRs)) for each of the outcomes for all included studies was performed. Studies investigating male adults (≥18 years old) diagnosed with hypogonadism and divided into 2 arms (a treatment arm [any TTh] and a control arm [observation or placebo]) and assessing the risk of death and/or cardiovascular events were included. Single arm, non-comparative studies were excluded as well as studies that did not report the HRs for the chosen outcomes. This systemic review was registered on PROSPERO (CRD42022301592) and performed according to MOOSE and PRISMA guidelines.
Outcomes: Overall mortality and cardiovascular events of any type.
Results: Overall, 10 studies were included in the meta-analysis, involving 179,631 hypogonadal men. Hypogonadal men treated with TTh were found to be at lower mortality risk from all causes relative to the control (observation or placebo) arm (HR: 0.70; 95% Confidence Interval [CI]: 0.54−0.90; P < .01), whilst any unfavorable effect of TTh in hypogonadal men in terms of cardiovascular events compared to untreated/observed hypogonadal men was found (HR: 0.98; 95% CI 0.73−1.33; P=.89).
Clinical implications: TTh in hypogonadal men might play a role in reducing the overall risk of death without increasing cardiovascular events risk.
Strengths & Limitations: Main limitations are represented by the high heterogeneity among the studies in terms of included population, the definition for hypogonadism, type of TTh, the definition of cardio-vascular event used, and the length of follow-up.
Conclusion: According to time-related measures of risk only, an increased risk of long-term morbidity and early mortality for untreated hypogonadal men was depicted, further outlining the clinical importance and safety of TTh in true hypogonadal men, with the urgent need of collecting long-term follow-up data.
INTRODUCTION
Published studies showed that primary hypogonadal men are at increased risk of cardiovascular events, newly-diagnosed cancers, and greater mortality rates, thus supporting the concept of the need to achieve testosterone levels within physiological ranges to prevent potential consequences of hypogonadism.1−7 However, data are not always unidirectional, as the findings of the UK Biobank prospective cohort study of community-dwelling men aged 40−69 years old, followed for 11 years, showed that lower serum testosterone was independently associated with higher all-cause and cancer-related, but not cardiovascular diseases-related, mortality in middle-aged to older men.8 Rationally, the same study depicted that lower serum sex hormone-binding globulin (SHBG) is independently associated with lower all-cause, cardiovascular diseases-related, and cancer-related mortality.8
Overall, the goal of testosterone therapy (TTh) is ideally to establish and maintain secondary sexual characteristics, sexual function, body composition, and quality of life and eventually ameliorate overall men’s health status by preventing cardiometabolic disorders, oncological malignancies and decreasing the risk of death, at least in some subpopulations.9−15 In this context, the effects of exogenous testosterone are still scantly analyzed and unknown, as it exerts a wide range of effects on various organs. Data regarding the long-term safety of TTh on overall men’s health, cancer development, and cardiovascular disease onset remained uncertain because of the lack of adequately powered trials investigating the long-term impact of such a therapy in hypogonadal men. An early suggestion of potential cardiovascular risks and increase mortality associated with the use of exogenous testosterone came from the prematurely terminated Testosterone in Older Men with Mobility Limitations (TOM) trial.16 Several meta-analyses investigated the role of TTh in promoting cardiovascular events and mortality in hypogonadal men, with conflicting findings. Some reports suggested an increase in cardiovascular risk,17,18 whilst others showed no effect.19−21 Of note, most of those studies are based on underpowered small retrospective investigations or prospective randomized and non−randomized trials, where mortality and cardiovascular events have been analyzed only as secondary outcomes. In addition, in most of the published meta-analyses, these 2 outcomes were analyzed as non-time related events, that is, by the use of relative-risk or odds-ratio, with potential undisclosed relevant biases.
