{"paper_id":"2b959ac2-9147-4570-bb84-b5bea478ceb2","body_text":"Cardiovascular Safety Outcomes of Testosterone Replacement Therapy Formulations in Adult Male Hypogonadism: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Cardiovascular Safety Outcomes of Testosterone Replacement Therapy Formulations in Adult Male Hypogonadism: A Systematic Review Carlos Rios Gonzalez This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9631066/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Male hypogonadism is a prevalent endocrine condition associated with metabolic dysregulation and elevated cardiovascular risk. Testosterone replacement therapy (TRT) is widely prescribed to restore physiological hormone levels, yet its cardiovascular safety profile has been the subject of sustained controversy due to conflicting findings from observational and randomised studies. Main body: This systematic review, conducted in accordance with PRISMA 2020 guidelines, synthesises evidence from 26 unique studies—comprising 3 randomised controlled trials (RCTs), 15 systematic reviews and meta-analyses, and 8 observational studies—identified from seven databases searched from January 2015 to January 2026. Sample sizes ranged from 65 to over 4.3 million participants. The TRAVERSE trial (n = 5,246; mean follow-up 33 months) demonstrated non-inferiority of transdermal testosterone versus placebo for major adverse cardiovascular events (MACE; HR 0.96, 95% CI 0.78–1.17; p < 0.001). Pooled RCT meta-analyses confirmed no significant increase in MACE risk (OR 0.90–1.07). Individual outcomes of myocardial infarction, stroke, cardiovascular mortality, and heart failure showed no consistent harm signal. Specific safety signals identified in TRAVERSE included higher incidences of atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone group. An elevated cardiovascular event rate during the first year of therapy was observed in men aged ≥ 65 years (RR 2.90, 95% CI 1.35–6.21). Heterogeneity was low for MACE (I² = 26%) and substantial for broader composites (I² = 75%). All formulation comparisons were indirect; no head-to-head randomised trials exist. GRADE certainty was moderate for MACE, atrial fibrillation, and venous thromboembolism (VTE), and low for outcomes beyond three years. Conclusion TRT at physiological doses does not increase MACE risk in appropriately selected hypogonadal men, including those with pre-existing cardiovascular disease. Structured monitoring for atrial fibrillation, pulmonary embolism, and acute kidney injury is warranted. Particular caution is required during the first year of therapy in men aged ≥ 65 years. Adequately powered head-to-head formulation trials and long-term randomised follow-up beyond five years remain research priorities. testosterone replacement therapy hypogonadism cardiovascular safety major adverse cardiovascular events TRAVERSE trial atrial fibrillation venous thromboembolism systematic review Figures Figure 1 Background Male hypogonadism, defined by insufficient testicular testosterone production, affects approximately 2–6% of adult men, with prevalence rising to 20–30% in men over 60 years. [ 1 , 2 ] The condition is associated with sexual dysfunction, loss of muscle mass, fatigue, mood disturbances, and metabolic abnormalities including insulin resistance, dyslipidaemia, and metabolic syndrome, all of which contribute to elevated cardiovascular risk. [ 3 – 5 ] TRT prescriptions tripled in the United States between 2001 and 2011, with approximately 2.3 million men treated annually. [ 6 ] Multiple formulations are available—intramuscular injections, transdermal gels and patches, oral testosterone undecanoate, subcutaneous pellets, and intranasal gels—each characterised by distinct pharmacokinetic profiles and safety considerations. [ 7 ] TRT demonstrably improves sexual function, bone mineral density, body composition, and quality of life in hypogonadal men. [ 8 , 9 ] The cardiovascular safety of TRT has remained debated since observational studies published between 2013 and 2014 reported increased risks of myocardial infarction, stroke, and mortality, prompting regulatory warnings from the U.S. Food and Drug Administration. [ 10 – 13 ] Subsequent randomised evidence produced conflicting results. The 2023 TRAVERSE trial—the first adequately powered RCT designed specifically to evaluate TRT cardiovascular safety—provided pivotal new data, [ 14 ] yet uncertainties persist regarding formulation-specific risks, age-related risk modification, and uncommon outcomes such as atrial fibrillation and VTE. [ 2 , 5 ] This systematic review aims to synthesise contemporary high-quality evidence on the cardiovascular safety of different TRT formulations in adult men with documented hypogonadism. Methods Study design and registration This systematic review was conducted following PRISMA 2020 guidelines. [ 15 ] All methodological decisions were pre-specified before database searching commenced. Formal prospective registration in PROSPERO was not completed prior to study initiation, which is acknowledged as a limitation. No ethics approval was required as all data derive from previously published studies. Eligibility criteria Population. Adult men (≥ 18 years) with biochemically confirmed hypogonadism (total testosterone < 300 ng/dL or < 10.4 nmol/L on two separate morning measurements with compatible symptoms). Both organic and functional hypogonadism were eligible; functional hypogonadism studies were required to apply a pre-specified diagnostic threshold. Interventions. Any approved TRT formulation (intramuscular, transdermal, oral, subcutaneous pellets, intranasal) at any dose. Comparators. Placebo, no treatment, usual care, or alternative TRT formulations. Outcomes. Primary: MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), arrhythmias, VTE, heart failure, and cardiovascular mortality. Secondary: blood pressure, lipid profile, and haematocrit changes. Study designs. RCTs, systematic reviews and meta-analyses, and high-quality observational studies with appropriate confounder adjustment. Minimum treatment duration: 3 months; minimum cardiovascular follow-up: 6 months. Exclusions. Studies involving women, children, transgender populations, non-therapeutic testosterone use, case reports, narrative reviews, editorials, studies published before January 2015, and non-English language studies. Search strategy Seven electronic databases were searched from January 2015 to January 2026: PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov. Search strategies combined controlled vocabulary (MeSH and Emtree terms) and free-text terms. Reference lists of included studies and relevant reviews were hand-searched; conference abstracts from major endocrinology and cardiology congresses were screened. Study selection and data extraction Two reviewers independently screened titles and abstracts, followed by full-text assessment. Discrepancies were resolved by consensus or third-reviewer adjudication. Inter-rater agreement was assessed using Cohen's kappa (κ = 0.83, indicating strong agreement). Data were extracted using a standardised form capturing study design, population, TRT formulation, comparator, follow-up duration, cardiovascular outcomes with effect estimates, and adverse events. Risk of bias and certainty of evidence RCTs were appraised using the Cochrane Risk of Bias 2 (RoB 2) tool; [ 16 ] systematic reviews using AMSTAR 2; [ 17 ] and observational studies using the Newcastle–Ottawa Scale (NOS). [ 18 ] Certainty of evidence for each primary outcome was evaluated using the GRADE framework. Two preprint studies included in the evidence base are explicitly identified and assigned lower certainty weighting. Synthesis A narrative synthesis was conducted, stratified by study design, TRT formulation, cardiovascular outcome, and patient subgroup. No new pooled meta-analysis was performed given the availability of multiple recent high-quality syntheses; published pooled estimates were compared across independent analyses. Heterogeneity (I²) and certainty data were extracted from source meta-analyses where available. Results Study selection Database searching retrieved 247 records; 18 duplicates were removed, yielding 229 for title and abstract screening. Following full-text evaluation, 63 articles were excluded: wrong population (n = 18), no cardiovascular outcomes (n = 21), ineligible design (n = 14), duplicate publication (n = 4), and insufficient follow-up (n = 6). Four duplicate reference pairs were identified and consolidated, yielding 26 unique studies in the final synthesis (Fig. 1 ). The evidence base comprised 3 RCTs, 15 systematic reviews and meta-analyses, and 8 observational studies published between 2016 and 2024, with sample sizes ranging from 65 to over 4.3 million participants. Characteristics of included studies (Table 1 ) Table 1 Characteristics of included studies (n = 26) Study Design N Intervention Follow-up Outcomes Quality TRAVERSE (Lincoff 2023) RCT 5,246 Gel vs placebo 33 mo MACE, AF, PE, AKI Low TestES IPD (Cruickshank 2024) SR/IPD 5,601 Any TRT vs PBO ≥ 3 mo Mortality, CV events Low–Mod STRIDE (Rao 2022) RCT 65 TU vs placebo 12 mo CV safety, metabolic Moderate Rachman et al., 2024 SR/MA — Any TRT vs control Variable MACE Moderate Corona et al., 2024 SR/MA — Any TRT vs control Variable MACE, AF, VTE Moderate Silva et al., 2024 SR/MA — Review Variable CV mechanisms Moderate Borges, 2024 (Oral)* SR/MA — Oral TU Variable CV safety, BP Low Borges, 2024 (VTE)* SR/MA — Any TRT Variable Thromboembolic risk Low Abichandani et al., 2023 SR/MA — TRT, obesity/T2DM Variable Efficacy + CV safety Moderate Krishnan et al., 2024 SR/MA — TRT, older men Variable CV risk Moderate Albert et al., 2016 SR/MA — Any TRT Variable CV events by age Moderate Elliott et al., 2017 SR/MA — Network MA Variable Multiple CV Moderate Corona et al., 2018 SR/MA — Interventional Variable CV risk Moderate Huo et al., 2016 SR/MA — Any TRT Variable CV outcomes Moderate Sood et al., 2023 SR/MA — RCTs Variable CV outcomes Moderate Hackett, 2024 SR — TRAVERSE review ~ 33 mo Long-term CV safety Moderate Quang et al., 2018 SR/MA — TRT, T2DM/MetS