Over the past decade there has been an increase in awareness of the clinical syndrome of male hypogonadism and its association with comorbid conditions and among older age groups. This increase in awareness, among physicians and the general population, has led to a large increase in the number of patients diagnosed with hypogonadism and testosterone replacement therapy (TRT). The increase in testosterone prescriptions has raised concerns by the regulatory bodies that low testosterone levels, with or without clinical symptoms, when associated comorbid conditions such as chronic illness and aging may not be an actual medical syndrome. This has also led to concerns that testosterone is overprescribed and over marketed 1, including its misuse by competitive athletes, body builders and older male patients in antiaging clinics. Over the past year, several studies raised new concerns regarding cardiovascular (CV) risks and TRT which led to a FDA Drug Safety Communication indicating their plan to investigate the possibility that TRT might be a risk factor for CV events. This had a ripple effect that resulted in numerous lay and medical press reports stating cardiac problems as a potential side effect of TRT. To date, the literature has been conflicting whether there are beneficial or detrimental effects on cardiovascular morbidity and mortality.
This study reviews studies focusing on recent trials of TRT on cardiovascular risk.
Background: cardiovascular events in hypogonadal men
Low testosterone levels have been associated with metabolic syndrome, obesity, diabetes, hypertension, atherosclerosis, increased fat mass, adverse lipid profile, thrombosis, and insulin resistance 2 all of which is believed to increase a man’s risk of having cardiovascular disease (CVD) or a CV event. Notably, hypogonadism has been projected to be involved in the development of ∼1.3 million new cases of CV disease 3.
Until recently, hypogonadism was seen as a risk factor for CV disease and TRT was proposed as a possible preventive measure. In 2010, a prospective study 4 was conducted on 1954 men with measured serum testosterone levels at baseline and 195 deaths during an average 7.2-year follow-up. Of the 1954 men, 98 men were found to be hypogonadal and 1856 were found to be eugonadal. After adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low serum testosterone levels were found to be associated with increased mortality. The study concluded that in a cause-specific analysis, low serum testosterone levels predicted increased risk of death from CVD. Also in 2010, a tertiary referral cardiothoracic center studied 930 men with coronary disease referred for diagnostic angiography showed an overall prevalence of biochemical testosterone deficiency of 20.9% of the cohort. In these 930 men, the only parameters found to influence time to all-cause and vascular mortality in multivariate analyses were the presence of left ventricular dysfunction, aspirin therapy, β-blocker therapy and low serum ‘biologically active’ testosterone (bio-T) 5.
Other epidemiological studies suggested that the patient characteristics in terms of CV events and risk factors differ between untreated hypogonadal patients and eugonadal patients treated with TRT before starting treatment. Using claims data from the USA, Li et al. 6 found a higher prevalence of CV events and CV risk factors among males before initiating treatment with testosterone compared with those who did not receive testosterone treatment. This suggests that the men who received TRT were already at higher risk for CVD/events.
Evaluation of testosterone replacement therapy and cardiovascular risk factors
The effect of testosterone on lipid profiles has been investigated in several studies including studies on metabolic syndrome and diabetes 7.
A number of studies have found that testosterone therapy results in a small but statistically significant fall in total cholesterol and in some studies reduced low-density lipoprotein cholesterol 8. A meta-analysis of randomized controlled trials (RCTs) evaluated several endpoints associated with testosterone treatment including serum lipid profile in men aged at least 49 years. The meta-analysis revealed that TRT reduced total cholesterol in hypogonadal men compared with eugonadal men. The studies revealed no change in the low-density lipoprotein cholesterol. The overall effect on high-density lipoprotein cholesterol of testosterone treatment was not statistically significant 9. In some studies, pharmacologic doses of oral androgens resulted in reduced serum high-density lipoprotein.
In 2013, a meta-analyses conducted on hypogonadal men with metabolic syndrome and type 2 diabetes found that testosterone treatment was associated with a statistically significant reduction in triglyceride levels for both men with metabolic syndrome and men with type 2 diabetes 10.
The effects of testosterone on insulin sensitivity and glucose control have been noted in several studies 11–13. New data suggest that TRT improves insulin sensitivity 14 and reduces blood glucose and hemoglobin A1c levels in men with type 2 diabetes or obesity 15,16. Large-scale well-controlled studies are needed to confirm these findings.