*Thus, the aim of the current systematic review and meta-analysis is to summarize available evidence of the effect of TTh (whether injection, oral, or topical) on the risk of cardiovascular events and mortality as compared with placebo/observation in truly hypogonadal men by the use of a time-related measure of risk (ie, hazard ratios [HRs]).
DISCUSSION
Much has been said about the association between circulating testosterone and overall men’s health. Thereof, we focused our attention on the specific target of exogenous testosterone as a potential key player in men’s health (namely, cardiovascular morbidity and overall mortality) considering those studies which had applied only time-related measures of risk.
Novel findings of this meta-analysis showed that in hypogonadal males the use of TTh to recover physiological levels of circulating hormone is not associated with an increased risk of cardiovascular diseases as a time-dependent outcome. Likewise, TTh was not associated with greater mortality risk in hypogonadal men, where TTh might instead be even protective toward the risk of death compared to the condition of untreated hypogonadism.
In conclusion, the current meta-analysis, which has only considered time-related measures of risk, did not find an association between TTh and major cardiovascular events while a protective role of TTh emerged for overall mortality when compared to hypogonadal men who did not receive TTh. These results are consistent with most of the current literature. A meta-analysis taking into consideration 75 different placebo-controlled randomized trials observed no increase in cardiovascular risk in men with metabolic disorders.21 Fernandez-Balsells et al., in a meta-analysis including randomized and nonrandomized studies, observed no differences in all-cause mortality, the incidence of coronary bypass surgery, or myocardial infarction when comparing men who did with those who did not.20 Similarly, the evidence regarding the association between low levels of endogenous testosterone and the mortality risk from all-cause and from cardiovascular events are quite convincing. In this context, in a huge population-based study, Haring et al. found that low testosterone levels were linked with an increased risk of mortality.43 Moreover, Belladelli et al. using data from a population of men included in the National Health and Nutrition Examination Survey (NHANES) observed that those with low testosterone-to-estradiol ratio had a higher risk of cardiovascular mortality.44 A recent randomized clinical trial from Wittert et al., found that men aged 50−74 years with T2DM or impaired glucose tolerance and a serum testosterone concentration of 14 nmol/L or lower who randomly received intramuscular testosterone or placebo for 2 years did not show any difference in terms of cardiovascular events or mortality.45 Lastly, in a meta-analysis from Araujo et al. it was shown that low testosterone levels were associated with both increased all-cause and cardiovascular-related mortality.46
The rationale behind our study derives from the consideration that a true condition of hypogonadism may actually be associated with a greater risk of developing different morbidities − including cardiovascular problems − and even greater mortality risk as compared with the eugonadal status. However, to try and rigorously answer this doubt, we have inversely reasoned, thus developing a systematic review and meta-analysis to summarize available evidence of the effect of TTh on both those risks compared to either placebo treatment or observation in hypogonadal men via the use of time-related measures of risk (ie, HRs). This is in contrast with most of the published meta-analyses on the same topics, where ORs have been used as measures of the effect of TTh in hypogonadal men. However, this latter approach does not consider the time-to-event nature of data on either cardiovascular events or mortality, thus possibly biasing the results of pooled analyses. In addition, for several studies included in most of the previously published meta-analyses, cardiovascular events and mortality were secondary/safety outcomes and there were few events of that specific type for each of the included studies or an inadequate length of follow-up.47,48 To overcome these limitations and according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 6.2, 2021) - where it is stated that “the most appropriate way of summarizing time-to-event data is to use methods of survival analysis and express the intervention effect as a hazard ratio” - HRs from Cox models of the studies included in the current meta-analysis was used as a measure of effects for both cardiovascular events and mortality.49 In addition, most of the included studies are population registry-based studies with thousands of patients and hundreds of events analyzed.