Variable CV benefits/risks Moderate Saad et al., 2020 Obs — TU registry ≤ 12 yr MACE, mortality High (NOS 8) Andersen et al., 2022 Obs — IPD + aggregate Variable CV, mortality Moderate Traish et al., 2017 Obs — Registry Variable Cardiometabolic High (NOS 7) Oni et al., 2019 Obs — Post-MI cohort Variable Mortality, MI High (NOS 8) Borges, 2024 (cohort)* Obs — Prospective 10 yr CV disease risk Low (preprint) Corona et al., 2017 SR — Review Variable CV causes/consq. Low Cruickshank 2024 (full) SR/MA 5,601 TestES synthesis Variable Mortality, CV Low–Mod Chih et al., 2020 † Protocol — Planned review — Planned CV N/A Snyder et al., 2022 ‡ Design — TRAVERSE design — Rationale N/A RCT: randomised controlled trial; SR: systematic review; MA: meta-analysis; Obs: observational; TU: testosterone undecanoate; CV: cardiovascular; MACE: major adverse cardiovascular events; AF: atrial fibrillation; PE: pulmonary embolism; AKI: acute kidney injury; VTE: venous thromboembolism; NOS: Newcastle–Ottawa Scale; PBO: placebo; T2DM: type 2 diabetes mellitus; MetS: metabolic syndrome. *Preprint — not peer-reviewed. †Protocol only, no results. ‡Design paper only; results in TRAVERSE (ref. [ 14 ]). The three primary RCTs were: TRAVERSE (Lincoff et al., 2023[ 14 ]), enrolling 5,246 men aged 45–80 years with hypogonadism and pre-existing or high cardiovascular risk, randomised to transdermal testosterone gel versus placebo over a mean follow-up of 33 months; TestES IPD synthesis (Cruickshank et al., 2024[ 15 ]), an individual patient data meta-analysis of 35 RCTs (n = 5,601) focused on mortality and cardiovascular events; and the STRIDE study (Rao et al., 2022[ 23 ]), a placebo-controlled trial of testosterone undecanoate in 65 men with type 2 diabetes. Fifteen systematic reviews and meta-analyses provided pooled estimates across diverse populations and formulations. Eight observational studies, including registry-based analyses with follow-up extending up to 12 years, contributed long-term evidence. Risk of bias (Table 2 ) Table 2 Risk of bias assessment (key studies) Study Design D1 D2 D3 D4 D5 D6 Overall TRAVERSE (Lincoff 2023) RCT Low Low Low Low Low Low Low TestES IPD (Cruickshank 2024) SR Low Low Mod Low Low Mod Low–Mod STRIDE (Rao 2022) RCT Low Mod Mod Mod Mod Mod Moderate Saad et al., 2020 Obs — — — NOS 8 — — High Traish et al., 2017 Obs — — — NOS 7 — — High Oni et al., 2019 Obs — — — NOS 8 — — High Borges 2024 (cohort)* Obs — — — Preprint — — Low D1: randomisation; D2: deviations from intended interventions; D3: missing outcome data; D4: outcome measurement; D5: selective reporting; D6: AMSTAR 2 domain / NOS overall score. For observational studies, NOS score replaces individual RoB 2 domains. Mod: moderate concern. *Preprint — not peer-reviewed. TRAVERSE was rated low risk of bias across all RoB 2 domains, supported by robust randomisation, double-blinding, and independent event adjudication. TestES was rated low-to-moderate overall. STRIDE was rated moderate, primarily due to small sample size and baseline imbalances. Registry-based observational studies achieved NOS scores of 7–9. The two preprint studies were rated low quality. Overall GRADE certainty was moderate for MACE, atrial fibrillation, and VTE, and low for outcomes beyond three years and for newer formulations (Table 3 ). Table 3 GRADE evidence summary by cardiovascular outcome Outcome Evidence base Direction of effect Effect estimate GRADE Verdict MACE High-quality RCT + IPD MA No significant increase HR 0.96 (0.78–1.17) Moderate Neutral Myocardial infarction Moderate No significant increase MACE component Moderate Neutral Stroke Moderate No significant increase MACE component Moderate Neutral CV mortality Moderate — few events No significant increase Non-significant trends Moderate Neutral Atrial fibrillation Moderate — TRAVERSE signal Higher with TRT HR > 1 (TRAVERSE) Moderate Signal Pulmonary embolism Moderate — TRAVERSE signal Higher with TRT HR > 1 (TRAVERSE) Moderate Signal Acute kidney injury Moderate — TRAVERSE signal Higher with TRT HR > 1 (TRAVERSE) Moderate Signal Heart failure Low — limited reporting Inconclusive No dedicated RCT Low Uncertain VTE (overall) Moderate No significant increase Pooled ORs ~ 1.0 Moderate Neutral CV outcomes > 3 yr Low — observational only Potential benefit (confounded) Registry data Low Uncertain MACE: major adverse cardiovascular events; CV: cardiovascular; VTE: venous thromboembolism; HR: hazard ratio; OR: odds ratio; GRADE: Grading of Recommendations Assessment, Development and Evaluation. Signal: specific safety signal warranting clinical monitoring. Uncertain: insufficient evidence to draw conclusions. Major adverse cardiovascular events In TRAVERSE, MACE occurred in 7.0% (testosterone) versus 7.3% (placebo), confirming non-inferiority (HR 0.96, 95% CI 0.78–1.17; p < 0.001 for non-inferiority). [ 14 ] This finding was consistent with pooled RCT meta-analyses reporting no significant increase in MACE risk (OR 0.90, 95% CI 0.74–1.10[ 1 ]; OR 1.07, 95% CI 0.81–1.42[ 15 ]). Heterogeneity was low (I² = 26%) for MACE across RCT syntheses. Individual cardiovascular outcomes Myocardial infarction and stroke, as components of the TRAVERSE primary composite, showed no meaningful excess with TRT. [ 14 ] Cardiovascular and all-cause mortality were neutral in both TRAVERSE and the TestES IPD synthesis (OR approximately 0.90–1.07 across analyses). [ 14 , 15 ] Heart failure was not increased across available RCT data, though dedicated trials in patients with established heart failure are lacking. Specific safety signals TRAVERSE identified higher incidences of atrial fibrillation , pulmonary embolism , and acute kidney injury in the testosterone group. [ 14 ] Earlier meta-analyses, limited by statistical power for these uncommon events, generally showed no significant differences. [ 2 , 16 ] These signals are biologically plausible: TRT-induced erythrocytosis increases thrombotic risk, and potential pro-arrhythmic electrophysiological effects have been described. [ 3 , 5 ] An elevated cardiovascular event rate during the first year of therapy was identified in men aged ≥ 65 years (RR 2.90, 95% CI 1.35–6.21) in one meta-analysis, [ 8 ] underscoring the importance of cautious initiation in older patients. Formulation-specific findings (Table 4 ) Table 4 Formulation-specific cardiovascular evidence (indirect comparisons only) Formulation MACE evidence Lipid / haematocrit Max. follow-up Key notes Intramuscular (enanthate / cypionate / undecanoate) Neutral (RR 0.96; 95% CI 0.46–1.98) HDL decrease; haematocrit increase Up to 12 year (observational) No AF or PE signal in pooled analyses; most long-term observational data Transdermal gel Non-inferior (HR 0.96; TRAVERSE) HDL decrease; haematocrit increase ~ 33 mo (RCT) Strongest RCT MACE evidence; AF, PE, AKI signals from TRAVERSE Oral testosterone undecanoate Limited; no large cardiovascular RCT Some systolic BP increase reported Short-term only Lower certainty; BP concern; fewer outcome data Subcutaneous pellets Insufficient Insufficient Insufficient No cardiovascular outcome conclusions possible Intranasal gel Insufficient Insufficient Insufficient No cardiovascular outcome conclusions possible All comparisons are indirect — no head-to-head randomised trials comparing cardiovascular outcomes across TRT formulations exist. MACE: major adverse cardiovascular events; AF: atrial fibrillation; PE: pulmonary embolism; AKI: acute kidney injury; BP: blood pressure; RCT: randomised controlled trial. All formulation comparisons are indirect, as no head-to-head RCTs addressing cardiovascular outcomes exist. Intramuscular testosterone demonstrated neutral pooled cardiovascular risk (RR 0.96, 95% CI 0.46–1.98), with the longest observational follow-up (up to 12 years with testosterone undecanoate). [ 8 , 7 ] Transdermal testosterone has the strongest MACE safety evidence through TRAVERSE[ 14 ] but carries the atrial fibrillation, pulmonary embolism, and acute kidney injury signals. Oral testosterone undecanoate has a more limited cardiovascular outcome evidence base with some concern for blood pressure elevation. [ 9 , 11 ] Evidence for pellet and intranasal formulations is insufficient for conclusions. Cardiometabolic effects TRT consistently reduced total cholesterol and triglycerides, improved insulin sensitivity, and decreased HDL cholesterol, while increasing haematocrit. [ 15 , 22 ] At the level of hard cardiovascular endpoints, these opposing metabolic effects translated into a neutral MACE signal in the medium term, though individual susceptibility to erythrocytosis or arrhythmia may alter this balance. Discussion This systematic review confirms that TRT at physiological doses does not increase MACE risk in appropriately selected hypogonadal men, including those with pre-existing or high cardiovascular risk. The convergence of TRAVERSE [ 14 ] with multiple independent meta-analyses—yielding pooled MACE estimates between OR 0.90 and 1.07—substantially consolidates this conclusion and resolves much of the controversy generated by methodologically limited observational studies published a decade ago. The identification of specific safety signals in TRAVERSE—atrial fibrillation, pulmonary embolism, and acute kidney injury [ 14 ]—is the most clinically actionable finding of this review. These outcomes were not consistently detected in pre-TRAVERSE meta-analyses, which lacked statistical power. The biological plausibility of these signals (erythrocytosis-driven thromboembolic risk, pro-arrhythmic mechanisms, haemodynamic effects on renal perfusion) supports their clinical relevance and the need for structured monitoring protocols beyond conventional MACE surveillance. The time-dependent risk pattern—elevated cardiovascular event rates during the first year of therapy in men aged ≥ 65 years [ 8 ]—has direct implications for clinical practice. Conservative dose titration, careful baseline cardiovascular assessment, and early clinical follow-up visits in older patients may mitigate this early vulnerability. Concurrently, TRAVERSE's demonstration of overall MACE non-inferiority in men up to 80 years [ 14 ] confirms