Effects of Long-term Testosterone Treatment on Cardiovascular Outcomes in Men with Hypogonadism

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madman

Super Moderator
ABSTRACT

Background:
Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately powered randomized trial.

Study Design: The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel-group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence of pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event (MACE) composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated MACE endpoints have occurred to assess whether the 95% (2- sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high-grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. As of July 1, 2021, 5,076 subjects had been randomized.

Conclusions: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.




INTRODUCTION

Testosterone replacement therapy (TRT) is approved for the treatment of hypogonadism associated with known diseases of the testis, pituitary, and the hypothalamus, but it is not approved by the United States Food and Drug Administration (FDA) for the treatment of age-associated decline in testosterone levels (1). Prior to the development of radioimmunoassays for the measurement of circulating testosterone levels, men diagnosed with severe hypogonadism typically suffered from clinically apparent testosterone deficiency, in whom the diagnosis relied upon the loss of secondary sex characteristics, gynecomastia, and small testes. In young men with severe hypogonadism, testosterone treatment-induced visible changes in secondary sex characteristics and body habitus and restored sexual function with low frequency of adverse events. However, 80% of testosterone prescriptions have historically been written for men 45 - 74 years (1-2), who often report symptoms that are also common with aging; testosterone levels in these middle-aged and older men are typically either in the low-normal range or only mildly reduced, and these men have few overt physical signs of testosterone deficiency. Neither the long-term efficacy nor the long-term safety of testosterone treatment in middle-aged and older men with age-related decline in testosterone levels has been demonstrated in adequately powered randomized trials (3).

Between the years 2000 and 2013, the prescription sales of testosterone products underwent explosive growth (4-5), driven by several historical factors, including direct-to-consumer advertising of testosterone products; the availability of easy-to-use transdermal testosterone products; and the development of men's health clinics that catered almost exclusively to men's sexual and genitourinary problems (6). In 2013, in response to a petition by a citizen's interest group and conflicting reports of cardiovascular (CV) events from small clinical trials, retrospective analyses of medical records data, and pharmacovigilance studies of testosterone-treated men, the FDA conducted an extensive review of the available information (7). FDA concluded that “the studies...have significant limitations that weaken their evidentiary value for confirming a causal relationship between testosterone and adverse cardiovascular outcomes”. An independent review conducted by the European Medicines Agency also found no consistent evidence of an increased risk of coronary heart disease associated with testosterone treatment of men with hypogonadism. Given the broad and growing use of TRT among middle-aged and older men with or at risk for CV disease, the FDA issued updated testosterone labeling inclusive of a limitation of use in men with “age-related hypogonadism”, along with a guidance “… requiring manufacturers of approved testosterone products to conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products.” The Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was designed in response to this FDA guidance to determine the effects of testosterone treatment on the incidence of major adverse CV events in middle-aged and older men with hypogonadism with or at high risk of CV disease.





*TESTOSTERONE TREATMENT AND THE RISK OF CARDIOVASCULAR EVENTS
-Physiologic effects of testosterone on the cardiovascular system.
-Epidemiological studies of the association of endogenous testosterone levels with cardiovascular disease
-Retrospective analyses of testosterone replacement therapy
-Randomized Trials



*Uncertainty About the Effects of Testosterone Therapy on Prostate Health


*Gaps in the Current Understanding of the Efficacy of Testosterone Replacement Therapy


*TRAVERSE STUDY OBJECTIVES AND DESIGN

-Study Population
-Intervention and Management


*Study Outcomes
-Safety Outcomes
-Efficacy Outcomes


A limited number of pre-specified efficacy endpoints are included as secondary outcomes in five efficacy domains (Table 2). The following efficacy endpoints will be evaluated in sub-studies or analyses of subpopulations using validated patient-reported outcome (PRO) questionnaires:

1. Improvement in sexual activity in hypogonadal men with low libido

2. Remission of depression in hypogonadal men with late-onset, low-grade PDD

3. Reduction in the incidence of clinical fractures

4. Correction of anemia in a subset of participants with baseline anemia, and incidence of anemia among randomized subjects who did not have anemia at baseline

5. Reduction in progression from pre-diabetes to diabetes in a subset of participants with prediabetes at baseline, and glycemic remission in a subset of participants with diabetes at baseline



*STATISTICAL ANALYSES

*Determination of Sample Size

*STUDY ORGANIZATION




PERSPECTIVE


TRAVERSE is the largest and longest duration randomized study of TRT ever conducted. With a greater number of MACE endpoints than all other randomized trials to date combined, TRAVERSE will address the uncertainty regarding CV safety of this therapy among middle-aged or older men with or at high risk for CV disease. By virtue of its large sample size and treatment duration, this study will also allow assessment of prostate safety and provide potentially useful information regarding the long-term efficacy of TRT in improving sexual function, depressive symptoms, anemia, progression from prediabetes to diabetes, or glycemic remission in those with diabetes, and risk of bone fractures.
 

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Defy Medical TRT clinic doctor

madman

Super Moderator
Table 1. Cardiovascular Inclusion Criteria
Screenshot (9608).png
 

madman

Super Moderator
*TRAVERSE is the largest and longest duration randomized study of TRT ever conducted. With a greater number of MACE endpoints than all other randomized trials to date combined, TRAVERSE will address the uncertainty regarding CV safety of this therapy among middle-aged or older men with or at high risk for CV disease
 

Nelson Vergel

Founder, ExcelMale.com

Nelson Vergel

Founder, ExcelMale.com
The data on the above post #10 is supported by these old data. Too bad we don't have dropout rates for T injections.

 

madman

Super Moderator

*there was no increased risk of prostate cancer between the two groups and no increased risk of lower urinary tract symptoms between the two groups


28:30-29:47

Investigator Reported Adverse Events - statistically significant increase in non-fatal arrhythmias, atrial fibrillation, acute kidney injury)

*again while statistically significant the absolute numbers don't seem that different
 

madman

Super Moderator


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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