TRT & CV Risk: The Definitive Analysis from TRAVERSE

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

The TRAVERSE trial definitively showed that TRT does not increase major adverse cardiovascular events (MACE) in hypogonadal men with high CV risk. While some minor risks were noted, overall CV safety is reassuring.

TRT and Cardiovascular Risk: The Definitive Analysis

The relationship between Testosterone Replacement Therapy (TRT) and cardiovascular (CV) risk has been a subject of intense debate and scrutiny. Early observational studies and some meta-analyses raised concerns, leading to widespread apprehension. However, recent large-scale, well-designed randomized controlled trials (RCTs), particularly the TRAVERSE trial, have provided a more definitive and reassuring picture.

Historically, the concern stemmed from conflicting data. Some studies suggested an increased risk of major adverse cardiovascular events (MACE) in men receiving TRT, while others showed a neutral or even beneficial effect, especially in men with pre-existing cardiovascular disease. This inconsistency led to confusion among both patients and clinicians, often resulting in undertreatment of symptomatic hypogonadism due to fear of CV complications.

The TRAVERSE trial (Lincoff et al., 2023) was a pivotal, placebo-controlled, randomized clinical trial designed specifically to assess the cardiovascular safety of TRT. It enrolled over 5,000 middle-aged and older men with hypogonadism and pre-existing cardiovascular disease or high cardiovascular risk. The primary outcome was a composite of MACE, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

The results of the TRAVERSE trial were clear: TRT did not increase the risk of MACE compared to placebo. While there was a slight increase in the incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group, the overall cardiovascular safety profile was deemed acceptable. This finding aligns with several recent meta-analyses of RCTs that have also concluded TRT does not increase CVD risk in hypogonadal men (Jaiswal et al., 2024).

Testosterone plays a complex role in cardiovascular health. Low testosterone is independently associated with an increased risk of cardiovascular disease, metabolic syndrome, and mortality. TRT, by restoring physiological testosterone levels, can improve several cardiovascular risk factors, including insulin sensitivity, body composition (reducing visceral fat), lipid profiles, and endothelial function. These beneficial effects likely counterbalance any potential adverse effects, leading to a neutral overall impact on MACE.

Unlike the earlier, less robust studies that fueled much of the controversy, the TRAVERSE trial provides high-quality evidence due to its large sample size, long duration (median follow-up of 33 months), and rigorous methodology. This makes it a definitive analysis that should guide clinical practice. It differentiates from observational studies which can be confounded by various factors, making it difficult to establish causality.

It is important to note that while TRT appears safe for cardiovascular health in appropriately selected men, it is not a treatment for cardiovascular disease itself. Men considering TRT, especially those with pre-existing CV conditions, should undergo a thorough cardiovascular evaluation and have their treatment closely monitored by a physician. The goal is to optimize testosterone levels within the physiological range, not to achieve supraphysiological levels.

In clinical practice, we can now confidently discuss the cardiovascular safety of TRT with our patients, armed with robust evidence. A 65-year-old patient with a history of myocardial infarction and symptomatic hypogonadism can be reassured that initiating TRT, under careful medical supervision, is unlikely to increase his risk of another cardiovascular event. This allows us to focus on the significant quality-of-life improvements TRT can offer.

The practical takeaway is that the definitive evidence from the TRAVERSE trial and other recent meta-analyses indicates that Testosterone Replacement Therapy does not increase the risk of major adverse cardiovascular events in men with hypogonadism and established cardiovascular disease or high risk. While careful patient selection and monitoring remain paramount, concerns about TRT exacerbating heart disease should no longer be a primary barrier to treatment for appropriate candidates. Discuss your cardiovascular health and hormonal status with your doctor to make an informed decision about TRT.