madman
Super Moderator
Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis (2022)
Jemma Hudson, Moira Cruickshank, Richard Quinton, Lorna Aucott, Magaly Aceves-Martins, Katie Gillies, Shalender Bhasin, Peter J Snyder, Susan S Ellenberg, Mathis Grossmann, Thomas G Travison, Emily J Gianatti, Yvonne T van der Schouw, Marielle H Emmelot-Vonk, Erik J Giltay, Geoff Hackett, Sudarshan Ramachandran, Johan Svartberg, Kerry L Hildreth, Kristina Groti Antonic, Gerald B Brock, J Lisa Tenover, Hui Meng Tan, Christopher Ho Chee Kong, Wei Shen Tan, Leonard S Marks, Richard J Ross, Robert S Schwartz, Paul Manson, Stephen Roberts, Marianne Skovsager Andersen, Line Velling Magnussen, Rodolfo Hernández, Nick Oliver, Frederick Wu, Waljit S Dhillo, Siladitya Bhattacharya, Miriam Brazzelli*, Channa N Jayasena*
Summary
Background
Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyze subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.
Methods
We did a systematic review and meta-analysis of randomized controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles, and anonymized IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of the intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. The risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than with placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92–1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82–1·15]; p=0·69), smoking status (interaction 1·68 [0·41–6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89–4·82; p=0·025) were not associated with cardiovascular risk.
Interpretation
We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone.
Research in context
Evidence before this study Testosterone treatment is most often given to men aged 40–65 years. Testosterone has potentially favourable effects on cardiovascular risk such as increased lean-to-fat body mass and improved insulin sensitivity and glycaemia. Conversely, testosterone treatment increases haematocrit, might lower high-density lipoprotein (HDL) cholesterol, and some studies have observed increased cardiovascular event risk. The US Food & Drugs Administration (FDA) has mandated a box label warning of potential cardiovascular risks for all testosterone products. Uncertainty regarding the safety of testosterone might unduly influence decision making regarding the management of men with hypogonadism who could otherwise derive substantial benefits from treatment. We designed highly sensitive search strategies to identify reports of published, ongoing, and unpublished randomised controlled trials assessing the clinical effectiveness of testosterone treatment in men with hypogonadism. Searches were restricted to reports published in English from 1992. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and CENTRAL), clinical trial registries, and contacted clinical experts. We focused on trials with at least a 3-month treatment duration and a mean baseline total testosterone of 12 nmol/L or less (or equivalent) before treatment. We established a collaborative group of investigators of all identified trials (35 trials) and collected individual patient data (IPD) from 17 trials (3431 participants in total). In general, the risk of bias in IPD trials was low.
Added-value of this study
This individual IPD meta-analysis allowed us to conduct a reliable assessment of the frequency of mortality and cardiovascular events (including subtypes) during testosterone treatment in men with hypogonadism. Few deaths have occurred during trials of testosterone in men. Furthermore, testosterone treatment is not associated with an increased risk of any recorded cardiovascular event subtype in the short to medium term. The only detected adverse effects of testosterone were oedema and a modest lowering of HDL cholesterol.
Implications of all the available evidence
Men with hypogonadism should be counselled that there is no current evidence that testosterone treatment increases cardiovascular risk in the short to medium term. The long-term safety of testosterone is not yet established; an FDA-mandated study is ongoing.