that advanced age does not categorically preclude TRT but demands individualised clinical judgement. Formulation-specific guidance remains limited by the absence of head-to-head randomised comparisons. Intramuscular testosterone, particularly long-acting undecanoate, appears neutral for cardiovascular events in pooled analyses and offers the most extended observational follow-up. [ 7 , 8 ] Transdermal preparations have the strongest medium-term RCT safety evidence but carry the non-MACE safety signals identified in TRAVERSE. [ 14 ] These distinctions, derived exclusively from indirect comparisons, should inform—but not rigidly determine—formulation selection. This review has several limitations. The study protocol was not prospectively registered in PROSPERO. Non-English language studies were excluded, introducing potential language bias. Two preprint studies were included; their removal does not materially alter the conclusions. Heterogeneity was substantial for broader cardiovascular composites (I² = 75%), reflecting differences in populations, formulations, and outcome definitions. Randomised evidence beyond 33 months is absent, and long-term cardiovascular safety beyond three years rests on observational data. Conclusions Contemporary evidence supports the cardiovascular safety of physiological-dose TRT for MACE outcomes in appropriately selected hypogonadal men. Structured clinical monitoring for atrial fibrillation, pulmonary embolism, and acute kidney injury is warranted. Elevated early-period cardiovascular risk in men aged ≥ 65 years requires cautious initiation and close surveillance. Adequately powered head-to-head formulation trials and long-term randomised follow-up beyond five years represent the most important research priorities in this field. Abbreviations AKI: acute kidney injury; CI: confidence interval; CV: cardiovascular; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; MACE: major adverse cardiovascular events; MI: myocardial infarction; NOS: Newcastle–Ottawa Scale; OR: odds ratio; PE: pulmonary embolism; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT: randomised controlled trial; RR: relative risk; TRT: testosterone replacement therapy; VTE: venous thromboembolism. Declarations Ethics approval and consent to participate Not applicable. This systematic review analysed data from previously published, publicly available studies. No primary data involving human participants, human tissue, or identifiable patient data were collected. No institutional ethics approval was required. Consent for publication Not applicable. This manuscript does not contain data from any individual person. Funding This systematic review received no external funding. The study was entirely self-funded by the author. No funding body played any role in the design of the study, data collection, analysis, interpretation, or writing of the manuscript. Author Contribution C.M.R.G. conceived and designed the study, defined the eligibility criteria, and developed the search strategy. C.M.R.G. conducted all database searches, performed title and abstract screening, carried out full-text eligibility assessment, extracted data, assessed risk of bias using RoB 2, AMSTAR 2, and the Newcastle–Ottawa Scale, evaluated certainty of evidence using the GRADE framework, synthesised the findings, and wrote the manuscript in its entirety. C.M.R.G. prepared all tables and Figure 1. C.M.R.G. read and approved the final manuscript. References Rachman IM et al (2024) Assessing cardiovascular safety of testosterone replacement therapy for male hypogonadism: a systematic review and meta-analysis. Indonesian J Urol. 10.32421/juri.v31i3.988 Corona G et al (2024) Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis. Exp Opin Drug Saf. 10.1080/14740338.2024.2337741 Silva AB et al (2024) Cardiovascular disease and testosterone therapy in male hypogonadism. Annals of the New York Academy of Sciences. 10.1111/nyas.15211 Borges C (2024) Oral testosterone therapy in hypogonadal men: a systematic review and meta-analysis. Series of Endocrinology, Diabetes and Metabolism. 10.54178/jsedmv6i3001 Borges C (2024) Thromboembolic risk and testosterone replacement therapy. Preprint Res Square. 10.21203/rs.3.rs-5134020/v1 Krishnan A et al (2024) Testosterone therapy and the risk of cardiovascular disease in older, hypogonadal men. Prog Cardiovasc Dis. 10.1016/j.pcad.2024.02.015 Saad F et al (2020) Long-term treatment with testosterone undecanoate injections in men with hypogonadism. Aging Male. 10.1080/13685538.2019.1575354 Albert SG et al (2016) Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin Endocrinol. 10.1111/CEN.13084 Elliott J et al (2017) Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open. 10.1136/BMJOPEN-2016-015284 Abichandani V et al (2023) A systematic review assessing TRT in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus. Chron Diabetes Res Pract. 10.4103/cdrp.cdrp_CDRP_20_22 Borges C (2024) Inverse association between TRT and cardiovascular disease risk. Preprint, bioRxiv. 10.1101/2024.06.21.24309326 Huo S et al (2016) Treatment of men for 'low testosterone': a systematic review. PLoS ONE. 10.1371/JOURNAL.PONE.0162480 Andersen MS et al (2022) Adverse cardiovascular events and cause mortality in men during testosterone treatment. J Endocr Soc. 10.1210/jendso/bvac150.1414 Lincoff AM et al (2023) Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 10.1056/NEJMoa2215025 Cruickshank M et al (2024) The effects and safety of testosterone replacement therapy: the TestES evidence synthesis. Health Technol Assess. 10.3310/jryt3981 Sood A et al (2023) Cardiovascular outcomes of hypogonadal men receiving TRT: a meta-analysis of randomised controlled trials. Endocr Pract. 10.1016/j.eprac.2023.09.012 Corona G et al (2018) Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med. 10.1016/J.JSXM.2018.04.641 Page MJ et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. 10.1136/bmj.n71 Sterne JAC et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 10.1136/bmj.l4898 Shea BJ et al (2017) AMSTAR 2: a critical appraisal tool for systematic reviews. BMJ. 10.1136/bmj.j4008 Wells GA et al (2000) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Accessed 1 Jan 2026 Rao PM et al (2022) The effect of TRT on cardiovascular safety — the STRIDE Study. J Endocr Soc. 10.1210/jendso/bvac150.1451 Traish AM et al (2017) Long-term testosterone therapy improves cardiometabolic function. J Cardiovasc Pharmacol Therap. 10.1177/1074248417691136 Oni OA et al (2019) Relation of testosterone normalization to mortality and myocardial infarction in men with previous MI. Am J Cardiol. 10.1016/J.AMJCARD.2019.07.019 Hackett G (2024) Long-term cardiovascular safety of testosterone therapy: a review of the TRAVERSE study. World J Men's Health. 10.5534/wjmh.240081 Quang TH et al (2018) Cardiovascular benefits and risks of TRT in hypogonadal men with T2DM and/or metabolic syndrome. Br J Diabetes. 10.15277/BJD.2018.192 Corona G et al (2017) Testosterone and cardiovascular diseases: causes or consequences. Curr Sex Health Rep. 10.1007/S11930-017-0132-3 Chih HJ et al (2020) Effect of testosterone treatment on cardiovascular events: protocol for a systematic review. JMIR Res Protocols. 10.2196/15163 Snyder PJ et al (2022) Effects of long-term testosterone treatment on cardiovascular outcomes: rationale and design of TRAVERSE. Am Heart J. 10.1016/j.ahj.2021.11.016 Borges C (2024) The inverse association between TRT and cardiovascular disease risk. Preprint, bioRxiv. 10.1101/2024.06.21.24309326 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-9631066\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Systematic Review\",\"associatedPublications\":[],\"authors\":[{\"id\":636574560,\"identity\":\"d332bfa8-9c12-4e68-b58d-074ed6f32a78\",\"order_by\":0,\"name\":\"Carlos Rios Gonzalez\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIie2RvWrDMBRGryh0UtBWVFrQK9wQKB0Mfo2OCgF3CTRjRk3NVLI69BG6BAyeFbzGdFXx4izeCh4zeKiU/oSC7ayF6gyShu9w74cAPJ6/CdH2oJ9vBGDulrN+57dyqZyCp5UjqL/cLtgiL3XdpNfibqLP5rMgHL2+jOsSQbAL3arw7T1uVo8FHZpIki1G49S8J9wuNlw9y1YFIYJsoKwST5EozOSNyddOkVh0KKyCjDZOeaidEo7iPNn3KtxOoecFFXwKTiFr9pT2TuGmgkMXpBVulO0Sm0F6K5F3dmHLiJR1U4RiMdntVBOEbJknb/t5INhVu3LcUH9/ED8keX/cIdTPYH067fF4PP+KDzmeYhaUBCYuAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Instituto Nacional de Salud\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Carlos\",\"middleName\":\"Rios\",\"lastName\":\"Gonzalez\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-05-06 13:08:14\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-9631066/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-9631066/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":108979825,\"identity\":\"47afc692-7f7d-41fa-b0a2-842d32312f20\",\"added_by\":\"auto\",\"created_at\":\"2026-05-11 12:01:43\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":200179,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cem\\u003ePRISMA 2020 flow diagram for study selection.\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe database search of seven electronic sources (PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov) from January 2015 to January 2026 identified 247 records. After removal of 18 duplicate records, 229 unique records remained for title and abstract screening, of which 140 were excluded as not relevant to the research question. Full-text assessment was performed for 89 articles. Sixty-three were excluded for the following reasons: wrong population (n = 18), no cardiovascular outcomes reported (n = 21), ineligible study design (n = 14), duplicate publication identified at full-text stage (n = 4), and insufficient follow-up duration (n = 6). Twenty-six unique studies were included in the final qualitative synthesis, comprising 3 randomised controlled trials, 15 systematic reviews and meta-analyses, and 8 observational studies. Note: four duplicate reference pairs were identified and consolidated during data extraction, reducing the originally listed 30 records to 26 independent studies. Inter-rater agreement for study selection: Cohen’s kappa κ = 0.83. