Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia

Kario, Kazuomi; Nishizawa, Masafumi; Kiuchi, Mari; Kiyosue, Arihiro; Tomita, Fumishi; Oda, Hiroshi; Abe, Yasuhisa; Kuga, Hideyo; Miyazaki, Shôzo; Kasai, Takatoshi; Hongou, Makiko; Yasu, Takanori; Kuramochi, Jin; Hisatome, Ichiro

doi:10.1111/jch.14153

Cited by 27 publications

(23 citation statements)

References 43 publications

(104 reference statements)

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“…A significant reduction in systolic and diastolic BP was reported in a comprehensive meta-analysis of 10 prospective and retrospective studies involving 738 patients 85 treated with allopurinol with a substantial homogeneity across the studies despite a remarkable difference in the characteristics of the study populations. The effects of ULT on BP control is apparently more evident with drugs showing a greater inhibition of XOR activity 86 again supporting its possible involvement in the mechanism of BP increase in patients with hyperuricemia.…”

Section: Treatment Of Hyperuricemia and Hypertensionmentioning

confidence: 72%

Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk

et al. 2022

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Uric acid is the final product of purine metabolism, and its increased serum levels have been directly involved in the pathogenesis and natural history of hypertension. The relationship between elevated uric acid and hypertension has been proven in both animals and humans, and its relevance is already evident in childhood and adolescent population. The mechanism responsible for blood pressure increase in hyperuricemic subjects is implicating both oxidative stress and intracellular urate activity with a primary involvement of XOR (xanthine-oxidoreductase activity). An increase in the relative risk of hypertension has been confirmed by genetic data and by large meta-analyses of epidemiological data. The effects of urate-lowering treatment on blood pressure control in patients with elevated serum uric acid has been investigated in a small number of reliable studies with a large heterogeneity of patient populations and study designs. However, 2 large meta-analyses suggest a significant effect of urate-lowering treatment on blood pressure, thus confirming the significant relationship between high serum urate and blood pressure. The future research should be focused on a more appropriate identification of patients with cardiovascular hyperuricemia by considering the correct cardiovascular threshold of serum urate, the time-course of uricemia fluctuations, and the identification of reliable markers of urate overproduction that could significantly clarify the clinical and therapeutic implications of the interaction between serum uric acid and hypertension.

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Section: Treatment Of Hyperuricemia and Hypertensionmentioning

confidence: 72%

Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk

et al. 2022

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“…24 Epidemiologically, levels of uric acid and XOR have been reported to be independent risks factor for hypertension. 6,[32][33][34][35][36] The presence of elevated serum uric acid levels has also been reported to be associated with the risk of cardiovascular events in patients with hypertension, even when blood pressure is well controlled. 37 In addition, treatment with the XOR inhibitor topiroxostat in hypertensive patients with hyperuricemia has been shown to improve the urine albumin-to-creatinine ratio (UACR) and blood pressure.…”

Section: Discussionmentioning

confidence: 99%

The reality of treatment for hyperuricemia and gout in Japan: A historical cohort study using health insurance claims data

Akari

Nakamura

Furusawa

et al. 2022

J of Clinical Hypertension

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Hyperuricemia causes gout and has also been associated with metabolic syndrome and cardiovascular disease. Uric acid-lowering drugs (ULDs) are used to reduce uric acid levels for the treatment of hyperuricemia and gout. However, there is a lack of robust and real-world data on the history and treatment of patients with newly diagnosed hyperuricemia or gout in Japan. This retrospective, longitudinal, historical cohort study determined the characteristics of patients with hyperuricemia and/or gout, and prescription of, and adherence to, ULDs using data from the JMDC Claims Database. The primary evaluation population included 64 677 patients with newly diagnosed hyperuricemia and/or gout. Of these, only 26 501 (41.0%) had a prescription for ULDs at diagnosis. Even when ULDs were prescribed, the persistence rate of prescriptions declined over time, with a 54.4% persistence rate for ULDs at 12 months after the index diagnosis. In subgroups of patients with or without hypertension and diabetes, the rate of ULD prescription continuation was significantly higher in those with comorbidities than in those without (76.8% vs. 42.6% in those with vs. without hypertension, and 78.7% vs. 52.2% in those with vs. without diabetes). These finding suggest that therapeutic interventions to lower serum uric acid levels are under-utilized for patients with newly diagnosed hyperuricemia and/or gout in Japan.

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“…Although the underlying mechanism of this association has not been fully elucidated, several factors related to NAFLD/NASH, including insulin resistance, dietary intake, altered lipid metabolism, the gut microbiome, and the proinflammatory state, are considered to play roles in the pathogenesis of atherosclerosis (36)(37)(38). Supporting the clinical evidence mentioned above, NASH mice fed CDAHFD exhibited significantly augmented neointimal proliferation induced by carotid artery ligation (P < 0.001).Topiroxostat is reported to inhibit plasma XOR activity more effectively than other XOR inhibitors, allopurinol and febuxostat, in both mice (39) and humans (40). Furthermore, XOR inhibition by topiroxostat reversed both increased plasma XOR activity and the progression of neointima formation in NASH model mice of the present study to similar levels observed in control mice independent of liver dysfunction (Figure 4, E and F).…”

Section: Discussionmentioning

confidence: 72%

Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation

et al. 2021

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Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9–derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

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Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 27 publications

References 43 publications

Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk

Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk

The reality of treatment for hyperuricemia and gout in Japan: A historical cohort study using health insurance claims data

Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation

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