Evaluation of testosterone replacement therapy in placebo-controlled trials
In 2010, a randomized, placebo-controlled study (TOM trial) looked at the efficacy of TRT on frail men aged at least 65 years. The trial was stopped early because of an imbalance in CV associated adverse events in the TRT arm compared with the placebo-treated arm. Twenty-three of the 106 individuals in the testosterone group, compared with five of the 103 individuals in the placebo group, had cardiovascular-related adverse events. The authors concluded that testosterone therapy may increase the risk of cardiac events in elderly frail men 17. An editorial cautioned against overinterpreting the results as: it was an efficacy trial in a relatively frail population and not designed to investigate CV risk/events; none of the events were primary or secondary endpoints; and the two groups of men had different baseline characteristics with a higher rate of hyperlipidemia and hypertension in the participants randomized to the testosterone group. In addition, the small size of the trial, the unique population of frail elderly men, and the early termination of the trial make it difficult to draw generalizable conclusions regarding the safety of testosterone therapy. The editorial published in the same journal suggested the need for further investigation and to hold off on interpretation of the safety data for the TOM trial 18.
Trials before this study that were similar in design, methods, and participants to the TOM trial showed a low incidence of adverse cardiac events that was not different between testosterone-treated and placebo-treated groups. It was noted in Srinivas et al.’s 19 study that there were a total of two major adverse cardiac events and both occurred in the placebo group. A randomized placebo-controlled study by Kenny et al.20 examined the effects of testosterone on bone density and muscle strength in 131 men. The mean age of the participants was 77.1. The study design included two arms in the study, a TRT group with testosterone gel and a placebo group, for 12 months. After 1 year of follow-up, there were three deaths in the testosterone-treated group compared with seven deaths in the placebo group. The authors reported that other CV events did not differ between testosterone and placebo.
The studies above provide a conflicting report regarding CV events between the testosterone and placebo groups and it is possible the TOM trial was terminated too early to make any conclusions regarding CV risk/events.
Meta-analyses of testosterone replacement therapy and cardiovascular events
There have been several meta-analyses evaluating the safety of TRT-related and CV-related events. A meta-analysis of 19 randomized clinical trials was conducted to determine the risks of adverse events associated with TRT in men aged at least 45 years with low or low-normal testosterone levels. The odds ratio for all cardiac events was not significantly different 21. Similar results were seen where a systematic review and meta-analysis of randomized trials that assessed the effect of testosterone use on CV events 22. Fernández-Balsells et al.23 also found no significant difference in the rates of CV events between the testosterone and the placebo or nonintervention groups in a meta-analysis of 51 randomized and nonrandomized placebo-controlled trials.
Another meta-analysis reported on 10 RCTs that each included more than 100 participants to evaluate the effect of testosterone treatment on CV risk. The authors found no statistically significant difference between placebo and testosterone treatment on CV risk 24.
In contrast, Xu et al.25 conducted a systematic review and meta-analysis of placebo-controlled randomized trials of testosterone therapy published through 2012 among men lasting more than 3 months reporting CV-related events. The 27 trials included 2994 mostly middle-aged or older men. In the study, 1733 men were on testosterone and the other 1261 men were on placebo. Of these men with low testosterone and/or chronic diseases, it was found that there were 180 CV-related events and 33 CV-related deaths. The authors reported an increased risk of CV-related events in the testosterone-treated compared with placebo-treated populations. However, only one of the 27 studies found a statistically significant increase of cardiovascular events. While the authors concluded that there was an increase in the risk of CV-related events, Xu et al.’s 25 meta-analysis had limitations, given that it included the TOM’s trial, which was terminated early, and it included the Copenhagen study 26, which was conducted on alcoholic cirrhotic patients and included esophageal varices as a CV event.
Of the meta-analyses that were conducted on TRT and CV events only one analysis 25 suggested an increase in events but, as stated above, this meta-analysis had possible limitations.
Observational studies on testosterone replacement therapy and cardiovascular events
There have been several observational studies evaluating TRT including a study conducted by Shores et al.27 that was a retrospective, observation study using data from seven VA medical centers on men aged at least 40 with low testosterone levels. Testosterone treatment was associated with decreased mortality compared with no testosterone treatment.
A retrospective study was carried out to evaluate TRT’s safety; they reviewed 401 hypogonadal men’s charts who were receiving TRT with a mean follow-up of 5.4 years. At the end of the study, the authors determined that in a population with similar comorbidities as the TRT cohort, TRT may have beneficial effects on CV risk factors including circulating lipid and cholesterol levels 28.
Also, an observational study was carried out that examined the risk of myocardial infarction (MI) in a population-based cohort of 6355 older men receiving intramuscular testosterone from a Medicare claims database. This cohort was compared with 19 065 testosterone nonusers and a 1 : 3 odds ratio was found based on a composite MI prognostic score. It was concluded that TRT was not associated with an increased risk of MI 29. This study also noted that in men with highest risk for MI, TRT was associated with a reduced risk for developing an MI.
In contrast, two retrospective, observational studies by Vigen et al.30 and Finkle et al.31 raised significant concerns throughout the medical community regarding TRT and CV safety in patients older than 65.
