Could uric acid reduction by specific xanthine oxidase inhibition improve vascular function and reduce cardiovascular risk?
Year: 2019
Type: article
Abstract: For decades, the identification of independent and synergistic cardiovascular disease risk factors, coupled with strategies to mitigate the disease burden associated with these risk factors, has been a major goal of health care. Hyperuricemia, as a risk factor for and marker of cardiovascular disease, has been the source of significant examination, investigation, and debate. Given its relatively high prevalence, determining the precise role that hyperuricemia plays in the pathogenesis of cardiovascular disease is important, particularly as other inter-related cardiovascular risk factors such as hypertension, diabetes mellitus, obesity, and hyperlipidemia are becoming increasingly common. Of importance to the discussion of hyperuricemia in the pathogenesis of cardiovascular disease is the fact that there are highly effective pharmacologic agents which reduce serum uric acid levels. One such family of agents is the xanthine oxidase (XO) inhibitors. Xanthine oxidase inhibitors block a vital enzymatic step in purine metabolism needed for uric acid generation. Allopurinol, the first XO inhibitor discovered, was approved by the FDA in 1966 and has, since then, revolutionized the management of hyperuricemia. Allopurinol is a purine analog, structurally similar to naturally occurring purines such as hypoxanthine and xanthine. Inhibiting XO blocks the conversion of hypoxanthine and xanthine to uric acid which, in turn, lowers serum uric acid. However, allopurinol and its oxidized metabolite oxipurinol are non-selective XO inhibitors and block other steps in purine metabolism. This sometimes results in undesirable side effects. However, more recently, newer XO inhibitors have been developed, including febuxostat and topiroxostat. These agents are more selective to XO inhibition and do not affect other enzymatic steps in purine metabolism, and consequently, tend to be better tolerated. In this edition of the journal, Higa et al.1 in their paper entitled, “The effects of topiroxostat on vascular function in patients with hyperuricemia” explore whether serum uric acid reduction by topiroxostat could improve vascular (endothelial) function in individuals with hyperuricemia. They performed a retrospective cohort analysis to evaluate the effects of topiroxastat on vascular function as measured by flow-mediated dilation (FMD) in 23 individuals with hyperuricemia. Following approximately 8 weeks of topiroxostat treatment, serum uric acid significantly decreased from 7.31 ± 1.43 to 5.44 ± 1.11 mg/dL. The important finding of the study is that with treatment and reduction in serum uric acid levels, there was also a significant increase in the peak percentage change in FMD. The authors conclude that topiroxostat improves vascular endothelial function in individuals with hyperuricemia. This article adds to the discussion and debate regarding uric acid reduction in the mitigation of cardiovascular risk factor. Understanding uric acid metabolism is central to appreciating the role that drugs such as topiroxostat may play in improving endothelial function in persons with hyperuricemia. In humans, uric acid metabolism is somewhat peculiar, when compared to other mammalian species and provides clues into our evolutionary history. The production of uric acid starts with the breakdown of purines, a byproduct of cell turnover or derived from the diet. In most mammals, uric acid functions as an intermediate molecule, which is further broken down by the enzyme uricase to allantoin, a soluble compound that is excreted freely in urine by the kidney. As such, uric acid levels in most mammals are quite low, <2 mg/dL. However, in humans and higher primates, the gene that codes for uricase is non-functional, resulting in uric acid being the end point of purine metabolism in these species.2 The fate of uric acid in humans is quite different from that in our mammalian counterparts, as it is only partially excreted by the kidneys. In most individuals, as much as 90% of uric acid filtered by the kidney is reabsorbed in the renal tubules and returns to blood.3 Because of the impaired clearance of uric acid in humans, levels of uric acid are higher when compared to other mammals with normal serum levels in humans ranging from 2.4 to 6.0 mg/dL in females and 3.4-7.0 mg/dL in males. Additional factors that increase the serum uric acid levels include increased cell turn over, consumption of diets high in purines and/or decreased clearance of uric acid by the kidneys. For quite some time, the precise role hyperuricemia plays in cardiovascular disease has been uncertain and the topic of much debate. It is well known that elevations in uric acid can be observed in persons with cardiovascular disease as well as in those at increased cardiac risk. What has been more difficult to demonstrate is whether the association is causal or not in the development of cardiovascular disease.4, 5 Within the last two decades, several observational studies have added significant clarity to this question. Not only has it been shown that high levels of uric acid (typically those within the upper quartile) are an independent risk factor for overall cardiovascular mortality,6 but also that hyperuricemia is an independent risk factor for a number of non-fatal cardiac outcomes, such as myocardial infarction and stroke. As relates to coronary artery disease and stroke, a large prospective study published in 2007, noted that men with gout (a common manifestation of hyperuricemia) and pre-existing coronary heart disease were at increased risk of fatal and non-fatal myocardial infarction when compared to men who did not have gout. 7 Beyond this, as was seen in the Rotterdam study which comprised 4385 persons without a history of cardiovascular disease or stroke, the risk of myocardial infarction and stroke was shown to be