26th July 2023, Dr Chee L Khoo
It is coming up to 10 years now when we, as GPs, were suddenly not allowed to prescribe TRT for our patients with low serum testosterone levels. The rationale cited at the time was that testosterone replacement therapy (TRT) was potentially harmful because we were told that TRT is associated with increased cardiovascular risk in men with hypogonadism. Retrospective cohort studies had previously shown conflicting results (1-5). Thus, when the Testosterone in Older Men with Mobility Limitations (TOM) trial reported in 2009 that older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events, regulatory authorities started to worry (6). How robust was the evidence of harm in the first place? Do we have more robust data now?
The TOM trial was a placebo-controlled, randomised trial with a total of 209 community dwelling men >65 years old who had very limited mobility (e.g. having difficulty walking two blocks on a level surface or climbing) and total serum testosterone of 3.5 to 12.1 nmol/L or a free serum testosterone level of less than 173 pmol/L. Subjects were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Of note, both testosterone and placebo groups have high prevalence of hypertension, obesity, diabetes, hyperlipidaemia, and known cardiovascular disease. A greater proportion of men in the testosterone group than in the placebo group reported that they had received a diagnosis of hyperlipidaemia or were taking a statin.
While it was reported that testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group, the absolute numbers were actually very small. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events.
The cardiovascular adverse events were diverse: 5 myocardial infarction, 1 stroke, 1 atrial fibrillation, I heart failure exacerbation and a whole variety of “minor” events like syncope, peripheral oedema, hypertension and tachycardia. I must say the increased adverse event rate reported isn’t that impressive, really. The numbers were small and the duration were only short.
The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to determine the effects of TRT on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism and either preexisting or a high risk of cardiovascular disease (7). This was a big study: 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Note that all participants either have preexisting cardiovascular disease or at high risk of cardiovascular disease. That is the inclusion criteria.
Findings
A total of 1082 patients (20.8%) withdrew from the trial before end-of-trial visits began,The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis.
A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). In other words, in men with hypogonadism and preexisting or a high risk of cardiovascular disease, TRT did not contribute to an increase in major adverse cardiac events.
The increase in PSA levels from baseline was greater in patients in the testosterone group than in those in the placebo group (0.20±0.61 ng per milliliter vs. 0.08±0.90 ng per milliliter, respectively; P<0.001). However, there were no difference in the incidence of prostate cancer (0.5% vs 0.4% in the testosterone vs placebo groups).
Nonfatal arrhythmias warranting intervention occurred in 134 patients (5.2%) in the testosterone group and in 87 patients (3.3%) in the placebo group (P = 0.001). A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group.
This recently published large trial demonstrated that TRT does contribute to an increase cardiovascular risk in older men with low testosterone levels and preexisting CV disease or multiple risk factors. Of course, TRT in older men improves muscle strength, improves sexual function, increases volumetric and areal bone mineral density, corrects unexplained anemia and moderately reduces depressive symptoms.
This study should facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism. Of course, men with preexisting CVD or at high risk of needs aggressive management of all their risk factors irrespective of whether their serum testosterone levels. We do all that well in primary care. Further, as GPs, we are well versed in balancing the potential benefits vs harms of TRT.
References:
1. Baillargeon J, Urban RJ, Kuo Y-F, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 2014; 48: 1138-44.
2. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9(1): e85805.
3. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169: 725-33.
4. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: 2050-8.
5. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829-36.
6. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-22.
7. Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, Cunningham GR, Granger CB, Khera M, Thompson IM Jr, Wang Q, Wolski K, Davey D, Kalahasti V, Khan N, Miller MG, Snabes MC, Chan A, Dubcenco E, Li X, Yi T, Huang B, Pencina KM, Travison TG, Nissen SE; TRAVERSE Study Investigators. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023 Jul 13;389(2):107-117. doi: 10.1056/NEJMoa2215025. Epub 2023 Jun 16. PMID: 37326322.