Introduction
The steroid hormone testosterone is fundamental to male physical development and sexual behaviour. The deficiency of testosterone causes male hypogonadism, including diminished secondary sexual characteristics, sexual dysfunction, muscle wasting and weakness, osteoporosis, and reduced quality of life. Testosterone treatment is the standard of care for reversing the consequences of hypogonadism. Testosterone sales increased 12-fold globally from USD$150 million in 2000 to $1·8 billion in 2011.1 During this period, testosterone has been used increasingly in men aged 40–65 years, and has been over-prescribed by some clinicians.2,3 Despite the increasing use of testosterone, the USA Endocrine Society, American College of Physicians, and Endocrine Society of Australia have independently concluded that the cardiovascular safety of testosterone has not been adequately established.4–6 Furthermore, the European Urology Association (EAU) and the European Academy of Andrology (EAA) have recommended the assessment of cardiovascular risk before initiation of testosterone therapy.7,8
Testosterone exerts diverse effects on cardiovascular physiology. Some physiological testosterone effects could potentially reduce cardiovascular risk, including coronary vasodilatation and increased coronary blood flow, improved vascular reactivity, increased muscle mass, reduced whole body and visceral fat mass, shorter QTc interval, and normalisation of glycaemia during lifestyle interventions for prediabetes.4,9 Other testosterone actions could increase cardiovascular risk, including increased haematocrit, reduced high-density lipoprotein (HDL) cholesterol, induction of platelet aggregation by stimulation of thromboxane A2, sodium and water retention, and smooth muscle proliferation and increased expression of vascular cell adhesion molecules.4,10,11
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone compared with non-users, but the study designs have been widely criticised.12–14 Furthermore, a placebo-controlled trial was stopped early by its data and safety monitoring board following increased cardiovascular events in men aged 65 years and older who received 6 months of testosterone treatment.15 Other controlled trials have not observed significant effects of testosterone on cardiovascular events, but none were sufficiently powered to detect excess cardiovascular risks.16,17 Nevertheless, the US Food and Drug Administration (FDA) mandated box label warnings of potential cardiovascular risks for all testosterone products. The FDA also restricted testosterone approval to hypogonadism caused by documented pituitary or testicular disease, specifically excluding age-related hypogonadism.18 Following the FDA’s advisory about potential cardiovascular risk, testosterone prescription sales have declined in the USA.2 Conversely, the European Medicines Agency, EAU, and EAA have concluded that when hypogonadism is properly diagnosed and managed, there is currently no consistent evidence that testosterone therapy causes increased cardiovascular risk.7,8,19 Uncertainty about the cardiovascular safety of testosterone might be unduly influencing decision making regarding the management of men with hypogonadism who might otherwise derive substantial benefits from the treatment.
Previous meta-analyses of cardiovascular safety of testosterone treatment have been restricted to published, aggregate data, limiting the ability to confirm the quality and categorisation of source data, or analyse whether specific clinical benefits or adverse effects are associated with distinct subgroups such as patient age, baseline total and free testosterone, smoking, and diabetes status.20–28
To address ongoing uncertainty about the safety of testosterone, the Testosterone Efficacy and Safety Consortium were established as a global collaboration of principal investigators of testosterone trials. We report results of the most extensive individual participant dataset (IPD) of testosterone trials available and aimed to analyse subtypes of all cardiovascular events observed during treatment, and analyse the effect of incorporating data from trials not providing IPD.
Discussion
Our IPD meta-analysis of more than 3000 patients with hypogonadism from randomised placebo-controlled trials done by 17 research groups indicates that testosterone treatment is not associated with increased risk of various subtypes of cardiovascular events compared with placebo in the short to medium term. The small total number of deaths within our IPD analysis precluded a meaningful evaluation of the impact of testosterone treatment on mortality; furthermore, there was little available data evaluating the cardiovascular safety of testosterone beyond a 12-month duration of administration. Testosterone treatment did not have adverse effects on blood pressure or glycaemic markers compared with placebo; furthermore, it did not increase thrombotic events despite increased haematocrit. Testosterone treatment was associated with a modest lowering of total and HDL cholesterol and triglyceride concentrations compared with placebo.
Men with hypogonadism included in this IPD analysis had a higher prevalence of cardiovascular risk factors compared with the general population. Despite these risk factors, the overall incidence of cardiovascular events was not significantly higher during testosterone treatment than for placebo. Because most trials do not publish details of individual adverse events, the exact frequency of cardiovascular events occurring during testosterone treatment, up until this point, has been unclear. Two previous meta-analyses, which used different inclusion and exclusion criteria, have quantified the total number of reported cardiovascular events of any subtype, during testosterone therapy.21,22 Xu and colleagues21 reported 180 (6·0%) cardiovascular-related events among 2994 men from 27 trials while Corona and colleagues22 reported 210 (3·8%) cardiovascular events among 5464 men from 75 trials. Within our IPD analysis, two masked clinical investigators identified a total of 342 cardiovascular events from the included IPD, which to date is the highest published rate of cardiovascular events. There is currently no consensus on the components of cardiovascular endpoint constituting a major adverse cardiovascular event, which might prohibit the comparison, replication, and aggregation of data.56 Here, we have reported every cardiovascular event (including those classified by ACC32) encountered within several clinical trials providing IPD. Focusing on all cardiovascular events has enabled us to evaluate all aspects of cardiovascular safety for clinicians and patients, without making assumptions about the mechanisms of any potential association between testosterone and cardiovascular disease.