Notwithstanding this approach is a strength of the analysis, this study is certainly not devoid of limitations. First, the criterion for identifying hypogonadal men is still one of the biggest challenges in everyday clinical practice,10,11,14,42 particularly when considering different laboratory thresholds, a different number of testosterone assessments and measurement units among studies, different laboratory techniques, and the modality and time of blood withdrawal. The definition of hypogonadism used across the included studies ranged from a rigorous application of the definition according to the international guidelines (serum testosterone deficiency and symptoms) to the identification of patients likely hypogonadic on the sole base of a TTh prescription. No subanalysis was possible for those who were correctly identified as hypogonadic only, according to the international guideline’s definition. However, since the benefit of TTh emerged also in our more heterogeneous cohort, it is likely that this benefit of TTh in terms of decreased cardiovascular risk, might be more evident in the correct (“true”) hypogonadic population where the risk of major cardiovascular events is more pronounced. Second, some of the available studies did evaluate different sub-populations of patients (eg, patients with a previous history of known cardiovascular disease, patients with and without recovery of normal serum total testosterone levels, etc.) therefore resulting in a wide source of heterogeneity. Third, most published studies presented different lengths of follow-up, thus further contributing to the heterogeneity of the reported data. In addition, another source of heterogeneity was the TTh modality, varying in terms of dose, route of administration, and duration of treatment. Finally, given the retrospective nature of most of the included studies, there may be the risk of possible unmeasured biases. Given all these limitations, the risk of unmeasured biases, and the high heterogeneity of works published until now, the design of well-powered, prospective randomized control trials is of utmost importance.
CONCLUSION
The findings of this meta-analysis rigorously based on the use of time-related measures of risk only showed an increased risk of long-term morbidity and early mortality for untreated hypogonadal men, while further outlining the clinical importance and safety of testosterone therapy in true hypogonadal men deserving to be treated, with the urgent need of collecting long-term follow-up data.
Giuseppe Fallara, MD, Edoardo Pozzi, MD, Federico Belladelli, MD, Christian Corsini, MD, Luca Boeri, MD, Paolo Capogrosso, MD, Francesco Montorsi, MD, and Andrea Salonia, MD, PhD, FECSM
Abstract
Background: In the context of established male hypogonadism, testosterone therapy (TTh) has been employed to regain physiologic levels of circulating testosterone and improve sexual function and overall quality of life.
Aim: To assess the risk of cardiovascular disease and mortality as time-dependent outcomes in treated vs TTh untreated hypogonadal men.
Methods: A meta-analysis using weighted time-related measures of risk (hazard ratios (HRs)) for each of the outcomes for all included studies was performed. Studies investigating male adults (≥18 years old) diagnosed with hypogonadism and divided into 2 arms (a treatment arm [any TTh] and a control arm [observation or placebo]) and assessing the risk of death and/or cardiovascular events were included. Single arm, non-comparative studies were excluded as well as studies that did not report the HRs for the chosen outcomes. This systemic review was registered on PROSPERO (CRD42022301592) and performed according to MOOSE and PRISMA guidelines.
Outcomes: Overall mortality and cardiovascular events of any type.
Results: Overall, 10 studies were included in the meta-analysis, involving 179,631 hypogonadal men. Hypogonadal men treated with TTh were found to be at lower mortality risk from all causes relative to the control (observation or placebo) arm (HR: 0.70; 95% Confidence Interval [CI]: 0.54−0.90; P < .01), whilst any unfavorable effect of TTh in hypogonadal men in terms of cardiovascular events compared to untreated/observed hypogonadal men was found (HR: 0.98; 95% CI 0.73−1.33; P=.89).
Clinical implications: TTh in hypogonadal men might play a role in reducing the overall risk of death without increasing cardiovascular events risk.
Strengths & Limitations: Main limitations are represented by the high heterogeneity among the studies in terms of included population, the definition for hypogonadism, type of TTh, the definition of cardio-vascular event used, and the length of follow-up.
Conclusion: According to time-related measures of risk only, an increased risk of long-term morbidity and early mortality for untreated hypogonadal men was depicted, further outlining the clinical importance and safety of TTh in true hypogonadal men, with the urgent need of collecting long-term follow-up data.