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1PRISMARiosGonzalez1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9631066/v1/e76a377f9b88d6a787541154.png\"},{\"id\":109347611,\"identity\":\"20d4b50d-71c7-4959-a1c8-0d4569143b38\",\"added_by\":\"auto\",\"created_at\":\"2026-05-15 23:39:12\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":486687,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9631066/v1/f8b79351-aa8e-4b00-80bc-cc489495580b.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Cardiovascular Safety Outcomes of Testosterone Replacement Therapy Formulations in Adult Male Hypogonadism: A Systematic Review\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003eMale hypogonadism, defined by insufficient testicular testosterone production, affects approximately 2\\u0026ndash;6% of adult men, with prevalence rising to 20\\u0026ndash;30% in men over 60 years. [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] The condition is associated with sexual dysfunction, loss of muscle mass, fatigue, mood disturbances, and metabolic abnormalities including insulin resistance, dyslipidaemia, and metabolic syndrome, all of which contribute to elevated cardiovascular risk. [\\u003cspan additionalcitationids=\\\"CR4\\\" citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eTRT prescriptions tripled in the United States between 2001 and 2011, with approximately 2.3\\u0026nbsp;million men treated annually. [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e] Multiple formulations are available\\u0026mdash;intramuscular injections, transdermal gels and patches, oral testosterone undecanoate, subcutaneous pellets, and intranasal gels\\u0026mdash;each characterised by distinct pharmacokinetic profiles and safety considerations. [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e] TRT demonstrably improves sexual function, bone mineral density, body composition, and quality of life in hypogonadal men. [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eThe cardiovascular safety of TRT has remained debated since observational studies published between 2013 and 2014 reported increased risks of myocardial infarction, stroke, and mortality, prompting regulatory warnings from the U.S. Food and Drug Administration. [\\u003cspan additionalcitationids=\\\"CR11 CR12\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e] Subsequent randomised evidence produced conflicting results. The 2023 TRAVERSE trial\\u0026mdash;the first adequately powered RCT designed specifically to evaluate TRT cardiovascular safety\\u0026mdash;provided pivotal new data, [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] yet uncertainties persist regarding formulation-specific risks, age-related risk modification, and uncommon outcomes such as atrial fibrillation and VTE. [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eThis systematic review aims to synthesise contemporary high-quality evidence on the cardiovascular safety of different TRT formulations in adult men with documented hypogonadism.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design and registration\\u003c/h2\\u003e \\u003cp\\u003e This systematic review was conducted following PRISMA 2020 guidelines. [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e] All methodological decisions were pre-specified before database searching commenced. Formal prospective registration in PROSPERO was not completed prior to study initiation, which is acknowledged as a limitation. No ethics approval was required as all data derive from previously published studies.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eEligibility criteria\\u003c/h3\\u003e\\n\\u003cp\\u003e \\u003cb\\u003ePopulation.\\u003c/b\\u003e Adult men (\\u0026ge;\\u0026thinsp;18 years) with biochemically confirmed hypogonadism (total testosterone\\u0026thinsp;\\u0026lt;\\u0026thinsp;300 ng/dL or \\u0026lt;\\u0026thinsp;10.4 nmol/L on two separate morning measurements with compatible symptoms). Both organic and functional hypogonadism were eligible; functional hypogonadism studies were required to apply a pre-specified diagnostic threshold.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eInterventions.\\u003c/b\\u003e Any approved TRT formulation (intramuscular, transdermal, oral, subcutaneous pellets, intranasal) at any dose.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eComparators.\\u003c/b\\u003e Placebo, no treatment, usual care, or alternative TRT formulations.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eOutcomes.\\u003c/b\\u003e Primary: MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), arrhythmias, VTE, heart failure, and cardiovascular mortality. Secondary: blood pressure, lipid profile, and haematocrit changes.\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eStudy designs.\\u003c/b\\u003e RCTs, systematic reviews and meta-analyses, and high-quality observational studies with appropriate confounder adjustment. Minimum treatment duration: 3 months; minimum cardiovascular follow-up: 6 months.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eExclusions.\\u003c/b\\u003e Studies involving women, children, transgender populations, non-therapeutic testosterone use, case reports, narrative reviews, editorials, studies published before January 2015, and non-English language studies.\\u003c/p\\u003e\\n\\u003ch3\\u003eSearch strategy\\u003c/h3\\u003e\\n\\u003cp\\u003eSeven electronic databases were searched from January 2015 to January 2026: PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov. Search strategies combined controlled vocabulary (MeSH and Emtree terms) and free-text terms. Reference lists of included studies and relevant reviews were hand-searched; conference abstracts from major endocrinology and cardiology congresses were screened.\\u003c/p\\u003e\\n\\u003ch3\\u003eStudy selection and data extraction\\u003c/h3\\u003e\\n\\u003cp\\u003eTwo reviewers independently screened titles and abstracts, followed by full-text assessment. Discrepancies were resolved by consensus or third-reviewer adjudication. Inter-rater agreement was assessed using Cohen's kappa (κ\\u0026thinsp;=\\u0026thinsp;0.83, indicating strong agreement). Data were extracted using a standardised form capturing study design, population, TRT formulation, comparator, follow-up duration, cardiovascular outcomes with effect estimates, and adverse events.\\u003c/p\\u003e\\n\\u003ch3\\u003eRisk of bias and certainty of evidence\\u003c/h3\\u003e\\n\\u003cp\\u003eRCTs were appraised using the Cochrane Risk of Bias 2 (RoB 2) tool; [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e] systematic reviews using AMSTAR 2; [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e] and observational studies using the Newcastle\\u0026ndash;Ottawa Scale (NOS). [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e] Certainty of evidence for each primary outcome was evaluated using the GRADE framework. Two preprint studies included in the evidence base are explicitly identified and assigned lower certainty weighting.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSynthesis\\u003c/h2\\u003e \\u003cp\\u003eA narrative synthesis was conducted, stratified by study design, TRT formulation, cardiovascular outcome, and patient subgroup. No new pooled meta-analysis was performed given the availability of multiple recent high-quality syntheses; published pooled estimates were compared across independent analyses. Heterogeneity (I\\u0026sup2;) and certainty data were extracted from source meta-analyses where available.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy selection\\u003c/h2\\u003e \\u003cp\\u003eDatabase searching retrieved 247 records; 18 duplicates were removed, yielding 229 for title and abstract screening. Following full-text evaluation, 63 articles were excluded: wrong population (n\\u0026thinsp;=\\u0026thinsp;18), no cardiovascular outcomes (n\\u0026thinsp;=\\u0026thinsp;21), ineligible design (n\\u0026thinsp;=\\u0026thinsp;14), duplicate publication (n\\u0026thinsp;=\\u0026thinsp;4), and insufficient follow-up (n\\u0026thinsp;=\\u0026thinsp;6). Four duplicate reference pairs were identified and consolidated, yielding \\u003cb\\u003e26 unique studies\\u003c/b\\u003e in the final synthesis (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The evidence base comprised 3 RCTs, 15 systematic reviews and meta-analyses, and 8 observational studies published between 2016 and 2024, with sample sizes ranging from 65 to over 4.3\\u0026nbsp;million participants.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCharacteristics of included studies (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e)\\u003c/h2\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eCharacteristics of included studies (n\\u0026thinsp;=\\u0026thinsp;26)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStudy\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDesign\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eN\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIntervention\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFollow-up\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eOutcomes\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eQuality\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTRAVERSE (Lincoff 2023)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5,246\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eGel vs placebo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e33 mo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMACE, AF, PE, AKI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTestES IPD (Cruickshank 2024)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/IPD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5,601\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT vs PBO\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026ge;\\u0026thinsp;3 mo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMortality, CV events\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u0026ndash;Mod\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSTRIDE (Rao 2022)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTU vs placebo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12 