madman
Super Moderator
* It is the position of the Androgen Society that it has been conclusively determined that TTh is not associated with increased risk of heart attacks, stroke, or CV deaths.
Abstract
The Androgen Society is an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy (TTh). This position paper is written in response to results of the TRAVERSE study, published in June 2023, which reported no increased risk of major adverse cardiovascular events (MACE) in men who received TTh compared with placebo.
In 2013-2014, 2 observational studies reported increased cardiovascular (CV) risks with TTh and received wide media attention. Despite strong criticism of those 2 studies, in 2015, the Food and Drug Administration added a CV warning to testosterone product labels and required pharmaceutical companies to perform a CV safety study, which became the TRAVERSE trial.
TRAVERSE enrolled 5246 men at high risk for MACE based on existing heart disease or multiple risk factors. Participants were randomized to daily testosterone gel or placebo gel, with a mean follow up of 33 months. Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or venothrombotic events in men who received TTh compared with placebo.
Review of the prior literature reveals near uniformity of studies reporting no increased MACE with TTh. This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses.
In view of these findings, it is the position of the Androgen Society that it has now been conclusively determined that TTh is not associated with increased risks of heart attack, stroke, or CV death.
STUDIES SUGGESTING INCREASED CV RISK
Of dozens of studies that have directly investigated TTh and CV risk or mortality, only 5 have suggested increased risk (Table 1).12-14,30,31 The strength of evidence supporting increased CV risk was weak for each of these. We describe each of these in detail.
*Basaria et al, 201012
*Vigen et al, 201313
*Finkle et al, 201414
*Xu et al, 201330
*Budoff et al, 201731
STUDIES INDICATING NO INCREASED OR REDUCED RISK WITH TTH
As shown in Table 2, a moderately sized body of evidence derived from RCTs has found no increased MACE risk with TTh, and RCTs have found benefits for other CV disease or risks.31,54-76 These include greater exercise tolerance without angina,72 improved physical activity and Vo2 max in men and women with heart failure,65, 69-71 reduced atherosclerosis, 68, 74 improved components of the metabolic syndrome, and improved glycemic control in men with type 2 diabetes or metabolic syndrome.55,61-63,73-76
Large RCTs
There have been 3 large, multicenter RCTs involving TTh published since 2016, including TRAVERSE. None of these found increased MACE in men receiving TTh compared with placebo
OTHER CV RISKS
In addition to the results for primary, secondary, and tertiary end points, the TRAVERSE authors reported a higher incidence of atrial fibrillation (AF) and pulmonary embolism (PE). Specifically, AF was reported in 91 men who received TTh and 63 who received placebo. Pulmonary embolism was reported in 24 men who received TTh and in 12 who received placebo.54
CONCLUSION
The TRAVERSE trial, supported by an extensive prior literature, has found beyond any reasonable doubt that TTh in testosterone deficient individuals is not associated with increased risk of MACE. This has been studied in multiple populations, all with the same result, including in men 65 years and older who were relatively healthy, in a diabetic and prediabetic population, and in men at high risk for MACE. We believe this is now “settled science” and see no reason to expend valuable resources to investigate this issue further.
Abstract
The Androgen Society is an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy (TTh). This position paper is written in response to results of the TRAVERSE study, published in June 2023, which reported no increased risk of major adverse cardiovascular events (MACE) in men who received TTh compared with placebo.
In 2013-2014, 2 observational studies reported increased cardiovascular (CV) risks with TTh and received wide media attention. Despite strong criticism of those 2 studies, in 2015, the Food and Drug Administration added a CV warning to testosterone product labels and required pharmaceutical companies to perform a CV safety study, which became the TRAVERSE trial.
TRAVERSE enrolled 5246 men at high risk for MACE based on existing heart disease or multiple risk factors. Participants were randomized to daily testosterone gel or placebo gel, with a mean follow up of 33 months. Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or venothrombotic events in men who received TTh compared with placebo.
Review of the prior literature reveals near uniformity of studies reporting no increased MACE with TTh. This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses.
In view of these findings, it is the position of the Androgen Society that it has now been conclusively determined that TTh is not associated with increased risks of heart attack, stroke, or CV death.
STUDIES SUGGESTING INCREASED CV RISK
Of dozens of studies that have directly investigated TTh and CV risk or mortality, only 5 have suggested increased risk (Table 1).12-14,30,31 The strength of evidence supporting increased CV risk was weak for each of these. We describe each of these in detail.
*Basaria et al, 201012
*Vigen et al, 201313
*Finkle et al, 201414
*Xu et al, 201330
*Budoff et al, 201731
STUDIES INDICATING NO INCREASED OR REDUCED RISK WITH TTH
As shown in Table 2, a moderately sized body of evidence derived from RCTs has found no increased MACE risk with TTh, and RCTs have found benefits for other CV disease or risks.31,54-76 These include greater exercise tolerance without angina,72 improved physical activity and Vo2 max in men and women with heart failure,65, 69-71 reduced atherosclerosis, 68, 74 improved components of the metabolic syndrome, and improved glycemic control in men with type 2 diabetes or metabolic syndrome.55,61-63,73-76
Large RCTs
There have been 3 large, multicenter RCTs involving TTh published since 2016, including TRAVERSE. None of these found increased MACE in men receiving TTh compared with placebo
OTHER CV RISKS
In addition to the results for primary, secondary, and tertiary end points, the TRAVERSE authors reported a higher incidence of atrial fibrillation (AF) and pulmonary embolism (PE). Specifically, AF was reported in 91 men who received TTh and 63 who received placebo. Pulmonary embolism was reported in 24 men who received TTh and in 12 who received placebo.54
CONCLUSION
The TRAVERSE trial, supported by an extensive prior literature, has found beyond any reasonable doubt that TTh in testosterone deficient individuals is not associated with increased risk of MACE. This has been studied in multiple populations, all with the same result, including in men 65 years and older who were relatively healthy, in a diabetic and prediabetic population, and in men at high risk for MACE. We believe this is now “settled science” and see no reason to expend valuable resources to investigate this issue further.
