lesinurad and Cardiovascular-Diseases

In observational studies, high serum urate levels are associated with adverse outcomes, including mortality. However, the hypothesis that urate-lowering may improve nongout outcomes has not been confirmed by placebo-controlled clinical trials. On the contrary, 7 recent placebo-controlled trials of urate-lowering drugs with different mechanisms of action (uricosuric: lesinurad; xanthine oxidase inhibition: febuxostat; uricase: pegloticase) have observed higher mortality or trends to higher mortality in gout patients, with the largest decreases in serum urate. Because all urate-lowering mechanisms were implicated, this raises safety concerns about urate-lowering itself. Far from unexpected, the higher mortality associated with more intense urate-lowering is in line with the U-shaped association of urate with mortality in some observational studies. Urate accounts for most of the antioxidant capacity of plasma, and strategies to increase urate are undergoing clinical trials in neurological disease. Post hoc analysis of recent trials should explore whether the magnitude of urate-lowering is associated with adverse outcomes, and safety trials are needed before guidelines recommend lowering serum urate below certain thresholds.

Topics: Cardiovascular Diseases; Gout Suppressants; Humans; Oxidative Stress; Polyethylene Glycols; Thioglycolates; Triazoles; Urate Oxidase; Uric Acid; Xanthine Oxidase

Cardiovascular disease affects more than 90 million Americans. Recent studies support an increased cardiovascular disease risk in inflammatory conditions, such as gout. Increased serum urate levels, or hyperuricemia, are a precursor to gout. Data from meta-analyses have shown hyperuricemia to be linked to hypertension and coronary heart disease. Similarly, gout has been associated with an increased risk of myocardial infarction, cerebrovascular accidents, and death from cardiovascular disease in randomized clinical trials. Urate-lowering therapy reduces serum urate and may decrease systemic inflammation, generation of oxidative species, and reverses endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-independent pathways. Cardioprotective benefits of allopurinol, a first-line agent for the treatment of gout, have been demonstrated to potentially prevent myocardial infarction, stroke, atrial fibrillation, and other cardiovascular diseases in observational studies in select populations. Randomized controlled trials (RCTs) have also examined the role of newer urate-lowering therapies, such as febuxostat and lesinurad, and their risk of cardiovascular-specific mortality in comparison to allopurinol. A large post-marketing study of febuxostat vs. allopurinol showed higher all-cause and cardiovascular-specific mortality in the febuxostat group than in the allopurinol group; a major study limitation was that large numbers of patients were lost to follow-up or discontinued treatment. RCTs are required to assess the comparative effectiveness of urate-lowering therapies, validate findings of observational studies, and to determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate-lowering therapy. This review examines the data for increased cardiovascular disease in gout and potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress) and the effect of urate-lowering therapy on cardiovascular disease.

Topics: Allopurinol; Anti-Inflammatory Agents; Cardiovascular Diseases; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Thioglycolates; Treatment Outcome; Triazoles; Uric Acid

Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.. Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.. Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.. Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.. NCT01493531.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Cardiovascular Diseases; Creatinine; Double-Blind Method; Drug Therapy, Combination; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Renal Insufficiency; Retreatment; Symptom Flare Up; Thioglycolates; Triazoles; Uric Acid; Uricosuric Agents; Young Adult

Topics: Allopurinol; Cardiovascular Diseases; Cause of Death; Drug Labeling; Febuxostat; Gout; Gout Suppressants; Humans; Mortality; Polyethylene Glycols; Practice Patterns, Physicians'; Probenecid; Risk Factors; Thioglycolates; Triazoles; United States; United States Food and Drug Administration; Urate Oxidase

Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy.. Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years).. In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals.. At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Kidney Diseases; Male; Middle Aged; Randomized Controlled Trials as Topic; Thioglycolates; Treatment Outcome; Triazoles; Uric Acid; Xanthine Oxidase; Young Adult