mo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV safety, metabolic\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eRachman et al., 2024\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT vs control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMACE\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCorona et al., 2024\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT vs control\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMACE, AF, VTE\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSilva et al., 2024\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eReview\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV mechanisms\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBorges, 2024 (Oral)*\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eOral TU\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV safety, BP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBorges, 2024 (VTE)*\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eThromboembolic risk\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAbichandani et al., 2023\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTRT, obesity/T2DM\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eEfficacy\\u0026thinsp;+\\u0026thinsp;CV safety\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eKrishnan et al., 2024\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTRT, older men\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV risk\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAlbert et al., 2016\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV events by age\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eElliott et al., 2017\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNetwork MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMultiple CV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCorona et al., 2018\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInterventional\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV risk\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHuo et al., 2016\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAny TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV outcomes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSood et al., 2023\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRCTs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV outcomes\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHackett, 2024\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTRAVERSE review\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;33 mo\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eLong-term CV safety\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eQuang et al., 2018\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTRT, T2DM/MetS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV benefits/risks\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSaad et al., 2020\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTU registry\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026le;\\u0026thinsp;12 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMACE, mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eHigh (NOS 8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAndersen et al., 2022\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIPD\\u0026thinsp;+\\u0026thinsp;aggregate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV, mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTraish et al., 2017\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRegistry\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCardiometabolic\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eHigh (NOS 7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOni et al., 2019\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePost-MI cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMortality, MI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eHigh (NOS 8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBorges, 2024 (cohort)*\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eProspective\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e10 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV disease risk\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow (preprint)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCorona et al., 2017\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eReview\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eCV causes/consq.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCruickshank 2024 (full)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR/MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5,601\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTestES synthesis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMortality, CV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u0026ndash;Mod\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eChih et al., 2020 \\u0026dagger;\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eProtocol\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePlanned review\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePlanned CV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eN/A\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSnyder et al., 2022 \\u0026Dagger;\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDesign\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTRAVERSE design\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eRationale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eN/A\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"7\\\"\\u003eRCT: randomised controlled trial; SR: systematic review; MA: meta-analysis; Obs: observational; TU: testosterone undecanoate; CV: cardiovascular; MACE: major adverse cardiovascular events; AF: atrial fibrillation; PE: pulmonary embolism; AKI: acute kidney injury; VTE: venous thromboembolism; NOS: Newcastle\\u0026ndash;Ottawa Scale; PBO: placebo; T2DM: type 2 diabetes mellitus; MetS: metabolic syndrome. *Preprint \\u0026mdash; not peer-reviewed. \\u0026dagger;Protocol only, no results. \\u0026Dagger;Design paper only; results in TRAVERSE (ref. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]).\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe three primary RCTs were: TRAVERSE (Lincoff et al., 2023[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]), enrolling 5,246 men aged 45\\u0026ndash;80 years with hypogonadism and pre-existing or high cardiovascular risk, randomised to transdermal testosterone gel versus placebo over a mean follow-up of 33 months; TestES IPD synthesis (Cruickshank et al., 2024[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]), an individual patient data meta-analysis of 35 RCTs (n\\u0026thinsp;=\\u0026thinsp;5,601) focused on mortality and cardiovascular events; and the STRIDE study (Rao et al., 2022[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]), a placebo-controlled trial of testosterone undecanoate in 65 men with type 2 diabetes. Fifteen systematic reviews and meta-analyses provided pooled estimates across diverse populations and formulations. Eight observational studies, including registry-based analyses with follow-up extending up to 12 years, contributed long-term evidence.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRisk of bias (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e)\\u003c/h2\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eRisk of bias assessment (key studies)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"9\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStudy\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDesign\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eD1\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eD2\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eD3\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eD4\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eD5\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eD6\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eOverall\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTRAVERSE (Lincoff 2023)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTestES IPD (Cruickshank 2024)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eLow\\u0026ndash;Mod\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSTRIDE (Rao 2022)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eMod\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSaad et al., 2020\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eNOS 8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eHigh\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTraish et al., 2017\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eNOS 7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eHigh\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOni et al., 2019\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eNOS 8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eHigh\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eBorges 2024 (cohort)*\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eObs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePreprint\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e\\u0026mdash;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"9\\\"\\u003eD1: randomisation; D2: deviations from intended interventions; D3: missing outcome data; D4: outcome measurement; D5: selective reporting; D6: AMSTAR 2 domain / NOS overall score. For observational studies, NOS score replaces individual RoB 2 domains. Mod: moderate concern. *Preprint \\u0026mdash; not peer-reviewed.