Allopurinol and endothelial function: A systematic review with meta‐analysis of randomized controlled trials

Alem, Manal M.

doi:10.1111/1755-5922.12432

Cited by 47 publications

(40 citation statements)

References 55 publications

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“…A meta-analysis has shown that allopurinol therapy is associated with improved endothelial function, which is more pronounced in patients with normal SUA at baseline [65]. Similar results were found in a systematic review, where allopurinol use, with its antioxidant properties, had a significant benefit on endothelial dysfunction in patients with congestive heart failure and in patients with CKD, but not type 2 DM [66]. It seems that allopurinol benefit is independent of administered dose, duration of treatment, or its effect on SUA levels [67].…”

Section: Hyperuricemia and Cardiovascular Diseasesupporting

confidence: 61%

Hyperuricemia, the heart, and the kidneys – to treat or not to treat?

et al. 2020

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Background: Hyperuricemia is a state in which the serum levels of uric acid are elevated. As such it has a pronounced effect on vascular and renal function with their consequences, while also showing some antioxidant effects that show to be beneficial. Summary: Hyperuricemia has shown to have a J-shaped relationship with mortality, is frequently associated with development and progression of heart and kidney disease, and is correlated with malnutrition-inflammation-atherosclerosis syndrome, although several Mendelian studies have failed to show an association with morbidity and mortality. Hyperuricemia is usually associated with gout flares and tophi development but can also present as asymptomatic hyperuricemia. It is still uncertain whether asymptomatic hyperuricemia is an independent risk factor for cardiovascular or renal disease and as such its treatment is questionable. Key messages: Some possible tools for future decision making are the use of noninvasive techniques such as pulse wave analysis, urinary sediment analysis, and joint ultrasound, which could help identify individuals with asymptomatic hyperuricemia that could benefit from urate lowering therapy most.

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Section: Hyperuricemia and Cardiovascular Diseasesupporting

confidence: 61%

Hyperuricemia, the heart, and the kidneys – to treat or not to treat?

et al. 2020

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“…20 In a recent clinical trial evaluating the cardiovascular safety of febuxostat, a non-purine xanthine oxidase inhibitor, compared with allopurinol, all-cause and cardiovascular-specific mortality were lower in subjects treated with allopurinol. [25][26][27] An observational study assessing allopurinol and cardiovascular outcomes in diabetes is warranted to determine whether a large clinical trial in diabetes is indicated. 22 The potential impact of allopurinol in diabetes is of particular importance because individuals with diabetes are more likely to have hyperuricaemia and are at higher risk of cardiovascular events and death.…”

Section: Introductionmentioning

confidence: 99%

“…23,24 While some studies have showed improved endothelial function and reduced oxidative stress in response to allopurinol in subjects with diabetes, results have not been consistent and may be dose dependent. [25][26][27] An observational study assessing allopurinol and cardiovascular outcomes in diabetes is warranted to determine whether a large clinical trial in diabetes is indicated.…”

Section: Introductionmentioning

confidence: 99%

Association between allopurinol and cardiovascular outcomes and all‐cause mortality in diabetes: A retrospective, population‐based cohort study

Weisman

Tomlinson

Lipscombe

et al. 2019

Diabetes Obesity Metabolism

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Aim: To assess the association between allopurinol and mortality and cardiovascular outcomes in an allopurinol-treated diabetes cohort. Materials and Methods:We conducted a population-based retrospective cohort study in Ontario, Canada. Eligible subjects were ≥ 66 years old with diabetes and a first prescription for allopurinol between 1 April, 2002 and 31 March, 2012 and were followed until 31 March, 2016.The primary outcome was a composite: all-cause mortality, non-fatal cardiovascular event (myocardial infarction, revascularization procedure, or stroke) or congestive heart failure (CHF). Secondary outcomes were components of the primary outcome and pneumonia as a negative tracer. Allopurinol was modelled as time-varying exposed versus unexposed, daily dose category and cumulative dose using sex-specific multivariable Cox proportional hazards models. Results: Over a median follow-up of 4.65 years (interquartile range 1.79-7.81), 16 266/23 103 males and 10 571/15 313 females experienced the primary outcome. Allopurinol was associated with a reduction in the primary outcome [adjusted hazard ratios (aHR) 0.77 (95% confidence interval 0.75-0.80) and 0.81 (0.78-0.84) for males and females, respectively], driven by marked reductions in all-cause mortality and modest reductions in cardiovascular events/CHF. There was no effect of cumulative allopurinol dose on any outcome, and allopurinol was also associated with reduced risk of pneumonia in males [aHR 0.88 (0.83, 0.93)]. Conclusions: Allopurinol was associated with reduced mortality and cardiovascular outcomes. However, lack of cumulative dose effect and a positive tracer outcome in males suggests residual bias. Future research assessing whether allopurinol prevents vascular complications in diabetes requires a clinical trial. K E Y W O R D S cardiovascular disease, diabetes complications, pharmaco-epidemiology, population study

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“…The weight of evidence also suggests that high levels of circulating XO act as a major driver of endothelial dysfunction and atherosclerosis [ 183 ], reviewed in [ 184 ]. The pathogenic role of XO is further emphasised by data produced by several meta-analyses and prospective studies demonstrating a significant and large improvement in endothelial function following XO inhibition in patients with CVD [ 84 , 185 – 187 ]. A recent meta-analysis of large prospective randomised controlled trials (RCTs) has also reported large reductions in cardiovascular morbidity and mortality achieved by the inhibition of XO by allopurinol [ 188 ].…”

Section: The Roles Of Platelet Activation Xanthene Oxidase and Myelomentioning

confidence: 99%

“…One mechanism which appears to be associated with the positive effects of XO is a decrease in systemic and vascular oxidative stress [ 84 , 185 – 187 ]. This is unsurprising given the fact that circulating activated XO is a major, if not the predominant, source of hydrogen peroxide and superoxide in patients displaying high levels of systemic inflammation and oxidative stress [ 183 , 189 , 190 ].…”

Section: The Roles Of Platelet Activation Xanthene Oxidase and Myelomentioning

confidence: 99%

Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

Morris

Puri²,

Olive

et al. 2020

BMC Med

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Background Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. Main text Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. Conclusions Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.

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Allopurinol and endothelial function: A systematic review with meta‐analysis of randomized controlled trials

Cited by 47 publications

References 55 publications

Hyperuricemia, the heart, and the kidneys – to treat or not to treat?

Hyperuricemia, the heart, and the kidneys – to treat or not to treat?

Association between allopurinol and cardiovascular outcomes and all‐cause mortality in diabetes: A retrospective, population‐based cohort study

Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

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