Vigen et al.30 conducted a retrospective national cohort study of men with low testosterone levels who underwent coronary angiography in the VA system between 2005 and 2011. The study included 8709 men, of which 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. At 3 years after coronary angiography, the Kaplan–Meier estimated cumulative percentages with CV events was 19.9% in the no testosterone therapy group versus 25.7% in the testosterone therapy group. It was from this estimation that the authors felt that the use of testosterone therapy was associated with increased risk of adverse outcomes.
The strengths of Vigen et al.’s 30 study were the size of the database and the availability of laboratory results. There were several limitations/criticisms to the study, one of which is that the detected higher CV risk may have been influenced by patient characteristics. The men included in the study had undergone coronary angiography suggesting they were at increased risk for a CV event making it difficult to generalize the result to all patients receiving TRT. In addition to the patient population issues about study, the investigators twice corrected the online publication suggesting initial flaws in the study results and design.
Finkle et al.31 performed an observational analysis that utilized an electronic health records database providing information on medical claims and prescriptions to assess whether TRT was associated with an increased risk of acute MI. The study sample was generated from 2006 to 2010. It included over 55 000 individuals who reportedly had received a testosterone prescription. The authors compared the incidence rate of MI in the 90 days following the initial prescription with the rate in the 1 year before the initial prescription. They also did the same comparison of TRT patients with a prescription of PDE5 inhibitor (PDE5i). The authors concluded that patients over the age of 65 years had an increased risk of acute MI in the 90 days after filling a prescription of testosterone compared with the 1-year baseline period before treatment. In the same study, patients younger than 65 years of age with a history of heart disease were reported to have had a higher rate of adverse events following TRT when compared with the baseline period before treatment. A relevant increase in the rate of acute MI was not observed in a PDE5i treated cohort.
The strength in the Finkle et al.’s 31 study is its size; however, the study design has been criticized with questions raised whether it could adequately answer the question about CV events and TRT. Critics have questioned whether a PDE5i cohort was the appropriate comparison group given that the underlying conditions used for prescribing both of these medications are different. It is also possible that a PDE5i which increases NO levels might serve a cardiac vasodilator. Another drawback to this study was the very short duration of treatment (90 days) and the apparent reduction of observed effect with time; the study was also criticized for lack of testosterone measurements at the 90-day postprescription period assessing if the patient was adequately treated or not. Given that hypogonadism itself may be a risk factor for an MI it is hard to assign causality to TRT.
While these two papers 30,31 have resulted in a question of whether TRT increases CV events and risk the study design and the baseline characteristics of the patients already had an increased CV risk. After the publication of these two papers, the issue of cardiovascular risk was discussed at an FDA advisory meeting in September 2014. The data were reviewed and the advisory board concluded that there were insufficient long-term quality data to resolve the issue of CV risk from TRT 1. An additional meta-analysis was published that concluded that there was no convincing evidence of increased CV risks with TRT 32.
To date, there have been no large randomized, placebo-controlled, clinical trial of TRT in terms of CV outcomes. Further investigation will need to be done to determine if there is a relationship between TRT and CV risks or events. There is a placebo-controlled 800 men efficacy study (TTrial) supported by the NIH that has now completed but the results have not yet been reported. The study may have data on short-term cardiovascular and other safety parameters, but will not resolve the long-term safety controversies discussed above.
After review of the literature, studies suggest a higher prevalence of baseline CV risk factors and events among hypogonadal males than compared with the general male population. Placebo-controlled studies of testosterone replacement in hypogonadal individuals do not suggest an association between testosterone use and CV adverse outcomes.
Only one of the meta-analyses studies reported an association between CV events. Two observational studies do report an association; however, based on descriptive analyses, the results are likely related to underlying hypogonadism rather than testosterone therapy.
The FDA Advisory Committee and many Medical Societies have argued the importance of doing a large scale, long-term safety trial focusing on cardiovascular and prostate adverse effects. The Endocrine Society released a statement 33 on 7 February 2014 that supported more large-scale RCTs to determine the true risks of testosterone therapy in older men. We strongly support such a trial and wait for more data regarding CV outcomes.
On 3 March 2015 the FDA released a statement stating, ‘requiring labeling changes for all prescription testosterone products to reflect the possible increased risk of heart attacks and strokes associated with testosterone use’ 34. Despite the FDA statement, we believe it is prudent to await the results of a large-scale RCT to determine the true risks of testosterone therapy in older men before making a definitive statement on the safety of TRT. Nevertheless, we agree with the FDA that patients should be made aware of the unresolved controversies in the literature regarding potential CV risks associated with TRT.
Conflicts of interest
There are no conflicts of interest.
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