Discussion
An important strength of this IPD meta-analysis is its large size compared with individual testosterone trials, which have provided limited and situation-dependent information on cardiovascular safety. This IPD meta-analysis draws data from multiple, geographically diverse studies with approximately five-times more participants than the largest single participating trial. Definitive conclusions about the long-term cardiovascular safety of testosterone therapy cannot be made without the results of an adequately powered clinical trial. However, this study has allowed us to more precisely estimate the incidence of cardiovascular events associated with testosterone treatment, which might be generalisable to patients worldwide. Furthermore, utilising previously collected data, we have actively reduced research waste.66 We did not detect any significant funnel plot asymmetry in our analyses, suggesting that publication bias is not likely to be present in the overall IPD set. Several meta-analyses of published aggregate data have investigated the cardiovascular safety of testosterone treatment in men. Xu and colleagues analysed cardiovascular episodes of any type within the international statistical classification of diseases (ICD-10) and observed an increased cardiovascular risk during testosterone treatment.21 By contrast, Corona and colleagues and Diem and colleagues did three separate meta-analyses of five-point major adverse cardiovascular events as the primary outcome, and any cardiovascular event as a secondary outcome; testosterone treatment was neither associated with major adverse cardiovascular events nor other cardiovascular events in any meta-analysis.5,22,59 Fernandez-Balsells and colleagues reported that testosterone treatment did not significantly modify risks of myocardial infarction, all-cause mortality, coronary artery bypass, and arrhythmia but did reduce HDL cholesterol concentrations.20 Both Alexander and colleagues and Elliot and colleagues analysed risks of discrete major adverse cardiovascular event subtypes during testosterone treatment; neither myocardial infarction, stroke, nor mortality risks were associated with testosterone therapy.28,58 Guo and colleagues observed a reduction in total cholesterol during testosterone therapy but did not analyse lipid subtypes, or cardiovascular event risk.57 Most of these meta-analyses failed to observe increased cardiovascular event risk with testosterone; however, many guidelines recommend that cardiovascular risk is considered when commencing testosterone treatment.
The current study has several strengths compared with all previous meta-analyses. Firstly, our access to unpublished cardiovascular events, which were independently adjudicated by investigators masked to the treatment allocation, allows for more robust scrutiny of cardiovascular safety. Secondly, we have been able to investigate whether subgroups of patients have distinct cardiovascular risk profiles during testosterone administration. Some previous meta-analyses of published data have comprised studies in which the relatively high baseline serum testosterone concentrations have allowed non-hypogonadal patients to be included.5,20,28,57 By contrast, this IPD metaanalysis is restricted to patients with serum testosterone <12 nmol/L (350 ng/dL) using validated mass spectrometry or immunoassays; this threshold was chosen after consideration that all current clinical guidelines on testosterone treatment recommend serum testosterone thresholds of between 8 and 12 nmol/L to ensure the inclusion of hypogonadal men exclusively. Variation among testosterone assay measurements limits the extent to which results from different studies can be compared.67 Our IPD approach was further strengthened by subgroup analyses to assess whether any observed effect of testosterone was consistent across subgroups of patients. We did not observe any significant association between baseline testosterone and risks of any adverse outcome. Unlike some other meta-analyses, we excluded studies of patient groups with distinct risk profiles such as cancer, HIV, and cirrhosis,22,27 or those with less than 3 months of testosterone exposure.28 Finally, our analysis compared physiological markers in a more standardised manner compared with previous meta-analyses, by analysing the outcome at the timepoint closest to 12 months of testosterone treatment, regardless of whether that data had been previously published. Two meta-analyses have reported that testosterone improves glycaemic parameters in men.68,69 Furthermore, Corona and colleagues reported an improvement in blood pressure during testosterone treatment.70 However, our study suggests that testosterone has no significant effects on either blood pressure or glycaemic indices.
*Results of this meta-analysis have potentially important implications for the management of men with hypogonadism. Worldwide prescribing of testosterone for hypogonadism is increasing;2 however, conflicting messages on testosterone safety might have caused variations in treatment among patients. We have conducted the most comprehensive study to date investigating the safety of testosterone treatment for hypogonadism. Testosterone treatment did not increase cardiovascular event risk in the short term to medium term. Furthermore, we did not identify subgroups with high cardiovascular risk. An ongoing trial (NCT03518034) is investigating the longer-term safety of testosterone, and future studies are needed to analyse the risk-benefit and cost-effectiveness of testosterone therapy. However, the current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism.
