TRT and MACE Trial Data: Understanding Cardiovascular Event Risk

Written by Adam Maggio | Medically reviewed by Dr. Mitchell Ross, MD, ABAARM

Major Adverse Cardiovascular Events (MACE) are a critical endpoint in evaluating the safety of testosterone replacement therapy (TRT). Recent meta-analyses and large trials, including TRAVERSE, generally indicate that TRT does not increase MACE risk in appropriately selected hypogonadal men, though some studies have shown conflicting results or specific adverse event signals.

TRT and MACE Trial Data: What the Evidence Shows

When discussing testosterone replacement therapy (TRT), the term Major Adverse Cardiovascular Events (MACE) frequently arises. MACE is a composite endpoint commonly used in clinical trials to assess the overall cardiovascular safety of a treatment, typically including events like cardiovascular death, nonfatal myocardial infarction (heart attack), and nonfatal stroke. Understanding the relationship between TRT and MACE is crucial for both patients and clinicians.

Historically, concerns about TRT and cardiovascular risk emerged from observational studies and some smaller trials that suggested a potential increase in MACE. This led to a 2015 FDA mandate requiring manufacturers to conduct large-scale, well-designed trials to definitively assess cardiovascular safety. The subsequent research, particularly large randomized controlled trials and comprehensive meta-analyses, has significantly clarified this picture.

Key Findings from Recent Trials and Meta-Analyses

The most robust evidence comes from studies like the TRAVERSE trial (Lincoff et al., 2023), which we've discussed previously. TRAVERSE, a large noninferiority trial, found that TRT was not associated with an increased risk of MACE in men with hypogonadism and pre-existing cardiovascular disease or high risk. The incidence of MACE was 7.0% in the testosterone group versus 7.3% in the placebo group, demonstrating noninferiority.

Beyond TRAVERSE, several meta-analyses have pooled data from multiple randomized controlled trials (RCTs) to provide a broader perspective. A meta-analysis published in the Journal of the American College of Cardiology (JACC) involving 9,112 patients reported that the incidence of MACE was 6.6% in the TRT arm and 6.8% in the placebo arm, with no significant difference (OR=0.97, 95% CI: 0.85-1.11). This updated analysis reinforces the neutral effect of TRT on MACE risk in hypogonadal men (Corona et al., 2024).

Another systematic review and meta-analysis of 30 RCTs similarly concluded that TRT does not increase the risk of cardiovascular disease or all-cause mortality in patients with hypogonadism (Jaiswal et al., 2024). These findings collectively suggest that for appropriately selected men with documented testosterone deficiency, TRT does not elevate the risk of major cardiovascular events.

Conflicting Data and Nuance

It's important to acknowledge that the literature isn't entirely uniform. Some earlier observational studies and a few meta-analyses have reported conflicting results. For example, a retrospective propensity-weighted analysis by Bal et al. (2026) found that men receiving TRT had a 26% higher risk for MACE (HR 1.27, 95% CI: 1.05-1.54). Unlike the large RCTs, these studies often suffer from methodological limitations, such as selection bias, varying definitions of hypogonadism, and inconsistent monitoring protocols. This highlights the importance of relying on high-quality, prospective, randomized data when assessing safety outcomes.

Furthermore, while overall MACE risk appears neutral, specific adverse events have been noted. As seen in TRAVERSE, there was a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group. These are not typically classified as MACE but are important considerations for patient safety and monitoring. Unlike the composite MACE endpoint, which focuses on severe ischemic events, these individual adverse events require careful attention during TRT management.

Practical Takeaway

The current body of evidence, particularly from large, well-designed trials and comprehensive meta-analyses, provides strong reassurance that TRT does not increase the overall risk of Major Adverse Cardiovascular Events (MACE) in men with symptomatic hypogonadism. However, it's not a therapy to be undertaken lightly. You'll need a thorough diagnostic workup to confirm hypogonadism, and your physician will carefully monitor your cardiovascular health, blood parameters, and watch for specific adverse events like atrial fibrillation or pulmonary embolism. Always ensure your TRT is managed by a knowledgeable practitioner who adheres to established clinical guidelines.