Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis

ABSTRACT

Introduction

The cardiovascular (CV) safety of testosterone (T) replacement therapy (TRT) is still conflicting. Recent data suggested a TRT-related increased risk of atrial fibrillation (AF). The aim of this study was to systematic review and meta-analyze CV risk related to TRT as derived from placebo controlled randomized trials (RCTs).

Areas covered

An extensive Medline, Embase, and Cochrane search was performed. All placebo-controlled RCTs reporting data on TRT-related CV safety were considered. To better analyze the role of T on AF, population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were also included and analyzed.

Expert opinion

Out of 3.615, 106 studies were considered, including 8.126 subjects treated with TRT and 7.310 patients allocated to placebo. No difference between TRT and placebo was observed when major adverse CV events were considered. Whereas the incidence of non-fatal arrhythmias and AF was increased in the only trial considering CV safety as the primary endpoint, this was not confirmed when all other studies were considered (MH-OR 1.61[0.84;3.08] and 1.44[0.46;4.46]). Similarly, no relationship between endogenous T levels and AF incidence was observed after the adjustment for confounders Available data confirm that TRT is safe and it is not related to an increased CV risk.

KEYWORDS:

• Atrial fibrillation
• non-fatal arrhythmias
• MACE
• hypogonadism
• testosterone
• testosterone replacement therapy

Article highlights

• Data from TRAVERSE study suggested an increased risk of non-fatal arrhythmias and atrial fibrillation in subjects treated with testosterone in comparison with placebo.

• Data derived from randomized placebo controlled trials with cardiovascular safety as secondary endpoint (non-TRAVERSE studies) do not confirm the increased risk of non-fatal arrhythmias and atrial fibrillation in relation of testosterone replacement therapy.

• TRAVERSE and non-TRAVERSE studies showed a neutral effect of testosterone replacement therapy when major adverse cardiovascular events were considered.

• Data derived from population-based studies investigating relationships between endogenous T levels and non-fatal arrhythmias suggest a possible protective role for T on AF, although the association was not confirmed in a fully adjusted model or when outliers’ studies were excluded.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2024.2337741

Additional information

Funding

We acknowledge co-funding from Next-Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society”. This resource was co-financed by the Next-Generation EU [DM 1557 11.10.2022]. The views and opinions expressed are only those of the authors and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.