INTRODUCTION
Published studies showed that primary hypogonadal men are at increased risk of cardiovascular events, newly-diagnosed cancers, and greater mortality rates, thus supporting the concept of the need to achieve testosterone levels within physiological ranges to prevent potential consequences of hypogonadism.1−7 However, data are not always unidirectional, as the findings of the UK Biobank prospective cohort study of community-dwelling men aged 40−69 years old, followed for 11 years, showed that lower serum testosterone was independently associated with higher all-cause and cancer-related, but not cardiovascular diseases-related, mortality in middle-aged to older men.8 Rationally, the same study depicted that lower serum sex hormone-binding globulin (SHBG) is independently associated with lower all-cause, cardiovascular diseases-related, and cancer-related mortality.8
Overall, the goal of testosterone therapy (TTh) is ideally to establish and maintain secondary sexual characteristics, sexual function, body composition, and quality of life and eventually ameliorate overall men’s health status by preventing cardiometabolic disorders, oncological malignancies and decreasing the risk of death, at least in some subpopulations.9−15 In this context, the effects of exogenous testosterone are still scantly analyzed and unknown, as it exerts a wide range of effects on various organs. Data regarding the long-term safety of TTh on overall men’s health, cancer development, and cardiovascular disease onset remained uncertain because of the lack of adequately powered trials investigating the long-term impact of such a therapy in hypogonadal men. An early suggestion of potential cardiovascular risks and increase mortality associated with the use of exogenous testosterone came from the prematurely terminated Testosterone in Older Men with Mobility Limitations (TOM) trial.16 Several meta-analyses investigated the role of TTh in promoting cardiovascular events and mortality in hypogonadal men, with conflicting findings. Some reports suggested an increase in cardiovascular risk,17,18 whilst others showed no effect.19−21 Of note, most of those studies are based on underpowered small retrospective investigations or prospective randomized and non−randomized trials, where mortality and cardiovascular events have been analyzed only as secondary outcomes. In addition, in most of the published meta-analyses, these 2 outcomes were analyzed as non-time related events, that is, by the use of relative-risk or odds-ratio, with potential undisclosed relevant biases.
*Thus, the aim of the current systematic review and meta-analysis is to summarize available evidence of the effect of TTh (whether injection, oral, or topical) on the risk of cardiovascular events and mortality as compared with placebo/observation in truly hypogonadal men by the use of a time-related measure of risk (ie, hazard ratios [HRs]).
DISCUSSION
Much has been said about the association between circulating testosterone and overall men’s health. Thereof, we focused our attention on the specific target of exogenous testosterone as a potential key player in men’s health (namely, cardiovascular morbidity and overall mortality) considering those studies which had applied only time-related measures of risk.
Novel findings of this meta-analysis showed that in hypogonadal males the use of TTh to recover physiological levels of circulating hormone is not associated with an increased risk of cardiovascular diseases as a time-dependent outcome. Likewise, TTh was not associated with greater mortality risk in hypogonadal men, where TTh might instead be even protective toward the risk of death compared to the condition of untreated hypogonadism.