Jemma Hudson, Moira Cruickshank, Richard Quinton, Lorna Aucott, Magaly Aceves-Martins, Katie Gillies, Shalender Bhasin, Peter J Snyder, Susan S Ellenberg, Mathis Grossmann, Thomas G Travison, Emily J Gianatti, Yvonne T van der Schouw, Marielle H Emmelot-Vonk, Erik J Giltay, Geoff Hackett, Sudarshan Ramachandran, Johan Svartberg, Kerry L Hildreth, Kristina Groti Antonic, Gerald B Brock, J Lisa Tenover, Hui Meng Tan, Christopher Ho Chee Kong, Wei Shen Tan, Leonard S Marks, Richard J Ross, Robert S Schwartz, Paul Manson, Stephen Roberts, Marianne Skovsager Andersen, Line Velling Magnussen, Rodolfo Hernández, Nick Oliver, Frederick Wu, Waljit S Dhillo, Siladitya Bhattacharya, Miriam Brazzelli*, Channa N Jayasena*
Summary
Background
Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyze subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.
Methods
We did a systematic review and meta-analysis of randomized controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles, and anonymized IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of the intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. The risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than with placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92–1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82–1·15]; p=0·69), smoking status (interaction 1·68 [0·41–6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89–4·82; p=0·025) were not associated with cardiovascular risk.
Interpretation
We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone.
Research in context
Evidence before this study Testosterone treatment is most often given to men aged 40–65 years. Testosterone has potentially favourable effects on cardiovascular risk such as increased lean-to-fat body mass and improved insulin sensitivity and glycaemia. Conversely, testosterone treatment increases haematocrit, might lower high-density lipoprotein (HDL) cholesterol, and some studies have observed increased cardiovascular event risk. The US Food & Drugs Administration (FDA) has mandated a box label warning of potential cardiovascular risks for all testosterone products. Uncertainty regarding the safety of testosterone might unduly influence decision making regarding the management of men with hypogonadism who could otherwise derive substantial benefits from treatment. We designed highly sensitive search strategies to identify reports of published, ongoing, and unpublished randomised controlled trials assessing the clinical effectiveness of testosterone treatment in men with hypogonadism. Searches were restricted to reports published in English from 1992. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and CENTRAL), clinical trial registries, and contacted clinical experts. We focused on trials with at least a 3-month treatment duration and a mean baseline total testosterone of 12 nmol/L or less (or equivalent) before treatment. We established a collaborative group of investigators of all identified trials (35 trials) and collected individual patient data (IPD) from 17 trials (3431 participants in total). In general, the risk of bias in IPD trials was low.
Added-value of this study
This individual IPD meta-analysis allowed us to conduct a reliable assessment of the frequency of mortality and cardiovascular events (including subtypes) during testosterone treatment in men with hypogonadism. Few deaths have occurred during trials of testosterone in men. Furthermore, testosterone treatment is not associated with an increased risk of any recorded cardiovascular event subtype in the short to medium term. The only detected adverse effects of testosterone were oedema and a modest lowering of HDL cholesterol.
Implications of all the available evidence
Men with hypogonadism should be counselled that there is no current evidence that testosterone treatment increases cardiovascular risk in the short to medium term. The long-term safety of testosterone is not yet established; an FDA-mandated study is ongoing.
