Heart attack, stroke, blood clots and death in men receiving testosterone treatment

July 2022

Clinical guideline recommendations are based on data from randomised controlled trials (RCTs) and meta-analyses of those trials. Previous meta-analyses of cardiovascular safety of testosterone treatment have been restricted to aggregate data, which has limitations that can lead to inaccurate inferences and false conclusions.

Here we summarise the results from a meta-analysis that aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment.1

Key Points

  • New meta-analysis of comprehensive safety data from RCTs confirm the safety of testosterone therapy, showing that in men with hypogonadism, there is no significant difference in mortality or adverse cardiovascular events between those receiving treatment with testosterone vs. placebo.
  • Numerically, there were fewer deaths in men receiving testosterone treatment (six [0.4%] of 1621) than placebo (12 [0.8%] of 1537).
  • There was no adverse effect of testosterone therapy on systolic or diastolic blood pressure.
  • Despite increased hematocrit in men receiving testosterone treatment, there were only 5 deep vein thromboses, compared to 7 men in the placebo group.

What is known about the effect of testosterone therapy on cardiovascular disease and mortality

Long-term real-world evidence (RWE) studies have shown that long-term treatment with testosterone undecanoate injection is both safe and effective, and that untreated hypogonadism actually is associated with worse cardiovascular disease and prostate cancer outcomes, as well as premature mortality, compared to men with hypogonadism who receive testosterone treatment.2, 3

Testosterone has been used as a safe and effective treatment of hypogonadism since the 1940s.4 However, in the past decade, a few poorly designed studies suggested increased risk of myocardial infarction and stroke with testosterone therapy, creating unwarranted concerns about the safety of testosterone therapy.5 This has resulted in many suffering men being denied testosterone treatment and its substantial health benefits.

 

What this study adds

To strengthen the evidence base supporting the safety of testosterone therapy in men with hypogonadism, a meta-analysis was conducted of 35 primary studies (5601 participants, mean age 65 years).1 Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9.5 months) from nine different countries. Risk of bias was judged to be low in most IPD studies (71%).

Results showed that fewer deaths occurred with testosterone treatment (six [0.4%] of 1621) than placebo (12 [0.8%] of 1537).

Cardiovascular risk was similar during testosterone treatment (120 [7.5%] of 1601 events) and placebo treatment (110 [7.2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62).

Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176).

Despite increased hematocrit, deep vein thromboses were recorded in only 5 men receiving testosterone treatment, compared to 7 men in the placebo group.

There was no effect of testosterone on systolic or diastolic blood pressure.

Overall, patient age, baseline testosterone, smoking status or diabetes status (interaction 2·08 [0·89– 4·82; p=0·025) were not associated with cardiovascular risk.

It was concluded that there is no evidence that testosterone treatment increases short-term to medium-term cardiovascular risk in men with hypogonadism.1

 

Commentary

The present IPD meta-analysis of more than 3000 patients with hypogonadism from randomised placebo-controlled trials shows that testosterone treatment is not associated with increased risk of various subtypes of cardiovascular events in the short to medium term, compared with placebo.1 Data on mortality were also reassuring, with fewer deaths occurring with testosterone treatment. Despite increased hematocrit, there was no increase in thrombotic events. Testosterone treatment was associated with a modest lowering of total and HDL cholesterol, as well as triglyceride levels. Importantly, testosterone treatment did not have adverse effects on blood pressure.1 The lack of adverse effect on blood pressure is particularly notable, given that the FDA has added a requirement that testosterone product labels have a boxed warning about the risk for blood pressure elevation.

The findings in this IPD meta-analysis have been confirmed in several long-term RWE studies. In one RWE study, 428 men with hypogonadism received treatment with testosterone undecanoate injection, while 395 men with hypogonadism did not receive testosterone treatment and served as a control group.2 After a follow-up of 11 years, there was a significant reduction in body weight, waist size, blood pressure, pulse pressure, LDL and triglycerides, along with an increase in HDL in men receiving treatment with testosterone undecanoate injections. In contrast, in men with hypogonadism not receiving testosterone therapy, there was a significant deterioration in all parameters. Importantly, there were 77 (19.5%) deaths in the untreated group, but only and 23 (5.4%) in the testosterone group.2

