The TRAVERSE trial: cardiovascular safety of testosterone therapy for older men.

For decades, there has been controversy about whether testosterone therapy has deleterious effects on the risk of major cardiovascular events in older men. As the number of prescriptions for testosterone therapy has escalated, this controversy has heightened. 1 Bandari J Ayyash OM Emery SL Wessel CB Davies BJ Marketing and testosterone treatment in the USA: a systematic review. Eur Urol Focus. 2017; 3: 395-402 Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar Although some epidemiological studies have suggested an association between testosterone therapy and risk of major cardiovascular events, an equal (or greater) number of epidemiological studies have demonstrated no increase or even a decreased risk associated with testosterone therapy. 2 Thirumalai A Anawalt BD Relationships between endogenous and exogenous testosterone and cardiovascular disease in men. Rev Endocr Metab Disord. 2022; 23: 1305-1322 Crossref PubMed Scopus (3) Google Scholar Randomised trials have been underpowered, 3 Basaria S Coviello AD Travison TG et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363: 109-122 Crossref PubMed Scopus (1202) Google Scholar , 4 Basaria S Harman SM Travison TG et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA. 2015; 314: 570-581 Crossref PubMed Scopus (180) Google Scholar , 5 Snyder PJ Bhasin S Cunningham GR et al. Effects of testosterone treatment in older men. N Engl J Med. 2016; 374: 611-624 Crossref PubMed Scopus (579) Google Scholar , 6 Budoff MJ Ellenberg SS Lewis CE et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017; 317: 708-716 Crossref PubMed Scopus (262) Google Scholar , 7 Wittert G Bracken K Robledo KP et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021; 9: 32-45 Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar but they have generally suggested that testosterone therapy at approximately physiological dosages did not increase the risk of major cardiovascular events for men (table). TableMajor randomised, placebo-controlled testosterone trials with cardiovascular outcomes Participants Design Primary outcome Cardiovascular outcomes Comments TOM (2010) 3 Basaria S Coviello AD Travison TG et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363: 109-122 Crossref PubMed Scopus (1202) Google Scholar 209 men aged ≥65 years with limited mobility and serum testosterone 3·5–12·1 nmol/L Testosterone 100 mg transdermal gel vs placebo gel daily for 6 months Lower extremity strength and physical function Study stopped early due to increased cardiovascular risk with testosterone therapy Four major cardiovascular events (two myocardial infarctions, one stroke, and one cardiovascular-related death in testosterone group) vs no major cardiovascular events in placebo group TEAAM (2015) 4 Basaria S Harman SM Travison TG et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA. 2015; 314: 570-581 Crossref PubMed Scopus (180) Google Scholar 308 men aged ≥60 years with serum testosterone 3·47–13·9 nmol/L and no known identifiable pathology of HPT axis Testosterone 75 mg transdermal gel vs placebo gel daily for 3 years Carotid artery intimal thickness and coronary artery calcium scores No differences in progression of carotid intimal thickness or coronary artery calcium scores 12 major cardiovascular events (three myocardial infarctions, five coronary revascularisations, three strokes, and one cardiovascular-related death) in testosterone group vs four major cardiovascular events (two myocardial infarctions and two coronary revascularisations) in placebo group Testosterone Trials (2016) 5 Snyder PJ Bhasin S Cunningham GR et al. Effects of testosterone treatment in older men. N Engl J Med. 2016; 374: 611-624 Crossref PubMed Scopus (579) Google Scholar 790 men aged ≥65 years with serum testosterone ≥9·5 nmol/L and no known identifiable pathology of HPT axis Testosterone 50 mg transdermal gel vs placebo gel daily for 1 year Seven sub-studies with different primary outcomes No differences in major cardiovascular outcomes Overall study major cardiovascular outcomes: seven major cardiovascular events (two myocardial infarctions and five strokes) in testosterone group vs seven major cardiovascular events (one myocardial infarction, five strokes, and one cardiovascular-related death) in the placebo group during the 1-year treatment period; two major cardiovascular events (one myocardial infarction and one stroke) in the testosterone group vs nine major cardiovascular events (eight myocardial infarctions, one cardiovascular-related death) in placebo group during the 1-year post-treatment period Testosterone Trials (2017) 6 Budoff MJ Ellenberg SS Lewis CE et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017; 317: 708-716 Crossref PubMed Scopus (262) Google Scholar 170 men aged ≥65 years with serum testosterone ≥9·5 nmol/L and no known identifiable pathology of HPT axis Testosterone 50 mg transdermal gel vs placebo gel daily for 1 year Progression of non-calcified coronary artery plaque volume No differences in major cardiovascular outcomes Baseline non-calcified, calcified, and total plaque volumes and coronary artery calcium scores were about 50% higher in the placebo group vs the testosterone-treated group; no significant differences in coronary artery calcification scores (secondary outcome) T4DM (2021) 7 Wittert G Bracken K Robledo KP et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021; 9: 32-45 Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar 1007 men aged 50–74 years (mean age 60 years) with impaired glucose tolerance or newly diagnosed type 2 diabetes, serum testosterone ≤14 nmol/L, and no known identifiable pathology of HPT axis Testosterone undecanoate 1000 mg vs placebo intramuscular injection at 0 weeks and 6 weeks, then every 3 months for 2 years Prevention or reversion of diabetes No differences in major cardiovascular outcomes 21 major cardiovascular events (seven ischaemic heart disease, four cerebrovascular, eight arrhythmias, and two deep venous thromboses) in testosterone group vs 19 major cardiovascular events (13 ischaemic heart disease, three cerebrovascular, and three arrhythmias) in placebo group; 12% of testosterone group had type 2 diabetes vs 21% of placebo group at the end of 2-year treatment phase (type 2 diabetes was defined by oral glucose tolerance test results) TRAVERSE (2023) 8 Lincoff AM Bhasin S Flevaris P et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023; 389: 107-117 Crossref PubMed Scopus (9) Google Scholar 5246 men aged 45–80 years (mean age 63 years) with serum testosterone >3·5 nmol/L and ≤10·4 nmol/L, and no congenital or acquired hypogonadism for whom long-term therapy with placebo would not be medically appropriate Testosterone gel (titrated to maintain serum total testosterone concentrations between 12·1 nmol/L and 26·0 nmol/L and to maintain a hematocrit of ≤54%) vs placebo gel daily for mean of 22 months Composite of major cardiovascular adverse event (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular-related death) No signficant difference in the composite of major cardiovascular adverse events 191 major cardiovascular events (68 non-fatal myocardial infarctions, 36 non-fatal strokes, and 87 cardiovascular-related deaths) in testosterone group vs 203 major cardiovascular events (62 non-fatal myocardial infarctions, 38 non-fatal strokes, 103 cardiovascular-related deaths) in placebo group HPT=hypothalamic–pituitary–testicular. Open table in a new tab HPT=hypothalamic–pituitary–testicular.