TRT on cardiovascular outcomes in hypogonadal men

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Abstract

Objective


To investigate the impact of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men.


Methods

A meta-analysis of 26 randomized controlled trials involving 10 941 participants was conducted. Various clinical outcomes, including all-cause mortality, cardiovascular-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis, were assessed.


Results

No statistically significant differences were observed between the TRT group and the control group in terms of these clinical outcomes. Sensitivity analysis and publication bias assessments supported the robustness of the findings. Meta-regression analysis found no significant associations between clinical outcomes and potential covariates, including age, diabetes, hypertension, dyslipidemia, and smoking.


Discussion

Previous research on TRT and cardiovascular events, with comparisons to studies like the Testosterone Trials and the studies conducted by Vigen et al, Finkle et al, Layton et al, and Wallis et al, is provided. The significance of the systematic review and meta-analysis approach is emphasized, particularly its exclusive focus on hypogonadal patients.


Conclusion

This study offers reassurance that TRT does not increase mortality risk or worsen cardiovascular outcomes in hypogonadal men. However, further research, especially long-term studies involving diverse populations, is essential to strengthen the evidence base and broaden the applicability of these findings.





Introduction

Testosterone, a hormone that influences various bodily functions and metabolism, including muscle, adipose tissue, bone, and cells, plays a role in regulating lipids, carbohydrates, and protein metabolism.1-4 Low testosterone levels have been linked to cardiovascular (CV) disease, which can be caused by factors such as aging, chronic health issues, obesity, or medications.5,6 Symptoms of testosterone deficiency may include visible changes in secondary sexual characteristics and body composition.

Testosterone therapy was introduced in the 1940s and was reported to improve overall health without serious adverse effects.7 While testosterone replacement therapy (TRT) is approved for treating specific conditions, it is not Food and Drug Administration-approved for age-associated decline in testosterone levels. The CV effects of TRT in middle-aged and older men with hypogonadism are still unclear, with conflicting results from retrospective cohort studies.7-15 The Food and Drug Administration issued guidance to conduct clinical trials to determine TRT's CV risk due to conflicting data.16 Furthermore, it is imperative to recognize that TRT can exert both positive and negative effects on CV health. On one hand, it may induce sodium and water retention, potentially influencing blood pressure regulation. Conversely, TRT has displayed potential benefits, including enhancements in coronary vasodilation and endothelial function. Additionally, TRT offers advantages such as mood improvement, increased muscle mass, enhanced bone density, heightened libido, and potential cognitive enhancements. These affirmative effects can significantly augment overall well-being.

Nonetheless, it is essential to acknowledge that TRT also carries potential risks, including concerns about CV health, acne, testicular shrinkage, infertility, and possible psychological side effects.
While endogenous testosterone levels may not consistently predict CV events, lower levels have been correlated with elevated risks of all causes and CV mortality. Furthermore, circulating testosterone concentrations have shown an inverse association with subclinical atherosclerosis.17 Despite extensive research, the CV effects of TRT remain controversial, and this meta-analysis aims to provide further insights into its impact on CV outcomes.





Conclusion

In conclusion, the findings of this systematic review and meta-analysis indicate that TRT does not significantly impact all-cause mortality, CV-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis in hypogonadal patients. These results offer valuable evidence for clinicians and patients in making informed decisions regarding the use of TRT. However, further research, including long-term studies and more diverse populations, is necessary to gain a comprehensive understanding of the effects of TRT on clinical outcomes and to enhance the generalizability of the findings.
 

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Table 1
General Characteristics of the Included Trials
Screenshot (30957).png

Screenshot (30958).png
 
Fig. 2. Results of the meta-analysis showing comparison of (A) all-cause mortality, (B) cardiovascular-related mortality, (C) myocardial infarction, and (D) stroke between hypogonadal men receiving TRT and no treatment. CI ¼ confidence interval; RR ¼ risk ratio; TRT ¼ testosterone replacement therapy
Screenshot (30959).png
 
Fig. 3. Results of the meta-analysis showing comparison of (A) congestive heart failure, (B) atrial fibrillation, (C) pulmonary embolism, and (D) venous thrombosis between hypogonadal men receiving TRT and no treatment. CI ¼ confidence interval; RR ¼ risk ratio; TRT ¼ testosterone replacement therapy.
Screenshot (30960).png
 
Highlights

*Testosterone can exert both positive and negative effects on cardiovascular health.

*Association between TRT and cardiovascular outcomes has been heavily researched and has thus far yielded mixed outcomes.

*2018 guidelines from the Endocrine Society provide a comprehensive framework for the use of TRT in men with hypogonadism, considering various factors, including cardiovascular (CV) risk.

*TRAVERSE Study from 2023 revealed no increased risk in cardiovascular outcomes with TRT.

*We conclude that TRT is not associated with increased risk of cardiovascular outcomes in patients like atrial fibrillation, stroke, pulmonary embolism, heart failure, etc.
 
Clinical Relevance

Our text is clinically relevant because it addresses a clinically significant topic, employs rigorous research methods, and provides findings and discussions that healthcare providers can directly apply to their decision-making processes when managing hypogonadal patients.
 
 
My doctor told me I shouldn't get on TRT at age 50 because it increased the risk of Ischemic Heart Failure. Apparently he was basing this on one study that was done on men over 60, many of who had existing health conditions, including heart disease.
 
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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.
 
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