Introduction
The steroid hormone testosterone is fundamental to male physical development and sexual behaviour. The deficiency of testosterone causes male hypogonadism, including diminished secondary sexual characteristics, sexual dysfunction, muscle wasting and weakness, osteoporosis, and reduced quality of life. Testosterone treatment is the standard of care for reversing the consequences of hypogonadism. Testosterone sales increased 12-fold globally from USD$150 million in 2000 to $1·8 billion in 2011.1 During this period, testosterone has been used increasingly in men aged 40–65 years, and has been over-prescribed by some clinicians.2,3 Despite the increasing use of testosterone, the USA Endocrine Society, American College of Physicians, and Endocrine Society of Australia have independently concluded that the cardiovascular safety of testosterone has not been adequately established.4–6 Furthermore, the European Urology Association (EAU) and the European Academy of Andrology (EAA) have recommended the assessment of cardiovascular risk before initiation of testosterone therapy.7,8
Testosterone exerts diverse effects on cardiovascular physiology. Some physiological testosterone effects could potentially reduce cardiovascular risk, including coronary vasodilatation and increased coronary blood flow, improved vascular reactivity, increased muscle mass, reduced whole body and visceral fat mass, shorter QTc interval, and normalisation of glycaemia during lifestyle interventions for prediabetes.4,9 Other testosterone actions could increase cardiovascular risk, including increased haematocrit, reduced high-density lipoprotein (HDL) cholesterol, induction of platelet aggregation by stimulation of thromboxane A2, sodium and water retention, and smooth muscle proliferation and increased expression of vascular cell adhesion molecules.4,10,11
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone compared with non-users, but the study designs have been widely criticised.12–14 Furthermore, a placebo-controlled trial was stopped early by its data and safety monitoring board following increased cardiovascular events in men aged 65 years and older who received 6 months of testosterone treatment.15 Other controlled trials have not observed significant effects of testosterone on cardiovascular events, but none were sufficiently powered to detect excess cardiovascular risks.16,17 Nevertheless, the US Food and Drug Administration (FDA) mandated box label warnings of potential cardiovascular risks for all testosterone products. The FDA also restricted testosterone approval to hypogonadism caused by documented pituitary or testicular disease, specifically excluding age-related hypogonadism.18 Following the FDA’s advisory about potential cardiovascular risk, testosterone prescription sales have declined in the USA.2 Conversely, the European Medicines Agency, EAU, and EAA have concluded that when hypogonadism is properly diagnosed and managed, there is currently no consistent evidence that testosterone therapy causes increased cardiovascular risk.7,8,19 Uncertainty about the cardiovascular safety of testosterone might be unduly influencing decision making regarding the management of men with hypogonadism who might otherwise derive substantial benefits from the treatment.
Previous meta-analyses of cardiovascular safety of testosterone treatment have been restricted to published, aggregate data, limiting the ability to confirm the quality and categorisation of source data, or analyse whether specific clinical benefits or adverse effects are associated with distinct subgroups such as patient age, baseline total and free testosterone, smoking, and diabetes status.20–28
To address ongoing uncertainty about the safety of testosterone, the Testosterone Efficacy and Safety Consortium were established as a global collaboration of principal investigators of testosterone trials. We report results of the most extensive individual participant dataset (IPD) of testosterone trials available and aimed to analyse subtypes of all cardiovascular events observed during treatment, and analyse the effect of incorporating data from trials not providing IPD.
Discussion
Our IPD meta-analysis of more than 3000 patients with hypogonadism from randomised placebo-controlled trials done by 17 research groups indicates that testosterone treatment is not associated with increased risk of various subtypes of cardiovascular events compared with placebo in the short to medium term. The small total number of deaths within our IPD analysis precluded a meaningful evaluation of the impact of testosterone treatment on mortality; furthermore, there was little available data evaluating the cardiovascular safety of testosterone beyond a 12-month duration of administration. Testosterone treatment did not have adverse effects on blood pressure or glycaemic markers compared with placebo; furthermore, it did not increase thrombotic events despite increased haematocrit. Testosterone treatment was associated with a modest lowering of total and HDL cholesterol and triglyceride concentrations compared with placebo.
Men with hypogonadism included in this IPD analysis had a higher prevalence of cardiovascular risk factors compared with the general population. Despite these risk factors, the overall incidence of cardiovascular events was not significantly higher during testosterone treatment than for placebo. Because most trials do not publish details of individual adverse events, the exact frequency of cardiovascular events occurring during testosterone treatment, up until this point, has been unclear. Two previous meta-analyses, which used different inclusion and exclusion criteria, have quantified the total number of reported cardiovascular events of any subtype, during testosterone therapy.21,22 Xu and colleagues21 reported 180 (6·0%) cardiovascular-related events among 2994 men from 27 trials while Corona and colleagues22 reported 210 (3·8%) cardiovascular events among 5464 men from 75 trials. Within our IPD analysis, two masked clinical investigators identified a total of 342 cardiovascular events from the included IPD, which to date is the highest published rate of cardiovascular events. There is currently no consensus on the components of cardiovascular endpoint constituting a major adverse cardiovascular event, which might prohibit the comparison, replication, and aggregation of data.56 Here, we have reported every cardiovascular event (including those classified by ACC32) encountered within several clinical trials providing IPD. Focusing on all cardiovascular events has enabled us to evaluate all aspects of cardiovascular safety for clinicians and patients, without making assumptions about the mechanisms of any potential association between testosterone and cardiovascular disease.
