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Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.

ABSTRACT: BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

SUBMITTER: Xu L

PROVIDER: S-EPMC3648456 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.

Xu Lin L Freeman Guy G Cowling Benjamin J BJ Schooling C Mary CM

BMC medicine 20130418

<h4>Background</h4>Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease.<h4>Methods</h4>A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMe ...[more]

PMID: 23597181

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Project description:BackgroundStatins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.MethodsA meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.ResultsOf the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).ConclusionsStatins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.

Project description:Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism. Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease. However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI. Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment.PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching. RCTs including exclusively adult individuals, lasting ??4 weeks, with no language restriction, were eligible. Independent paired researchers selected studies and extracted data. Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis. Random-effects meta-regression was used to explore heterogeneity.The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (ORP =?0.71, 95% CI 0.46-1.09) and death (0.89, 0.59-1.33), but reduced risk of TCE (0.60, 0.44-0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23-0.76). Allopurinol protected for myocardial infarction (0.38, 0.17-0.83), hypertension (0.32, 0.18-0.58), TCE (0.48, 0.31 to 0.75, I2 =?55%) and serious TCE (0.56, 0.36 to 0.86, I2 =?44%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P?<?0.05). Accordingly, lower doses (??300 mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate.Purine-like XOI may reduce the incidence of adverse CV outcomes. However, higher doses of allopurinol (>?300 mg/day) may be associated with loss of CV protection.

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Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.

Publications

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.

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