31st May 2024, A/Prof Chee L Khoo
It’s coming to almost 10 years now when suddenly, we were not able to prescribe testosterone replacement therapy (TRT) to men with hypogonadism or low testosterone levels under the PBS. This came on the back of a decision by the US FDA in March 2015 to restrict the prescription of TRT (1). The FDA warned that “…that there may be increase cardiovascular risk associated with testosterone use”. The Australian authorities very quickly followed suit. As recent systematic review on the use of TRT and cardiovascular safety has rekindled discussions of the issue. While it will take some time for the powers to be to review those restrictions or to loosen the criteria for use, it is worthwhile revisiting the whole issue of cardiovascular safety of TRT that led to the issuance of the guidance back in March 2015.
As usual, whenever big pharma gets wind of a “disease”, marketing gets into full swing. Commercial operators also the jump onto the bandwagon. If you have “decreased energy”, “decreased sex drive”, “loss of body hair” or “erectile dysfunction”, you may have “low testosterone” levels. Many “Low-T Clinics” sprouted out. TRT were widely prescribed without consideration of testosterone levels nor the risks of TRT. In the US, there were 2 million TRT prescriptions in 2002 and it went by 500% for the subsequent decade.
Hypogonadism was supposed to cause a wide range of signs and symptoms including loss of libido, erectile dysfunction, diminished cognitive function, depression, lethargy, osteoporosis, loss of muscle mass and strength [3]. In a literature review on the burden of hypogonadism in adult men, Maggi et al demonstrated strong evidence associating hypogonadism with sexual dysfunction and cognitive impairment and less compelling evidence associating hypogonadism with depressive symptoms, fractures, and mortality (4). The other complicating issue was there were no universally accepted diagnostic criteria. There were also differences across racial and ethnic boundaries.
In 2015, the FDA stepped in and TRT is only approved for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that caused hypogonadism. The FDA concluded then that there is a possible increased cardiovascular risk associated with testosterone use.
As you would expect, TRT in those with low testosterone should improve symptoms of hypogonadism. We should also see improvements in mortality especially CV mortality. Indeed, Shores et al demonstrated that in veterans > 40 years old with testosterone levels < 8.7 nmol/L, TRT reduced mortality over 40.5 months (10.3 vs 20.7%) (5). Further, in a retrospective study, Muraleedharan et al showed that TRT in hypogonadal men with T2D improved survival (8.4 vs 19.2%) (6).
So, what reports did the FDA looked at which made them concerned about the cardiovascular safety of TRT? One of the studies looked at was a retrospective cohort study of men in the Veterans Affairs system in men with CHD evident at angiography (7). Of the 8709 men with a total testosterone level <10 nmol/L, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. At 3 years after coronary angiography, estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8%. However, there were a number of criticisms of the study. Notably, it was unclear whether those prescribed TRT actually had the TRT. 17.6% only filled one prescription. Initial raw data actually showed TRT reduced CV events but went the opposite direction after adjusting for 50 different variables. Further, 1132 subjects with MI or stroke, which were given testosterone after these events, were excluded from the analysis. This should be in the non-treatment group.
The second study that was cited was collected data retrospectively from a health-care insurance claims data base following 55,593 prescriptions for testosterone (8). The authors reported an increased risk of nonfatal MIs in the 3 months after the prescriptions were issued compared to the prior 12 months. In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90. In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased. There were criticisms of the paper: there were no data on the diagnosis of hypogonadism nor whether there were testosterone measured pre and post treatment. It was uncertain whether the men took the medications. Further, the risk of MI was actually low (3.48/1000 person years pretreatment vs 4.75/1000 person years post treatment).
Since the issuance of guidance by the FDA, subsequent meta-analyses showed variable results and most, including a recent patient-level meta-analysis did not confirm these findings. Cardiac events in those trials were not uniformly adjudicated, definitions were broad and inconsistent, and the trials were not adequately powered for cardiovascular outcomes. Retrospective observational studies, which were limited by potential confounding and selection bias, also showed conflicting findings, although one analysis from a large health care database suggested that an age of 65 years or older or preexisting cardiovascular disease might be important modifiers of increased risk with testosterone-replacement therapy.
The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study was a randomised, double-blind, placebo-controlled, parallel group, non-inferiority, multicentre study looking at 45 – 80 years, with serum testosterone concentration <10.4 nmol/L and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease (9). 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 cardiovascular endpoints (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) were similar between the groups. The conclusion from the study was that in men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. However, there was higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism in the testosterone group. This was published in June 2023.
In summary, prior to 2015, the prescription rates of testosterone replacement therapy was getting ridiculous and was done without any confirmation of testosterone deficiency. A number of clinical trials purportedly showed an increase in cardiovascular events with TRT. This led to a clamping down on prescription of TRT in the US. The robustness of the clinical trials referenced by the FDA have since been criticised. Subsequent studies and meta-analyses have had conflicting results. The TRAVERSE trial which published last year appears to show that TRT is safe in men either pre-existing CV disease or at high risk of CV disease.
References:
- Snyder PJ; FDA. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products, U.S.F.a.D. Administration, Editor. Drug Safety Coomunications. Available from: http: //www.fda.gov/Drugs/DrugSafety/ucm383904.htm.
- Snyder PJ; FDA. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products, U.S.F.a.D. Administration, Editor. Drug Safety Communications. Available from: http: //www.fda.gov/Drugs/DrugSafety/ucm383904.htm.
- Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients–2002 update
- Maggi M, Schulman C, Quinton R, Langham S, Uhl-Hochgraeber K. The burden of testosterone deficiency syndrome in adult men: economic and quality-of-life impact. J Sex Med. 2007;4:1056-1069.
- 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
- 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
- Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-36.
- Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014 Jan 29;9(1):e85805
- Lincoff et al.June 16, 2023 N Engl J Med 2023;389:107-117