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Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 16 of 176). Overall, patient age (interaction 0·97 99% CI 0·92-1·03; p=0·17), baseline testosterone (interaction 0·97 0·82-1·15; p=0·69), smoking status (interaction 1·68 0·41-6·88; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.
Hudson et al. (Wed,) studied this question.