In conclusion, the current meta-analysis, which has only considered time-related measures of risk, did not find an association between TTh and major cardiovascular events while a protective role of TTh emerged for overall mortality when compared to hypogonadal men who did not receive TTh. These results are consistent with most of the current literature. A meta-analysis taking into consideration 75 different placebo-controlled randomized trials observed no increase in cardiovascular risk in men with metabolic disorders.21 Fernandez-Balsells et al., in a meta-analysis including randomized and nonrandomized studies, observed no differences in all-cause mortality, the incidence of coronary bypass surgery, or myocardial infarction when comparing men who did with those who did not.20 Similarly, the evidence regarding the association between low levels of endogenous testosterone and the mortality risk from all-cause and from cardiovascular events are quite convincing. In this context, in a huge population-based study, Haring et al. found that low testosterone levels were linked with an increased risk of mortality.43 Moreover, Belladelli et al. using data from a population of men included in the National Health and Nutrition Examination Survey (NHANES) observed that those with low testosterone-to-estradiol ratio had a higher risk of cardiovascular mortality.44 A recent randomized clinical trial from Wittert et al., found that men aged 50−74 years with T2DM or impaired glucose tolerance and a serum testosterone concentration of 14 nmol/L or lower who randomly received intramuscular testosterone or placebo for 2 years did not show any difference in terms of cardiovascular events or mortality.45 Lastly, in a meta-analysis from Araujo et al. it was shown that low testosterone levels were associated with both increased all-cause and cardiovascular-related mortality.46
The rationale behind our study derives from the consideration that a true condition of hypogonadism may actually be associated with a greater risk of developing different morbidities − including cardiovascular problems − and even greater mortality risk as compared with the eugonadal status. However, to try and rigorously answer this doubt, we have inversely reasoned, thus developing a systematic review and meta-analysis to summarize available evidence of the effect of TTh on both those risks compared to either placebo treatment or observation in hypogonadal men via the use of time-related measures of risk (ie, HRs). This is in contrast with most of the published meta-analyses on the same topics, where ORs have been used as measures of the effect of TTh in hypogonadal men. However, this latter approach does not consider the time-to-event nature of data on either cardiovascular events or mortality, thus possibly biasing the results of pooled analyses. In addition, for several studies included in most of the previously published meta-analyses, cardiovascular events and mortality were secondary/safety outcomes and there were few events of that specific type for each of the included studies or an inadequate length of follow-up.47,48 To overcome these limitations and according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 6.2, 2021) - where it is stated that “the most appropriate way of summarizing time-to-event data is to use methods of survival analysis and express the intervention effect as a hazard ratio” - HRs from Cox models of the studies included in the current meta-analysis was used as a measure of effects for both cardiovascular events and mortality.49 In addition, most of the included studies are population registry-based studies with thousands of patients and hundreds of events analyzed.
Notwithstanding this approach is a strength of the analysis, this study is certainly not devoid of limitations. First, the criterion for identifying hypogonadal men is still one of the biggest challenges in everyday clinical practice,10,11,14,42 particularly when considering different laboratory thresholds, a different number of testosterone assessments and measurement units among studies, different laboratory techniques, and the modality and time of blood withdrawal. The definition of hypogonadism used across the included studies ranged from a rigorous application of the definition according to the international guidelines (serum testosterone deficiency and symptoms) to the identification of patients likely hypogonadic on the sole base of a TTh prescription. No subanalysis was possible for those who were correctly identified as hypogonadic only, according to the international guideline’s definition. However, since the benefit of TTh emerged also in our more heterogeneous cohort, it is likely that this benefit of TTh in terms of decreased cardiovascular risk, might be more evident in the correct (“true”) hypogonadic population where the risk of major cardiovascular events is more pronounced. Second, some of the available studies did evaluate different sub-populations of patients (eg, patients with a previous history of known cardiovascular disease, patients with and without recovery of normal serum total testosterone levels, etc.) therefore resulting in a wide source of heterogeneity. Third, most published studies presented different lengths of follow-up, thus further contributing to the heterogeneity of the reported data. In addition, another source of heterogeneity was the TTh modality, varying in terms of dose, route of administration, and duration of treatment. Finally, given the retrospective nature of most of the included studies, there may be the risk of possible unmeasured biases. Given all these limitations, the risk of unmeasured biases, and the high heterogeneity of works published until now, the design of well-powered, prospective randomized control trials is of utmost importance.
CONCLUSION
The findings of this meta-analysis rigorously based on the use of time-related measures of risk only showed an increased risk of long-term morbidity and early mortality for untreated hypogonadal men, while further outlining the clinical importance and safety of testosterone therapy in true hypogonadal men deserving to be treated, with the urgent need of collecting long-term follow-up data.