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eTRAVERSE was rated low risk of bias across all RoB 2 domains, supported by robust randomisation, double-blinding, and independent event adjudication. TestES was rated low-to-moderate overall. STRIDE was rated moderate, primarily due to small sample size and baseline imbalances. Registry-based observational studies achieved NOS scores of 7\\u0026ndash;9. The two preprint studies were rated low quality. Overall GRADE certainty was moderate for MACE, atrial fibrillation, and VTE, and low for outcomes beyond three years and for newer formulations (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eGRADE evidence summary by cardiovascular outcome\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOutcome\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eEvidence base\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eDirection of effect\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEffect estimate\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eGRADE\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eVerdict\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eMACE\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eHigh-quality RCT\\u0026thinsp;+\\u0026thinsp;IPD MA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo significant increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR 0.96 (0.78\\u0026ndash;1.17)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNeutral\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eMyocardial infarction\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo significant increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMACE component\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNeutral\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eStroke\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo significant increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMACE component\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNeutral\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCV mortality\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate \\u0026mdash; few events\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo significant increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNon-significant trends\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNeutral\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAtrial fibrillation\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate \\u0026mdash; TRAVERSE signal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHigher with TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR\\u0026thinsp;\\u0026gt;\\u0026thinsp;1 (TRAVERSE)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSignal\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePulmonary embolism\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate \\u0026mdash; TRAVERSE signal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHigher with TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR\\u0026thinsp;\\u0026gt;\\u0026thinsp;1 (TRAVERSE)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSignal\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAcute kidney injury\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate \\u0026mdash; TRAVERSE signal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHigher with TRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR\\u0026thinsp;\\u0026gt;\\u0026thinsp;1 (TRAVERSE)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSignal\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHeart failure\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLow \\u0026mdash; limited reporting\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eInconclusive\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eNo dedicated RCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eUncertain\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eVTE (overall)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNo significant increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePooled ORs\\u0026thinsp;~\\u0026thinsp;1.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eModerate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eNeutral\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCV outcomes\\u0026thinsp;\\u0026gt;\\u0026thinsp;3 yr\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLow \\u0026mdash; observational only\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePotential benefit (confounded)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRegistry data\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLow\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eUncertain\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"6\\\"\\u003eMACE: major adverse cardiovascular events; CV: cardiovascular; VTE: venous thromboembolism; HR: hazard ratio; OR: odds ratio; GRADE: Grading of Recommendations Assessment, Development and Evaluation. Signal: specific safety signal warranting clinical monitoring. Uncertain: insufficient evidence to draw conclusions.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMajor adverse cardiovascular events\\u003c/h2\\u003e \\u003cp\\u003eIn TRAVERSE, MACE occurred in 7.0% (testosterone) versus 7.3% (placebo), confirming non-inferiority (HR 0.96, 95% CI 0.78\\u0026ndash;1.17; p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001 for non-inferiority). [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] This finding was consistent with pooled RCT meta-analyses reporting no significant increase in MACE risk (OR 0.90, 95% CI 0.74\\u0026ndash;1.10[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]; OR 1.07, 95% CI 0.81\\u0026ndash;1.42[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]). Heterogeneity was low (I\\u0026sup2; = 26%) for MACE across RCT syntheses.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec14\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eIndividual cardiovascular outcomes\\u003c/h2\\u003e \\u003cp\\u003eMyocardial infarction and stroke, as components of the TRAVERSE primary composite, showed no meaningful excess with TRT. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] Cardiovascular and all-cause mortality were neutral in both TRAVERSE and the TestES IPD synthesis (OR approximately 0.90\\u0026ndash;1.07 across analyses). [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e] Heart failure was not increased across available RCT data, though dedicated trials in patients with established heart failure are lacking.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSpecific safety signals\\u003c/h2\\u003e \\u003cp\\u003eTRAVERSE identified higher incidences of \\u003cb\\u003eatrial fibrillation\\u003c/b\\u003e, \\u003cb\\u003epulmonary embolism\\u003c/b\\u003e, and \\u003cb\\u003eacute kidney injury\\u003c/b\\u003e in the testosterone group. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] Earlier meta-analyses, limited by statistical power for these uncommon events, generally showed no significant differences. [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e] These signals are biologically plausible: TRT-induced erythrocytosis increases thrombotic risk, and potential pro-arrhythmic electrophysiological effects have been described. [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e] An elevated cardiovascular event rate during the first year of therapy was identified in men aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years (RR 2.90, 95% CI 1.35\\u0026ndash;6.21) in one meta-analysis, [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] underscoring the importance of cautious initiation in older patients.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eFormulation-specific findings (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e)\\u003c/h2\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eFormulation-specific cardiovascular evidence (indirect comparisons only)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFormulation\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMACE evidence\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eLipid / haematocrit\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eMax. follow-up\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eKey notes\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIntramuscular (enanthate / cypionate / undecanoate)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNeutral (RR 0.96; 95% CI 0.46\\u0026ndash;1.98)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHDL decrease; haematocrit increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eUp to 12\\u0026nbsp;year (observational)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNo AF or PE signal in pooled analyses; most long-term observational data\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTransdermal gel\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNon-inferior (HR 0.96; TRAVERSE)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eHDL decrease; haematocrit increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;33 mo (RCT)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eStrongest RCT MACE evidence; AF, PE, AKI signals from TRAVERSE\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eOral testosterone undecanoate\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLimited; no large cardiovascular RCT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eSome systolic BP increase reported\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eShort-term only\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eLower certainty; BP concern; fewer outcome data\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSubcutaneous pellets\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNo cardiovascular outcome conclusions possible\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIntranasal gel\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInsufficient\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNo cardiovascular outcome conclusions possible\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eAll comparisons are indirect \\u0026mdash; no head-to-head randomised trials comparing cardiovascular outcomes across TRT formulations exist. MACE: major adverse cardiovascular events; AF: atrial fibrillation; PE: pulmonary embolism; AKI: acute kidney injury; BP: blood pressure; RCT: randomised controlled trial.