increased in persons with high serum uric acid levels.8 Beyond this, hyperuricemia has been found to be an independent risk factor for the development of hypertension, a major risk factor for cardiovascular disease. This association was seen in a meta-analysis conducted by Grayson, Kim et al, comprising 18 studies including over 55 000 individuals. This study further demonstrated that for each 1 mg/dL increase in serum uric acid above normal, the risk of hypertension increased by 13%.9 As a prognostic factor, serum uric acid levels have been used as a biomarker in many cardiovascular disease states. For instance, serum uric acid levels have been shown to have prognostic implications in patients with moderate-to-severe heart failure.10, 11 Similarly, prospective studies have demonstrated that serum uric acid levels are predictive of the development of atherosclerosis and coronary artery calcification.12 To date, the utility of this marker in everyday clinical practice in screening for cardiovascular disease and identifying persons at increased risk for the future development of cardiac disease is less established. The mechanism by which uric acid increases cardiovascular risk over time is multifaceted. Uric acid has been demonstrated to have pro-inflammatory qualities, via pro-oxidant properties by activating HMGB1/RAGE signaling leading to increased oxidative stress and endothelial dysfunction.13 Furthermore, uric acid is thought to lead to insensitivity of insulin-induced endothelial nitric oxide synthase (eNOS) release as well as to stimulate the renin-angiotensin aldosterone system leading to vasoconstriction, increased vascular stiffness, and elevations in blood pressure.14-16 The impact of hyperuricemia on the cardiovascular system may be demonstrated through changes in vascular and endothelial function and the development of endothelial dysfunction. This endothelial dysfunction frequently predates clinical symptoms by several years and functions as a worthwhile biomarker for detecting cardiovascular disease. Clinical methods of detecting endothelial dysfunction include coronary epicardial vasoreactivity, coronary microvascular function-Doppler wires, FMD, venous occlusion plethysmograph, and EndoPAT.17, 18 Collectively, these act as worthwhile methods of demonstrating heightened cardiovascular risk and has been used widely in clinical studies examining the role of hyperuricemia in the development of cardiovascular disease. In examining the role of hyperuricemia in cardiac disease a step further, recent studies have sought to determine whether lowering serum uric acid levels could translate into reductions in cardiovascular outcomes. One such study was conducted by Singh et al, which demonstrated a cardioprotective effect with the xanthine oxidase inhibitor allopurinol, particularly in persons with gout and diabetes.19 However, other studies have failed to come to the same conclusion. For instance, a recent randomized placebo control trial among overweight and obese persons with serum uric acid levels>/ = 5 mg/dL received allopurinol, or probenecid compared with placebo did not produce a statistically significant difference in endothelial function after an 8-week period of treatment. Adding further inconsistency, the XO selective, uric acid lowering drug, febuxostat was recently shown to increase the risk of future development of cardiovascular disease rather than offer cardioprotection as had been hypothesized. This finding based on the results of the Cardiovascular Safety of Febuxostat or Allopurinol in Patients in Gout and Cardiovascular Morbidities (CARES) trial.20 In this double-blind, non-inferiority trial consisting of 6190 patients with gout, all-cause mortality and cardiovascular mortality were higher in febuxostat when compared to allopurinol. The exact mechanism by which this increased risk of all-cause and cardiovascular mortality is conferred is not immediately clear. As a result of these findings, the FDA has placed warnings on the use of febuxostat, recommending that its use be restricted to patients with refractory gout, not responsive to allopurinol. Using changes in FMD of the brachial artery as a marker of changes in endothelial function, the data provided by Higa et al.1 demonstrate that an 8-week treatment with topiroxostat improves endothelial function. These results are welcomed, particularly in the wake of the concerns raised over the cardiovascular safety of the similar drug, febuxostat. At this point however, it is not certain whether this finding will translate into improved long-term cardiovascular disease outcomes and which patient population(s) may benefit most from this therapy. Notwithstanding, this study serves as a platform to encourage further research on this topic through randomized control trials. Thus, the paper by Higa et al.1 in this issue of the journal provides further motivation to search for strategies to optimize vascular/endothelial function in the presence of hyperuricemia and opens the door for continued discussion on this topic. Uric acid reduction is unlikely to completely solve the enhanced burden of cardiac disease but might function as a worthwhile strategy to lower cardiac risk in select individuals. In the future, further examination of this topic is key as we continue to search for strategies to identify persons at high risk for further development of cardiac disease and to find various modalities by which to reduce the global cardiovascular disease burden. Donald J. DiPette is a Distinguished Health Sciences Professor, University of South Carolina and University of South Carolina School of Medicine, Columbia, SC. The authors do not have a conflict of interest. The views expressed in this manuscript are solely those of the contributing authors and do not necessarily represent the views of the authors' associated institutions.
Source: Journal of Clinical Hypertension
DOI: 10.1111/jch.13693
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2976670220