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Cited by 1,003Hormonal and reproductive studiesMenopause: Health Impacts and TreatmentsLipoproteins and Cardiovascular Health

Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels

Vigen, Rebecca·2013·JAMA
DOI 10.1001/jama.2013.280386
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Abstract

IMPORTANCE: Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown. A recent randomized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety. OBJECTIVES: To assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease. DESIGN, SETTING, AND PATIENTS: A retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. MAIN OUTCOMES AND MEASURES: Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke. RESULTS: Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography, the Kaplan-Meier 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%(95%CI, -1.4%to 13.1%) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1% vs 11.3%; at 2 years, 15.4% vs 18.5%; and at 3 years, 19.9% vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P = .41). CONCLUSIONS AND RELEVANCE: Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.

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  • In Vigen et al., although a higher rate of adverse events was identified in the testosterone supplementation group after statistical manipulation of raw data, the wide discrepancy in groupings makes it unclear whether that group had a higher baseline risk and whether lower testosterone was an indirect indicator of overall comorbid burden.

    “Although the authors identified a higher rate of AEs in the T supplementation group (after statistical manipulation of the raw data), given the wide discrepancy in groupings, it is unclear if this group represented men with a higher baseline risk for subsequent events and that a lower T in this group was an indirect indicator of their overall comorbid burdens (despite lower ages).”

    From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [129]

  • In Vigen et al., groupings were not matched for age or testosterone levels.

    “Additionally, groupings were not matched for age or T levels.”

    From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [129]

  • In Vigen et al.'s retrospective analysis of a VA population, baseline comorbid states differed significantly between hypogonadal men receiving and not receiving testosterone supplementation, including obesity, obstructed coronary artery status, hypertension, hyperlipidemia, myocardial infarction, and cerebrovascular disease.

    “One recent example of poorly matched groupings was the Vigen et al’s retrospective analysis of a VA population, which compared hypogonadal men receiving or not receiving T supplementation.129 Baseline comorbid states were significantly different between groupings, including obesity, obstructed coronary artery status, hypertension, hyperlipidemia, myocardial infarction, and cerebrovascular disease,”

    From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [129]

  • Some epidemiological studies have reported an increase in cardiovascular mortality related to TRT while others have not been able to establish a correlation.

    “Some epidemiological studies have reported an increase in cardiovascular mortality related to TRT while others have not been able to establish a correlation between the two [19,20].”

    From The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes (2018) · cites this paper as [19]

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Authors
Vigen, R.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Vigen, Rebecca
ORCID
Vigen, Rebecca
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2013-11-06
Volume
310
Issue
17
Pages
1829
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2013.280386
OpenAlex
W2132123717
Cited by
1,003
References
39
Citations by year
2026: 25 · 2025: 45 · 2024: 48 · 2023: 62 · 2022: 52 · 2021: 52 · 2020: 60 · 2019: 70 · 2018: 87 · 2017: 101 · 2016: 96 · 2015: 136 · 2014: 162 · 2013: 5
FWCI
104.22
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
testosterone replacement therapy, androgen deficiency, hypogonadism, all-cause mortality, myocardial infarction, ischemic stroke, cardiovascular outcomes, coronary artery disease, male veterans, coronary angiography, men's health, hormone replacement therapy, early trial termination, sex differences in cardiovascular risk
MeSH terms
Aged, Coronary Artery Disease, Humans, Male, Middle Aged, Mortality, Myocardial Infarction, Retrospective Studies, Risk, Testosterone, Veterans, Cohort Studies, Coronary Angiography, Stroke, Andropause

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