Another report from this RWE study showed that men receiving testosterone undecanoate injections also had improvement in urinary parameters (assessed by IPSS) and reduced incidence of prostate cancer (3.2% vs. 6.9%).3 Importantly, in men receiving treatment with testosterone undecanoate injection, no myocardial infarction (MI) nor stroke occurred during the entire 11-year follow-up. Death from all causes occurred in 6.5% and 2.3% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively. In contrast, in men not receiving testosterone treatment, MI and stroke occurred in 18.9% and 14.9% of patients with moderate/severe erectile dysfunction, respectively, and 16% and 15.3% in patients with no/mild erectile dysfunction. Furthermore in this group of untreated men, death occurred in 14.6% and 21.3% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively.3

This RWE study supports the long-term safety and effectiveness of hypogonadism treatment with testosterone undecanoate injection in the context of a real-world everyday clinical setting, as opposed to artificially imposed ideal scenarios within the context of a randomized controlled trial. Furthermore, it also demonstrates that men with hypogonadism who do not receive testosterone therapy have severe deterioration in health over time, and increased incidence of premature mortality. Hence, when evaluating safety of testosterone therapy, it is essential to also consider the negative effects of untreated hypogonadism.

For more information about this RWE study, see “Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality”.

The results from the present IPD meta-analysis are in contrast to the results from a previous large population-based cohort study by Wallis and coworkers, which showed that short duration of testosterone therapy (median 2 months) was associated with increased risk of cardiovascular events and mortality, whereas longer duration (median 35 months) was associated with reduced mortality and cardiovascular events, compared with matched controls. For more information about this study, see “Survival and cardiovascular events in men treated with testosterone”.

However, this study was based on data collected from prescription databases, using the total number of days of testosterone therapy dispensed according to prescription records as a proxy for cumulative dose exposure. Data on compliance or actual testosterone levels were not provided. Therefore, the association between short duration of testosterone therapy (median 2 months) and increased risk of cardiovascular events and mortality could simply be due to inadequate testosterone treatment, allowing for health consequences of long-standing underlying hypogonadism to manifest. In contrast, the present IPD meta-analysis used comprehensive data collected from randomized trials of 3431 men receiving testosterone therapy for a mean duration 9.5 months, hence providing more credible evidence.

The results from the present IPD meta-analysis are also in contrast with finding from a recent electronic medical records study, in which a total of 5,842 men who received testosterone therapy and developed polycythemia (defined as a hematocrit over 52%) were matched and compared to 5,842 men who did not develop polycythemia.6 Men with polycythemia had a higher risk of MACE/VTE (5.15%) than men who had normal hematocrit (3.87%) while on testosterone therapy (OR 1.35, p <0.001). In other words, the development of secondary polycythemia during testosterone therapy was associated with increased risk of developing major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) during the first year of therapy, but testosterone therapy itself, in the absence of polycythemia, did not appear to increase risk of MACE or VTE in hypogonadal men.6 A limitation of this study was that it did not match the two groups by baseline hematocrit, as the men in the polycythemia group had a higher baseline hematocrit (47.4% and 42.5%). Therefore, the study cannot definitively determine whether the increased risk of MACE/VTE is due to hematocrit reaching 52% or due to higher baseline hematocrit before starting testosterone therapy.

It should be noted that a previous real-world evidence study showed the opposite, that men receiving long-term treatment with testosterone undecanoate injections have reduced mortality despite relatively high hematocrit up to 52%.7 For more information, see “Increased Hematocrit Linked to Reduced Death in Men Receiving Testosterone Therapy”.

It should be pointed out that this IPD meta-analysis was conducted by the Testosterone Efficacy and Safety Consortium, which is a global collaboration of principal investigators of testosterone trials. The rigorous data collection by prominent scientists lends high credibility to the conclusion that testosterone therapy is safe for men with hypogonadism.

References

  • Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. Lancet Healthy Longev. Jun 2022;3(6):e381-e393. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
  • Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Feb 20 2020;23(1):81-92. Return to content
  • Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev. Apr 2020;8(2):286-296. Return to content
  • Traish AM, Guay AT, Morgentaler A. Death by testosterone? We think not! The journal of sexual medicine. Mar 2014;11(3):624-9. Return to content
  • Ory J, Nackeeran S, Balaji NC, Hare JM, Ramasamy AR. Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of Therapy. J Urol. Jun 2022;207(6):1295-1301. Return to content
  • Strange RC, König CS, Ahmed A, et al. Testosterone Therapy: Increase in Hematocrit is Associated with Decreased Mortality. Androgens: Clinical Research and Therapeutics. 2021/12/01 2021;2(1):150-159. Return to content