FRI0241 The effect of febuxostat on inflammatory and cardiovascular biomarkers in hyperuricemic hypertensive patients
Authors: L. McLean, L. Gunamardhana, U. Thienel, J. Wu, G. Smithson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Hyperuricemia (HU) is associated with hypertension (HTN) and adverse cardiovascular (CV) events. Potential mechanisms include endothelial xanthine oxidoreductase (XO) activity, direct effects of circulating soluble urate, and inflammation from crystal deposits. A phase 2 double-blind placebo (PBO)-controlled randomised trial tested the ability of 6 weeks treatment with the selective XO inhibitor febuxostat (FBX) to reduce blood pressure in hyperuricemic HTN patients who had no history of gout. A planned subgroup analysis showed reduction of systolic blood pressure (SBP) by 6.7 mmHg (95% CI 0–13.3) as assessed by 24 hour ambulatory BP measurement (ABPM) in HTN subjects with normal renal function (eGFR ≥90).<sup><sup>1</sup></sup> <h3>Objectives</h3> To explore mechanistic links between HU and CV disease we examined the effect of treatment with FBX on inflammatory and vascular biomarkers. <h3>Methods</h3> Entry criteria included ABPM SBP of ≥130 and≤165 mmHg; taking ≤2 BP drugs at baseline; and baseline serum urate (sUA) of ≥420 µM. 121 subjects were randomised 1:1 to FBX 80 mg OD or PBO for 6 weeks. Serum and whole blood mRNA samples were taken at screening (d-21), d1 pre-treatment, after 3 w and after 6 w of FBX/PBO. Soluble markers were measured using a 50-analyte multiplex array (from Myriad RBM HuMAP panel v1.6) and included mediators previously implicated in gout and in CV associations with HU, including CCL2 (MCP-1), CXCL8 (IL-8), E- and P-selectins, cystatin C, ICAM-1, IL-6, leptin, MMPs, MPO, SerpinE1 (PAI-1), TNFα, VCAM-1 and vWF. Additional candidates (angiotensin (AT)-II, hsCRP, insulin) were measured by ELISA. RNAseq was done on the Illumina HiSeq2000 platform with 20–30 million 50 bp paired-end reads and analysed for fold change vs baseline. <h3>Results</h3> Serum urate was reduced by a mean of 190 µM at week 6 in FBX-treated subjects and 0 µM with PBO. Nominally significant differences in change from baseline between PBO and FBX were noted in ICAM-1 (PBO −9.5, FBX+7.0 ng/ml at w6; uncorrected p=0.006) and SerpinE1 (−4.1,+30.9; 0.004). There was no baseline association between sUA and key markers on univariate, multiple linear regression analyses, or principle component regression. Nonparametric analysis showed marginally significant differences between FBX and PBO in the changes in CRP (unadjusted p=0.26 at w3, 0.018 w6), ICAM-1 (0.023, 0.063) and LOX-1 (0.356, 0.044). The effect of FBX was not significant for other soluble mediators including AT-II, CCL2, CRP, CXCL8, insulin, or MMPs. Many mRNA transcripts of interest (including CXCL8, SERPINE1) showed low levels in blood and no association between fold-change and reduction in sUA. Changes in CST3, MIF, S100A8 and S100A9 expression were associated with change in sUA. <h3>Conclusions</h3> In these HU HTN subjects without gout no significant relationship was found between sUA and inflammatory or CV markers at baseline. FBX effects on these biomarkers are sporadic, expected when evaluating many markers in a relatively small sample. These findings do not support a direct role for soluble urate in HU-associated HTN or CV disease. Limitations include the non-gout population studied, the relatively narrow range of baseline BP, and short treatment duration. <h3>Reference</h3> [1] Gunawardhana, JAHA2017. doi:org/10.1161/JAHA.117.006683 <h3>Disclosure of Interest</h3> L. McLean Shareholder of: Takeda, Employee of: Takeda, L. Gunamardhana Shareholder of: Takeda, Employee of: Takeda, U. Thienel Employee of: Takeda (former), J. Wu Shareholder of: Takeda, Employee of: Takeda, G. Smithson Shareholder of: Takeda, Employee of: Takeda