Discussion
An important strength of this IPD meta-analysis is its large size compared with individual testosterone trials, which have provided limited and situation-dependent information on cardiovascular safety. This IPD meta-analysis draws data from multiple, geographically diverse studies with approximately five-times more participants than the largest single participating trial. Definitive conclusions about the long-term cardiovascular safety of testosterone therapy cannot be made without the results of an adequately powered clinical trial. However, this study has allowed us to more precisely estimate the incidence of cardiovascular events associated with testosterone treatment, which might be generalisable to patients worldwide. Furthermore, utilising previously collected data, we have actively reduced research waste.66 We did not detect any significant funnel plot asymmetry in our analyses, suggesting that publication bias is not likely to be present in the overall IPD set. Several meta-analyses of published aggregate data have investigated the cardiovascular safety of testosterone treatment in men. Xu and colleagues analysed cardiovascular episodes of any type within the international statistical classification of diseases (ICD-10) and observed an increased cardiovascular risk during testosterone treatment.21 By contrast, Corona and colleagues and Diem and colleagues did three separate meta-analyses of five-point major adverse cardiovascular events as the primary outcome, and any cardiovascular event as a secondary outcome; testosterone treatment was neither associated with major adverse cardiovascular events nor other cardiovascular events in any meta-analysis.5,22,59 Fernandez-Balsells and colleagues reported that testosterone treatment did not significantly modify risks of myocardial infarction, all-cause mortality, coronary artery bypass, and arrhythmia but did reduce HDL cholesterol concentrations.20 Both Alexander and colleagues and Elliot and colleagues analysed risks of discrete major adverse cardiovascular event subtypes during testosterone treatment; neither myocardial infarction, stroke, nor mortality risks were associated with testosterone therapy.28,58 Guo and colleagues observed a reduction in total cholesterol during testosterone therapy but did not analyse lipid subtypes, or cardiovascular event risk.57 Most of these meta-analyses failed to observe increased cardiovascular event risk with testosterone; however, many guidelines recommend that cardiovascular risk is considered when commencing testosterone treatment.
The current study has several strengths compared with all previous meta-analyses. Firstly, our access to unpublished cardiovascular events, which were independently adjudicated by investigators masked to the treatment allocation, allows for more robust scrutiny of cardiovascular safety. Secondly, we have been able to investigate whether subgroups of patients have distinct cardiovascular risk profiles during testosterone administration. Some previous meta-analyses of published data have comprised studies in which the relatively high baseline serum testosterone concentrations have allowed non-hypogonadal patients to be included.5,20,28,57 By contrast, this IPD metaanalysis is restricted to patients with serum testosterone <12 nmol/L (350 ng/dL) using validated mass spectrometry or immunoassays; this threshold was chosen after consideration that all current clinical guidelines on testosterone treatment recommend serum testosterone thresholds of between 8 and 12 nmol/L to ensure the inclusion of hypogonadal men exclusively. Variation among testosterone assay measurements limits the extent to which results from different studies can be compared.67 Our IPD approach was further strengthened by subgroup analyses to assess whether any observed effect of testosterone was consistent across subgroups of patients. We did not observe any significant association between baseline testosterone and risks of any adverse outcome. Unlike some other meta-analyses, we excluded studies of patient groups with distinct risk profiles such as cancer, HIV, and cirrhosis,22,27 or those with less than 3 months of testosterone exposure.28 Finally, our analysis compared physiological markers in a more standardised manner compared with previous meta-analyses, by analysing the outcome at the timepoint closest to 12 months of testosterone treatment, regardless of whether that data had been previously published. Two meta-analyses have reported that testosterone improves glycaemic parameters in men.68,69 Furthermore, Corona and colleagues reported an improvement in blood pressure during testosterone treatment.70 However, our study suggests that testosterone has no significant effects on either blood pressure or glycaemic indices.
*Results of this meta-analysis have potentially important implications for the management of men with hypogonadism. Worldwide prescribing of testosterone for hypogonadism is increasing;2 however, conflicting messages on testosterone safety might have caused variations in treatment among patients. We have conducted the most comprehensive study to date investigating the safety of testosterone treatment for hypogonadism. Testosterone treatment did not increase cardiovascular event risk in the short term to medium term. Furthermore, we did not identify subgroups with high cardiovascular risk. An ongoing trial (NCT03518034) is investigating the longer-term safety of testosterone, and future studies are needed to analyse the risk-benefit and cost-effectiveness of testosterone therapy. However, the current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism.