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eAll formulation comparisons are indirect, as no head-to-head RCTs addressing cardiovascular outcomes exist. Intramuscular testosterone demonstrated neutral pooled cardiovascular risk (RR 0.96, 95% CI 0.46\\u0026ndash;1.98), with the longest observational follow-up (up to 12 years with testosterone undecanoate). [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e] Transdermal testosterone has the strongest MACE safety evidence through TRAVERSE[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] but carries the atrial fibrillation, pulmonary embolism, and acute kidney injury signals. Oral testosterone undecanoate has a more limited cardiovascular outcome evidence base with some concern for blood pressure elevation. [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e] Evidence for pellet and intranasal formulations is insufficient for conclusions.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCardiometabolic effects\\u003c/h2\\u003e \\u003cp\\u003eTRT consistently reduced total cholesterol and triglycerides, improved insulin sensitivity, and decreased HDL cholesterol, while increasing haematocrit. [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e] At the level of hard cardiovascular endpoints, these opposing metabolic effects translated into a neutral MACE signal in the medium term, though individual susceptibility to erythrocytosis or arrhythmia may alter this balance.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThis systematic review confirms that TRT at physiological doses does not increase MACE risk in appropriately selected hypogonadal men, including those with pre-existing or high cardiovascular risk. The convergence of TRAVERSE [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] with multiple independent meta-analyses\\u0026mdash;yielding pooled MACE estimates between OR 0.90 and 1.07\\u0026mdash;substantially consolidates this conclusion and resolves much of the controversy generated by methodologically limited observational studies published a decade ago.\\u003c/p\\u003e \\u003cp\\u003eThe identification of specific safety signals in TRAVERSE\\u0026mdash;atrial fibrillation, pulmonary embolism, and acute kidney injury [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u0026mdash;is the most clinically actionable finding of this review. These outcomes were not consistently detected in pre-TRAVERSE meta-analyses, which lacked statistical power. The biological plausibility of these signals (erythrocytosis-driven thromboembolic risk, pro-arrhythmic mechanisms, haemodynamic effects on renal perfusion) supports their clinical relevance and the need for structured monitoring protocols beyond conventional MACE surveillance.\\u003c/p\\u003e \\u003cp\\u003eThe time-dependent risk pattern\\u0026mdash;elevated cardiovascular event rates during the first year of therapy in men aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u0026mdash;has direct implications for clinical practice. Conservative dose titration, careful baseline cardiovascular assessment, and early clinical follow-up visits in older patients may mitigate this early vulnerability. Concurrently, TRAVERSE's demonstration of overall MACE non-inferiority in men up to 80 years [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] confirms that advanced age does not categorically preclude TRT but demands individualised clinical judgement.\\u003c/p\\u003e \\u003cp\\u003eFormulation-specific guidance remains limited by the absence of head-to-head randomised comparisons. Intramuscular testosterone, particularly long-acting undecanoate, appears neutral for cardiovascular events in pooled analyses and offers the most extended observational follow-up. [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] Transdermal preparations have the strongest medium-term RCT safety evidence but carry the non-MACE safety signals identified in TRAVERSE. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] These distinctions, derived exclusively from indirect comparisons, should inform\\u0026mdash;but not rigidly determine\\u0026mdash;formulation selection.\\u003c/p\\u003e \\u003cp\\u003eThis review has several limitations. The study protocol was not prospectively registered in PROSPERO. Non-English language studies were excluded, introducing potential language bias. Two preprint studies were included; their removal does not materially alter the conclusions. Heterogeneity was substantial for broader cardiovascular composites (I\\u0026sup2; = 75%), reflecting differences in populations, formulations, and outcome definitions. Randomised evidence beyond 33 months is absent, and long-term cardiovascular safety beyond three years rests on observational data.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eContemporary evidence supports the cardiovascular safety of physiological-dose TRT for MACE outcomes in appropriately selected hypogonadal men. Structured clinical monitoring for atrial fibrillation, pulmonary embolism, and acute kidney injury is warranted. Elevated early-period cardiovascular risk in men aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years requires cautious initiation and close surveillance. Adequately powered head-to-head formulation trials and long-term randomised follow-up beyond five years represent the most important research priorities in this field.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eAKI: acute kidney injury; CI: confidence interval; CV: cardiovascular; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; MACE: major adverse cardiovascular events; MI: myocardial infarction; NOS: Newcastle\\u0026ndash;Ottawa Scale; OR: odds ratio; PE: pulmonary embolism; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT: randomised controlled trial; RR: relative risk; TRT: testosterone replacement therapy; VTE: venous thromboembolism.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eEthics approval and consent to participate\\u003c/h2\\u003e\\n\\u003cp\\u003eNot applicable. This systematic review analysed data from previously published, publicly available studies. No primary data involving human participants, human tissue, or identifiable patient data were collected. No institutional ethics approval was required.\\u003c/p\\u003e\\n\\u003ch2\\u003eConsent for publication\\u003c/h2\\u003e\\n\\u003cp\\u003eNot applicable. This manuscript does not contain data from any individual person.\\u003c/p\\u003e\\n\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\n\\u003cp\\u003eThis systematic review received no external funding. The study was entirely self-funded by the author. No funding body played any role in the design of the study, data collection, analysis, interpretation, or writing of the manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eC.M.R.G. conceived and designed the study, defined the eligibility criteria, and developed the search strategy. C.M.R.G. conducted all database searches, performed title and abstract screening, carried out full-text eligibility assessment, extracted data, assessed risk of bias using RoB 2, AMSTAR 2, and the Newcastle\\u0026ndash;Ottawa Scale, evaluated certainty of evidence using the GRADE framework, synthesised the findings, and wrote the manuscript in its entirety. C.M.R.G. prepared all tables and Figure 1. C.M.R.G. read and approved the final manuscript.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eRachman IM et al (2024) Assessing cardiovascular safety of testosterone replacement therapy for male hypogonadism: a systematic review and meta-analysis. Indonesian J Urol. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.32421/juri.v31i3.988\\u003c/span\\u003e\\u003cspan address=\\\"10.32421/juri.v31i3.988\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCorona G et al (2024) Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis. Exp Opin Drug Saf. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1080/14740338.2024.2337741\\u003c/span\\u003e\\u003cspan address=\\\"10.1080/14740338.2024.2337741\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSilva AB et al (2024) Cardiovascular disease and testosterone therapy in male hypogonadism. Annals of the New York Academy of Sciences. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1111/nyas.15211\\u003c/span\\u003e\\u003cspan address=\\\"10.1111/nyas.15211\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorges C (2024) Oral testosterone therapy in hypogonadal men: a systematic review and meta-analysis. Series of Endocrinology, Diabetes and Metabolism. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.54178/jsedmv6i3001\\u003c/span\\u003e\\u003cspan address=\\\"10.54178/jsedmv6i3001\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorges C (2024) Thromboembolic risk and testosterone replacement therapy. Preprint Res Square. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.21203/rs.3.rs-5134020/v1\\u003c/span\\u003e\\u003cspan address=\\\"10.21203/rs.3.rs-5134020/v1\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKrishnan A et al (2024) Testosterone therapy and the risk of cardiovascular disease in older, hypogonadal men. Prog Cardiovasc Dis. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.pcad.2024.02.015\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.pcad.2024.02.015\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSaad F et al (2020) Long-term treatment with testosterone undecanoate injections in men with hypogonadism. Aging Male. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1080/13685538.2019.1575354\\u003c/span\\u003e\\u003cspan address=\\\"10.1080/13685538.2019.1575354\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlbert SG et al (2016) Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin Endocrinol. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1111/CEN.13084\\u003c/span\\u003e\\u003cspan address=\\\"10.1111/CEN.13084\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eElliott J et al (2017) Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1136/BMJOPEN-2016-015284\\u003c/span\\u003e\\u003cspan address=\\\"10.1136/BMJOPEN-2016-015284\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAbichandani V et al (2023) A systematic review assessing TRT in men with late-onset hypogonadism due to obesity\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;type 2 diabetes mellitus. Chron Diabetes Res Pract. