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

July 2022

Medical guideline recommendations are based on data from studies known as randomised controlled trials (RCTs), and meta-analyses of those trials. Previous meta-analyses of heart disease 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 of testosterone studies available, to analyse subtypes of all cardiovascular events observed during treatment.1

KEY POINTS

  • New meta-analysis of comprehensive safety data confirms the safety of testosterone treatment, showing that in men with low testosterone, there is no significant difference in heart attack, stroke and death 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).
  • Testosterone treatment did not increase systolic or diastolic blood pressure.
  • Despite increased hematocrit in men receiving testosterone treatment, there were only 5 blood clots, compared to 7 blood clots in men in the placebo group.

What is known about the effect of testosterone treatment on heart disease and death

Real-world evidence studies have shown that long-term testosterone treatment is both safe and effective, and that untreated low testosterone actually is associated with more severe heart disease and prostate cancer, as well as premature death, compared to men with low testosterone who receive testosterone treatment.2, 3

Testosterone has been used as a safe and effective treatment of low testosterone since the 1940s.4 However, in the past decade, a few poorly designed studies suggested increased risk of heart attack and stroke with testosterone treatment, creating unwarranted concerns about the safety of testosterone treatment.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 treatment in men with low testosterone, a meta-analysis was conducted of 35 studies (5601 participants, mean age 65 years).1 Of these, 17 studies (49%) from nine different countries provided individual participant data (3431 participants, mean duration 9.5 months), as opposed to only providing group averages.

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

Heart disease risk was similar between testosterone treatment and placebo groups; the most common heart disease events, occurring at similar rates in both groups, were 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 heart attack (10 of 166 vs 16 of 176).

Despite increased hematocrit, blood clots occurred 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.

It was concluded that there is no evidence that testosterone treatment increases short-term to medium-term heart disease risks in men with low testosterone.1

 

Commentary

This meta-analysis of more than 3000 men with low testosterone shows that testosterone treatment is not associated with increased risk of heart disease 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 blood clots.

Testosterone treatment was associated with a modest lowering of total and HDL cholesterol, as well as triglyceride (blood fat) 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 meta-analysis have been confirmed in several long-term real-world evidence studies, showing that men with low testosterone receiving testosterone treatment for 11 years had a significant reduction in body weight, waist size, blood pressure, LDL and triglycerides, along with an increase in HDL. In contrast, in men with low testosterone not receiving testosterone treatment, there was a significant deterioration in all parameters. Importantly, there were also 3.6-fold more deaths (19.5%) in men not receiving testosterone treatment, compared to men receiving testosterone treatment (5.4%).2

Another report from this 11-year long study showed that men receiving testosterone treatment 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 testosterone treatment, no heart attack nor stroke occurred during the entire 11-year follow-up period. Death 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, heart attack 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 real-world evidence study supports the long-term safety and effectiveness of testosterone treatment 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 low testosterone who do not receive testosterone treatment have severe deterioration in health over time, and increased risk of premature mortality. Hence, when evaluating safety of testosterone treatment, it is essential to also consider the negative effects of untreated low testosterone.

The results from this meta-analysis are in contrast to the results from a previous large population-based study, which showed that short duration of testosterone treatment (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 treatment dispensed according to prescription records as a proxy for cumulative testosterone dose exposure. Data on compliance or actual testosterone levels were not provided. Therefore, the association between short duration of testosterone treatment (2 months) and increased risk of heart disease and mortality could simply be due to inadequate testosterone treatment, allowing for health consequences of long-standing underlying low testosterone to manifest. In contrast, the present meta-analysis used comprehensive data collected from randomized trials of 3431 men receiving testosterone treatment for a mean duration 9.5 months, hence providing more credible evidence.

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

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