Effect of Febuxostat on Ambulatory Blood Pressure in Subjects With Hyperuricemia and Hypertension: A Phase 2 Randomized Placebo‐Controlled Study

Abstract

BackgroundHyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double‐blind, placebo‐controlled trial was conducted to assess the potential BP‐lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL]).Methods and ResultsSubjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24‐hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24‐hour mean SBP and changes from baseline to Weeks 3 and 6 in 24‐hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, −6.7; 95% confidence interval −13.3 to −0.0; P=0.049.ConclusionsThis study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469.

<p>Hyperuricemia and Hypertension: Links and Risks</p>

“…189,190 The third multicenter trial included 109 adults (aged ≥ 18 years) with primary hypertension. 193 The use of febuxostat, compared with placebo, was evaluated over 6 weeks. No significant difference between the febuxostat and placebo groups was found in ambulatory daytime or nighttime BP, or clinic SBP or DBP, from baseline to week 6.…”

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

“…SGLT2 inhibitors increase the concentration of glucose in the proximal tubules, and current evidence indicates that the glucose competes with urate for the facilitative hexose/urate transporter GLUT9b, reducing urate reabsorption. Abbreviations: ABCG2, ATP-binding cassette transporter G2; GLUT9a/b, glucose transporter SLC2A9 isoform a or b; MRP-4, multidrug resistance-associated protein-4; NPT, sodium/phosphate co-transporter; OAT, organic anion transporter; SGLT, sodium/glucose co-transporter; URAT1, urate transporter SLC22A12 allopurinol and febuxostat which reduce uric acid production, modestly reduce blood pressure in hypertensive patients independently of antihypertensive therapies [50][51][52][53][54]. This suggests a possible pathogenic role of elevated uric acid in the development of elevated blood pressure.…”

Therapeutic value of stimulating the nitrate‐nitrite‐nitric oxide pathway to attenuate oxidative stress and restore nitric oxide bioavailability in cardiorenal disease

“…Based on the important role of XOR in the regulation of the nitrate–nitrite–NO pathway, one may speculate that chronic inhibition of this enzyme could be associated with adverse cardiovascular and renal effects, which is in contrast with that hypothesized in several studies . A recent study demonstrated that 8‐week treatment with febuxostat did not significantly alter renal and intraglomerular haemodynamics or systemic vascular functional parameters in healthy subjects .…”