Testosterone Replacement Therapy and CVD

[madman]

Abstract

Purpose of Review

The purpose of this review is to analyze the link between testosterone replacement therapy (TRT) and adverse cardiovascular (CV) events.

Recent Findings

A few published studies suggest a link between TRT and CV events. These studies contained flaws, and many other studies reveal a reduction in CV events. Hypogonadism is associated with increased mortality in men with CVD. TRT in hypogonadal men can improve many CVD risk factors, reduce QT interval prolongation, lead to better outcomes in heart failure patients, and slow the progression of atherosclerosis.

Summary

The use of TRT to achieve physiologic testosterone concentrations in men does not pose a threat to CV health and has demonstrated a cardioprotective effect.




*Testosterone Physiology


*Testosterone’s Role in the Heart


*Testosterone Deficiency


*Testosterone Replacement Therapy




Conclusion

The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) is a randomized, double-blind, placebo-controlled study with the goal of determining the safety of long-term TRT regarding major adverse cardiovascular events in middle-aged and older men with hypogonadism. TRAVERSE is the largest (5246 participants) and longest duration (up to 5 years) randomized study about the safety of TRT ever conducted. The patients either received daily transdermal 1.62% testosterone gel or matching placebo gel in metered-dose pumps. The average age of participants was 63.3±7.9 years. 54.2% of the testosterone group and 55.2% of the placebo group had pre-existing cardiovascular disease. Median testosterone level at baseline was 227 ng/dl interquartile range 188–285) for the testosterone group and 227 ng/dl (interquartile range 188–258) for the placebo group. The average duration of treatments for the testosterone and placebo groups was 21.8±14.2 and 21.6±14.0 months, respectively. At 12 months, the average increase in serum testosterone in the treatment group was 148 ng/dl, compared to 14 ng/dl in the placebo group. The primary safety end point was the first occurrence of any component of major adverse cardiac events, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis [76]. The study was completed on January 19, 2023 [77••, 78]. The data showed that TRT was noninferior to placebo in incidence of major adverse cardiac effects [76]. Prostate cancer occurred in 0.5% patients in the testosterone group and 0.4% of patients in the placebo group (P=0.87) [76]. Unexpectedly, the testosterone group has more cases of nonfatal arrhythmias warranting intervention (5.2% versus 3.3%, P=0.001) [76]. Atrial fibrillation occurred in 3.5% of the testosterone group and 2.4% of the placebo group, although this is not a significant difference (P= 0.02). This is at odds with a cohort study which suggested decreased atrial fibrillation incidence with testosterone normalization [52]. Acute kidney injury occurred in 2.3% of the T group and 1.5% of the placebo group (P=0.04) [76].These findings added to previous studies will facilitate a more informed consideration of potential benefits and risks regarding TRT in middle-aged and older hypogonadal men regarding the cardiovascular safety.

As with all therapies, the goal is to maximize the benefits and minimize the risks. This includes creating a standardized plan to monitor the patient’s symptoms, side effects, hemoglobin, and testosterone levels [72]. A review of data clearly supports the cardiovascular safety of appropriately monitored testosterone therapy.

 

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[madman]

Testosterone Therapy and the Risk of Cardiovascular Disease

Abstract The debate over the cardiovascular (CV) implications of testosterone therapy (TT) have resulted in diverging safety recommendations and clinical guidelines worldwide. This narrative review synthesizes and critically evaluates long-term studies examining the effects of TT within the...

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4. Conclusion

The therapeutic approach for TT for symptomatic hypogonadism and low testosterone levels associated with aging, obesity, and systemic illness presents challenges. These conditions are intricately linked with CVD outcomes and may confound the relationship between low testosterone and CVD. Although observational studies suggest an association between low testosterone and increased risk of CVD, results from testosterone supplementation are inconsistent. RCTs indicate that short-term TT at standard replacement is not associated with increased CVD risk. Nevertheless, the cardiovascular sub-study of T Trials observed increases in NCP and CAC, signaling the need for further investigation into potential long-term implications of TT.

The TRAVERSE trial, a landmark study unique in its capacity to evaluate CVD events, contributes valuable insights into the short-term safety of TT at lower physiological levels. However, the long-term effects and implications of mid to high physiological testosterone levels are not yet fully understood. The trials’ limitations — achievement of only low-normal testosterone levels, high discontinuation rates, brief follow-up period, and high loss to follow-up rate — suggest that the findings should be interpreted with caution. It is important to avoid generalizing the safety of TT based on these results alone and to approach the extrapolation of TRAVERSE’s conclusions to higher dosages or longer-term therapy with caution.

The decision to initiate TT requires a nuanced approach, which must account for current gaps in evidence regarding CV safety. A personalized assessment and management of CVD risk factors is essential for older men with known CVD. The CV effects of exogenous testosterone, when given to maintain physiological levels, remain to be fully explored. In this regard, an important question remains the identification of male patients with symptomatic hypogonadism who may benefit from TT. This topic continues to be the subject of ongoing debate. Hopefully, future trials will provide clarity on whether TT confers beneficial, neutral, or adverse cardiovascular effects in middle-aged and older men. Until definitive evidence surfaces, clinical practice should exercise caution and prioritize individualized care with informed discussions regarding the potential CV implications of TT.