Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis

Hudson, Jemma; Cruickshank, Moira; Quinton, Richard; Aucott, Lorna; Aceves‐Martins, Magaly; Gillies, Katie; Bhasin, Shalender; Snyder, Peter J.; Ellenberg, Susan S.; Grossmann, Mathis; Travison, Thomas G.; Gianatti, Emily J; Schouw, Yvonne T. van der; Emmelot-Vonk, Mariëlle H.; Giltay, Erik J.; Hackett, Geoff; Ramachandran, Sudarshan; Svartberg, Johan; Hildreth, Kerry L.; Antonič, Kristina Groti; Brock, Gerald; Tenover, J. Lisa; Tan, Hui Meng; Kong, Christopher Ho Chee; Tan, Wei Shen; Marks, Leonard S.; Ross, R. J. M.; Schwartz, Robert S.; Manson, Paul; Roberts, Stephen E.; Andersen, Marianne; Magnussen, Line Velling; Hernández, Rodolfo; Oliver, Nick; Wu, Frederick C. W.; Dhillo, Waljit; Bhattacharya, Siladitya; Brazzelli, Miriam; Jayasena, Channa N.

doi:10.1016/s2666-7568(22)00096-4

Cited by 60 publications

(38 citation statements)

References 65 publications

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“…The latter study also documented that an increased risk of CV diseases was observed in RCTs when T preparations were prescribed at dosages above those normally recommended, or when frail men were considered [66]. In line wih this evidence a more recent individual patient and aggregate data meta-analysis, including 35 primary studies (5601 participants, mean age 65 years) found no evidence that TRT increased shortterm to medium-term CV risks in men with hypogonadism [67]. Accordingly, the conclusion of the European Medicine Agency (EMA) did not align with the FDA opinion and stated the safety of TRT on the cardiovascular profile [68].…”

Section: Evidencementioning

confidence: 82%

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)

Isidori

Aversa

Calogero

et al. 2022

J Endocrinol Invest

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Purpose To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. Methods The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Results Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. Conclusions TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.

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Section: Evidencementioning

confidence: 82%

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)

Isidori

Aversa

Calogero

et al. 2022

J Endocrinol Invest

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“…But for older men, or those with chronic diseases, such as diabetes and certain inflammatory diseases, whose low testosterone levels are induced by nonorganic diseases, whether TRT will contribute to an increased risk of major adverse events still remains controversial [ 32 ]. Most recently, Hudson et al performed an updated meta-analysis covering 35 primary studies with 5601 participants, summarizing that TRT did not increase short- to medium-term cardiovascular risk in men with testosterone deficiency [ 33 ]. Hudson et al also proposed that due to the lack of relevant data, the long-term safety of TRT remained to be proven.…”

Section: Discussionmentioning

confidence: 99%

Low Testosterone Level and Risk of Adverse Clinical Events among Male Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Cohort Studies

Jin

et al. 2022

Journal of Healthcare Engineering

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The phenomenon of low testosterone level is extremely common in male patients with chronic kidney diseases (CKDs). This meta-analysis aimed to evaluate whether the low circulating testosterone could independently predict adverse outcomes among male patients with chronic kidney diseases (CKDs). The data till May 2022 were systematically searched from Pubmed, Web of Science, and Embase from inception. Studies meeting the PICOS (population, intervention/exposure, control/comparison, outcomes, and study design) principles were included in this meta-analysis. Study-specific effect estimates were pooled using fixed-effects (I2 > 50%) or random-effects models (I2 < 50%). Ultimately, 9 cohort studies covering 5331 patients with CKDs were involved in this meta-analysis. The results suggested that per 1-standard deviation (SD) decrease in total testosterone independently increased the risk of all-cause mortality by 27% [hazard risk (HR) 1.27, 95% confidence interval (CI) 1.16–1.38], cardiovascular mortality by 100% (HR 2.00, 95% CI 1.39–2.86), cardiovascular events by 20% (HR 1.20, 95% CI 1.04–1.39), and infectious events by 41% (HR 1.41, 95% CI 1.08–1.84). Besides, with per 1-SD decrease in free testosterone, the risk of overall adverse events increased by 66% (HR 1.66, 95% CI 1.34–2.05). Stratified analyses indicated that the negative relationship of the total testosterone with all-cause death risk was independent of factors involving age, race, body mass index, diabetes, hypertension, C-reactive protein, creatinine, and sex hormone binding globulin. In conclusion, it was identified that low endogenous testosterone could serve as an independent predictor of adverse clinical events among male patients with CKDs.

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“…A recent meta-analysis of 35 placebo-controlled TTh trials involving 5601 men with low baseline T concentrations (≤350 ng/dL) with a mean duration of treatment of 9.5 months found no significantly increased risk of CV events between the TTh group and placebo groups. 39 An additional study showed that active cigarette smoking nullified these beneficial effects of T normalization with TTh. 40 …”

Section: Normalization Of Testosterone In Men Is Associated With Redu...mentioning

confidence: 98%

“…TTh is associated with reduced risk of overall and vascular mortality. 17 Low T is associated with increased incidences of dementia and Alzheimer's disease. 18 …”

Section: Testosterone Deficiency Is a Serious Health Concern And Tth ...mentioning

confidence: 99%

Recognizing the True Value of Testosterone Therapy in Health Care

Morgentaler

Traish

Barua

et al. 2022

Androgens: Clinical Research and Therapeutics

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There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

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Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis

Cited by 60 publications

References 65 publications

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)

Low Testosterone Level and Risk of Adverse Clinical Events among Male Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Cohort Studies

Recognizing the True Value of Testosterone Therapy in Health Care

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