Peer-reviewed / Systematic review + Meta-analysis / People
- Meta-analysis of data from more than 3,400 patients with hypogonadism from 17 clinical trials finds little evidence that testosterone treatment increases the risk of cardiovascular events such as arrhythmia, heart attack, and stroke, in the short-to-medium term.
- The rate of cardiovascular events was not significantly higher for participants receiving testosterone treatment (120/1,601 [7·5%]) compared to placebo (110/1,519 [7·2%]). Fewer deaths were reported during testosterone (6/1,621 deaths, [0·4%]) than placebo (12/1,537 deaths, [0·8%]), but numbers were too small to establish whether testosterone reduced mortality risk.
- The authors say that while longer-term analysis of cardiovascular safety is required, the findings should reassure men with hypogonadism worldwide about the short-to-medium safety of testosterone.
Testosterone replacement therapy appears safe in the short-to-medium term to treat a condition caused by deficiency of the male sex hormone, according to the most comprehensive analysis of the treatment to date, published in The Lancet Healthy Longevity journal.
The findings suggest that men given testosterone to treat hypogonadism are at no greater risk of heart attack, stroke and other cardiovascular events in the short-to-medium term than men who do not receive testosterone treatment.
Testosterone replacement therapy is the standard treatment for hypogonadism, which can cause sexual dysfunction, weakening of bones and muscles, and reduced quality of life. Risk factors for the condition include aging (as testosterone levels decline with age), obesity (BMI of 30 kg/m2 or above), and diabetes.
Despite being widely used, the cardiovascular safety of testosterone treatment has until now remained unclear due to inconsistent findings. This is because most previous clinical studies have relied on aggregate data, rather than individual participant data and have not published details of individual adverse events.
Lead author, Jemma Hudson from the University of Aberdeen, explains: “Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment. Ongoing studies should help to determine the longer-term safety of testosterone but, in the meantime, our results provide much-needed reassurance about its short-to-medium term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide.” 
The authors conducted a systematic review identifying 35 eligible clinical trials published since 1992, of which 17 provided individual participant data. A blinded analysis by two independent clinicians enabled the classification of every cardiovascular event, allowing for a more robust analysis of the cardiovascular safety of testosterone treatment. A meta-analysis using individual participant data from 17 studies and a further meta-analysis integrating these data with the aggregate data provided by the 18 trials that did not provide individual participant data were performed.
Among the 17 trials with individual patient data, 1,750 participants received testosterone and 1,681 were given a placebo. The average length of testosterone treatment was 9.5 months. The average age of participants was 65 years, and most were white and did not smoke. Participants’ average BMI was 30 kg/m2, which is considered obese.
A meta-analysis showed there were 120/1,601 (7.5%) cardiovascular events in the testosterone group and 110/1,519 (7.2%) in the placebo group across 13 trials that provided this information. Patient age, smoking or diabetes status did not affect cardiovascular risk. Similarly, there was no significant difference in mortality rate between the testosterone group (6/1,621 deaths, 0.4%) and the placebo group (12/1,537 deaths, 0.8%) across the 14 trials that provided individual patient data on mortality, but only limited data were available.
The researchers also found that testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides compared with placebo. However, there were no significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between the testosterone and placebo groups.
The meta-analysis that integrated individual participant data with aggregate data showed similar results.
The authors acknowledge some limitations to their study. There was little available data evaluating the cardiovascular safety of testosterone treatment beyond 12 months, and the very small number of deaths recorded during testosterone trials hampered the authors’ ability to analyse why they occurred. However, the longer-term safety of testosterone treatment is currently being investigated in another clinical trial. While the meta-analysis of aggregate data showed similar results to the one involving individual patient data only, it cannot be ruled out with certainty that a high number of unreported cardiovascular events in the trials that did not provide individual participant data could alter the current conclusions.
NOTES TO EDITORS
These findings will be also presented on Monday 13 June at 11:00 am ET at ENDO 2022, the Endocrine Society’s annual meeting: https://endo2022.endocrine.org/
This study was funded by the UK NIHR Health Technology Assessment Programme. It was led by researchers from University of Aberdeen and Imperial College London in collaboration with University of Newcastle-on-Tyne, Harvard Medical School, University of Pennsylvania, University of Melbourne, Fiona Stanley Hospital, Utrecht University, Leiden University, Aston University, University Hospitals Birmingham, University Hospital of North Norway, University of Norway, University of Colorado, University of Ljubljana, Western University and Omega Fertility Center, VA Palo Alto Health Care System, Stanford University, University of Malaya, Taylor's University, Malaysia, University College London, UCLA, University of Sheffield, University of Manchester, and University of Southern Denmark.
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The Lancet Healthy Longevity
Method of Research
Subject of Research
Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis
Article Publication Date
CNJ reports research grants from Logixx Pharma. SBhas reports research grants from AbbVie and National Institutes of Health; consulting fees from Aditum; participation on the Data Safety Monitoring board of OKPO; a leadership or fiduciary role in the Endocrine Society; and a patent (free T calculator based on the ensemble allosteric model, reference 20200174026). SSE reports research grants from AbbVie. MG reports research grants from Otsuka, Bayer, Lilly, Weight Watchers, Novartis, National Health and the Medical Research Council Australia; speaker honoraria from Besins Healthcare, Bayer, and Otsuka; consulting fees from Bayer; and Royalties from Walter and Eliza Hall Institute Melbourne Australia. KLH reports research grants from NIA K23 Career Development Award; a leadership or fiduciary role from Kavod Senior Life Board of Directors, Executive Committee; and stock or stock options from Medaware Systems. NO reports research grants from Dexcom, Roche Diabetes, and Medtronic Diabetes; speaker honoraria from Roche Diabetes; consulting fees from Roche Diabetes and Medtronic Diabetes; payment for expert testimony from London law firm Wilmer Hale; and an issued patent for automatic closed loop glucose control with an adaptive meal bolus calculator. SR reports research grants from North Staffordshire Medical Institute and support for attending meetings or travel from Besins Healthcare. PJS reports research grants from Abbvie and payment for expert testimony from Teva. RQ reports speaker honoraria and support for attending meetings or travel from Bayer. SBhat reports speaker honoraria from Obstetrical & Gynaecological Society of Singapore, Merck SMART Masterclass, and Merck FERRING Forum; leadership or fiduciary role at National Health Service Grampian; editorial role (Editor in Chief of Human Reproduction Open, Special Senior Editor of Cochrane Gynaecology and Fertility); membership of NHS Grampian Board; other financial or non-financial interests from Oxford University Press; and Royalties from Cambridge University Press (Royalties for book Reproductive Medicine for the MRCOG, Cambridge University Press). GBB reports speaker honoraria and consulting fees from Acerus Pharmaceutical. HMT reports consulting fees from Besin Healthcare. EJGil reports provision of study materials from Bayer. All other authors declare no competing interests.