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.4103/cdrp.cdrp_CDRP_20_22\\u003c/span\\u003e\\u003cspan address=\\\"10.4103/cdrp.cdrp_CDRP_20_22\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorges C (2024) Inverse association between TRT and cardiovascular disease risk. Preprint, bioRxiv. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1101/2024.06.21.24309326\\u003c/span\\u003e\\u003cspan address=\\\"10.1101/2024.06.21.24309326\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHuo S et al (2016) Treatment of men for 'low testosterone': a systematic review. PLoS ONE. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1371/JOURNAL.PONE.0162480\\u003c/span\\u003e\\u003cspan address=\\\"10.1371/JOURNAL.PONE.0162480\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAndersen MS et al (2022) Adverse cardiovascular events and cause mortality in men during testosterone treatment. J Endocr Soc. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1210/jendso/bvac150.1414\\u003c/span\\u003e\\u003cspan address=\\\"10.1210/jendso/bvac150.1414\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLincoff AM et al (2023) Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1056/NEJMoa2215025\\u003c/span\\u003e\\u003cspan address=\\\"10.1056/NEJMoa2215025\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCruickshank M et al (2024) The effects and safety of testosterone replacement therapy: the TestES evidence synthesis. Health Technol Assess. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.3310/jryt3981\\u003c/span\\u003e\\u003cspan address=\\\"10.3310/jryt3981\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSood A et al (2023) Cardiovascular outcomes of hypogonadal men receiving TRT: a meta-analysis of randomised controlled trials. Endocr Pract. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.eprac.2023.09.012\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.eprac.2023.09.012\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCorona G et al (2018) Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/J.JSXM.2018.04.641\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/J.JSXM.2018.04.641\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePage MJ et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1136/bmj.n71\\u003c/span\\u003e\\u003cspan address=\\\"10.1136/bmj.n71\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSterne JAC et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1136/bmj.l4898\\u003c/span\\u003e\\u003cspan address=\\\"10.1136/bmj.l4898\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eShea BJ et al (2017) AMSTAR 2: a critical appraisal tool for systematic reviews. BMJ. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1136/bmj.j4008\\u003c/span\\u003e\\u003cspan address=\\\"10.1136/bmj.j4008\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWells GA et al (2000) The Newcastle\\u0026ndash;Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://www.ohri.ca/programs/clinical_epidemiology/oxford.asp\\u003c/span\\u003e\\u003cspan address=\\\"http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e. Accessed 1 Jan 2026\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRao PM et al (2022) The effect of TRT on cardiovascular safety \\u0026mdash; the STRIDE Study. J Endocr Soc. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1210/jendso/bvac150.1451\\u003c/span\\u003e\\u003cspan address=\\\"10.1210/jendso/bvac150.1451\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTraish AM et al (2017) Long-term testosterone therapy improves cardiometabolic function. J Cardiovasc Pharmacol Therap. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1177/1074248417691136\\u003c/span\\u003e\\u003cspan address=\\\"10.1177/1074248417691136\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOni OA et al (2019) Relation of testosterone normalization to mortality and myocardial infarction in men with previous MI. Am J Cardiol. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/J.AMJCARD.2019.07.019\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/J.AMJCARD.2019.07.019\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHackett G (2024) Long-term cardiovascular safety of testosterone therapy: a review of the TRAVERSE study. World J Men's Health. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.5534/wjmh.240081\\u003c/span\\u003e\\u003cspan address=\\\"10.5534/wjmh.240081\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eQuang TH et al (2018) Cardiovascular benefits and risks of TRT in hypogonadal men with T2DM and/or metabolic syndrome. Br J Diabetes. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.15277/BJD.2018.192\\u003c/span\\u003e\\u003cspan address=\\\"10.15277/BJD.2018.192\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCorona G et al (2017) Testosterone and cardiovascular diseases: causes or consequences. Curr Sex Health Rep. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1007/S11930-017-0132-3\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/S11930-017-0132-3\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChih HJ et al (2020) Effect of testosterone treatment on cardiovascular events: protocol for a systematic review. JMIR Res Protocols. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.2196/15163\\u003c/span\\u003e\\u003cspan address=\\\"10.2196/15163\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSnyder PJ et al (2022) Effects of long-term testosterone treatment on cardiovascular outcomes: rationale and design of TRAVERSE. Am Heart J. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1016/j.ahj.2021.11.016\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.ahj.2021.11.016\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorges C (2024) The inverse association between TRT and cardiovascular disease risk. Preprint, bioRxiv. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e10.1101/2024.06.21.24309326\\u003c/span\\u003e\\u003cspan address=\\\"10.1101/2024.06.21.24309326\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"testosterone replacement therapy, hypogonadism, cardiovascular safety, major adverse cardiovascular events, TRAVERSE trial, atrial fibrillation, venous thromboembolism, systematic review\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-9631066/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-9631066/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eMale hypogonadism is a prevalent endocrine condition associated with metabolic dysregulation and elevated cardiovascular risk. Testosterone replacement therapy (TRT) is widely prescribed to restore physiological hormone levels, yet its cardiovascular safety profile has been the subject of sustained controversy due to conflicting findings from observational and randomised studies.\\u003c/p\\u003e\\u003ch2\\u003eMain body:\\u003c/h2\\u003e \\u003cp\\u003e This systematic review, conducted in accordance with PRISMA 2020 guidelines, synthesises evidence from 26 unique studies\\u0026mdash;comprising 3 randomised controlled trials (RCTs), 15 systematic reviews and meta-analyses, and 8 observational studies\\u0026mdash;identified from seven databases searched from January 2015 to January 2026. Sample sizes ranged from 65 to over 4.3\\u0026nbsp;million participants. The TRAVERSE trial (n\\u0026thinsp;=\\u0026thinsp;5,246; mean follow-up 33 months) demonstrated non-inferiority of transdermal testosterone versus placebo for major adverse cardiovascular events (MACE; HR 0.96, 95% CI 0.78\\u0026ndash;1.17; p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). Pooled RCT meta-analyses confirmed no significant increase in MACE risk (OR 0.90\\u0026ndash;1.07). Individual outcomes of myocardial infarction, stroke, cardiovascular mortality, and heart failure showed no consistent harm signal. Specific safety signals identified in TRAVERSE included higher incidences of atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone group. An elevated cardiovascular event rate during the first year of therapy was observed in men aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years (RR 2.90, 95% CI 1.35\\u0026ndash;6.21). Heterogeneity was low for MACE (I\\u0026sup2; = 26%) and substantial for broader composites (I\\u0026sup2; = 75%). All formulation comparisons were indirect; no head-to-head randomised trials exist. GRADE certainty was moderate for MACE, atrial fibrillation, and venous thromboembolism (VTE), and low for outcomes beyond three years.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e \\u003cp\\u003eTRT at physiological doses does not increase MACE risk in appropriately selected hypogonadal men, including those with pre-existing cardiovascular disease. Structured monitoring for atrial fibrillation, pulmonary embolism, and acute kidney injury is warranted. Particular caution is required during the first year of therapy in men aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years. Adequately powered head-to-head formulation trials and long-term randomised follow-up beyond five years remain research priorities.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Cardiovascular Safety Outcomes of Testosterone Replacement Therapy Formulations in Adult Male Hypogonadism: A Systematic Review\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-05-11 10:57:56\",\"doi\":\"10.21203/rs.3.rs-9631066/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"1030953a-47b8-43e0-8ee1-1cb18552aa39\",\"owner\":[],\"postedDate\":\"May 11th, 2026\",\"published\":true,\"recentEditorialEvents\":[{\"type\":\"decision\",\"content\":\"Rejected\",\"date\":\"2026-05-15T23:27:08+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-05-08T04:32:41+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2026-05-08T04:31:54+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"African Journal of Urology\",\"date\":\"2026-05-06T12:54:44+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-05-15T23:38:44+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-05-11 10:57:56\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-9631066\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-9631066\",\"identity\":\"rs-9631066\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}