EXPERT ANALYSIS FROM RWCS 2016
MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – The recently approved uric acid–lowering drug lesinurad received a lukewarm reception at best when introduced during a ‘highlights of the year in gout’ session presented at the 2016 Rheumatology Winter Clinical Symposium.
Panelist Martin J. Bergman presented a dispassionate overview of the data from four pivotal randomized trials which in late December 2015 resulted in Food and Drug Administration approval of lesinurad (Zurampic) at 200 mg/day in combination with a xanthine oxidase inhibitor, but not as monotherapy at 400 mg/day.
After highlighting the drug’s safety concerns, including the black box warning about lesinurad’s risk of acute renal failure and its numerous potential drug interactions, Dr. Bergman opened the floor to discussion. An audience member immediately shot up his hand and asked, “Isn’t this drug a crappy drug?”
Dr. Bergman, chief of rheumatology at Taylor Hospital in Ridley Park, Pa., answered diplomatically: “It’s not the strongest drug, it’s not the best. Is this going to be something which revolutionizes the care of gout? I don’t think so. But it does give us a way to get to the treatment goal of a serum uric acid below 6.0 mg/dL in gout patients unable to get there on allopurinol or febuxostat [Uloric] alone. “
Faculty member Dr. Eric M. Ruderman was blunt in his appraisal of lesinurad: “I really don’t understand the place for this drug.”
“In the trial of combination therapy with febuxostat [the 324-patient CRYSTAL study] it didn’t meet the primary endpoint at the 200 mg/day dose. It’s amazing to me that the FDA will approve a drug when one of the pivotal trials didn’t meet the primary endpoint at the dose they approved. That’s bizarre. And in the trials with allopurinol [CLEAR 1 and 2, with a total of 1,213 patients] they didn’t use maximum-dose allopurinol. So I don’t see where this drug adds anything to our treatment paradigm,” said Dr. Ruderman, professor of medicine at Northwestern University in Chicago.
In the pivotal clinical trials, the 400 mg/day dose was more effective than 200 mg/day, but it was also associated with a doubling of serum creatinine in 1 in every 12 treated patients, as compared with a 1%-2% incidence at 200 mg. That’s why the FDA didn’t approve the higher dose.
Lesinurad is a selective inhibitor of uric acid resorption which acts in the proximal tubule on URAT1, an inhibitor of uric acid transport.
Arhalofenate, a promising investigational gout drug, shares the same mechanism of action, but in addition it blocks release of interleukin-1beta. In a 239-patient, phase IIb trial presented at the 2015 annual meeting of the American College of Rheumatology, arhalofenate effectively reduced the rate of gout flares while lowering serum uric acid levels, and most notably it did so with no treatment-related serious adverse events and no cases of elevated serum creatinine. This is a drug to keep an eye on, according to Dr. Bergman.
Copanelist Dr. Orrin M. Troum of the University of Southern California, Los Angeles, presented highlights of other significant recent studies in the field of gout, some of them quite surprising:
• Colchicine reduces cardiovascular events in gout patients. A comparison between 501 Medicare gout patients on colchicine and an equal number of matched gout patients not on colchicine showed that during a median 16.5 months of follow-up, the colchicine users had an adjusted 49% reduction in the composite endpoint of acute MI, stroke, or TIA. They also had a 73% reduction in all-cause mortality, according to Dr. Daniel H. Solomon, professor of medicine at Harvard Medical School, Boston, and coinvestigators ( Ann Rheum Dis. 2015 Nov 18. doi: 10.1136/annrheumdis-2015-207984 ).
“Once my gout patients stop clutching their chest when they see the price of colchicine, which actually increases their cardiovascular risk, they are very excited when I tell them about this study,” Dr. Bergman quipped. “This study controlled for other comorbidities and for serum uric acid levels. Those relative risk reductions are not to be sneezed at.”
• Treating gout improves survival. In a prospective case-matched cohort study, Taiwanese investigators compared 764 gout patients on urate-lowering therapy with an equal number of matched gout patients who did not take a urate-lowering drug. During 6.5 years of follow-up, the group on urate-lowering medication had a 71% lower risk of cardiovascular mortality and a 53% reduction in all-cause mortality, compared with gout patients not on urate-lowering therapy. Moreover, in a separate analysis comparing 1,189 gout patients not taking urate-lowering therapy and three times as many matched controls without gout, the gout patients had a 2.43-fold greater rate of cardiovascular mortality and a 1.45-fold increased risk of all-cause mortality ( J Rheumatol. 2015 Sep;42:1694-701 ).
• Gout is associated with reduced risk of Alzheimer’s disease. Using a U.K. electronic medical record database to track nearly 60,000 patients with gout and 239,000 matched controls, investigators determined that the incidence of Alzheimer’s disease during a median 5 years of follow-up was reduced by 24% in an analysis extensively adjusted for smoking, alcohol intake, medications, comorbid conditions, social deprivation, and other potential confounders. The researchers concluded based upon this and other evidence that uric acid appears to be neuroprotective ( Ann Rheum Dis. 2016 Mar;75:547-51 ).
• Sleep apnea is an independent risk factor for gout. Patients newly diagnosed with sleep apnea had a 50% greater risk of developing gout in the next year, compared with BMI-matched controls without sleep apnea in a population-based study conducted by investigators in Boston and the United Kingdom. The study included 9,865 patients with a new physician diagnosis of sleep apnea and nearly 44,000 matched controls. The incidence of newly diagnosed gout was 8.4 per 1,000 person-years in the group with sleep apnea and 4.8 per 1,000 person-years in the comparison group.
In a multivariate analysis adjusted for numerous potential confounders, new-onset sleep apnea remained an independent predictor of increased risk for gout. The results raise the testable hypothesis that effective treatment of sleep apnea might reduce the risk of hyperuricemia and gout flares ( Arthritis Rheumatol. 2015 Dec;67:3298-302 ).
• Gout linked to increased risk of septic arthritis. In a population-based study, investigators at Boston University and Massachusetts General Hospital turned to the U.K. Health Improvement Network general practice database, where they identified 72,073 new-onset gout patients and 358,342 matched controls without gout. The incidence rate of a septic arthritis diagnosis during follow-up was 0.24 cases per 1,000 person-years in the gout group and 0.09 per 1,000 person-years in controls. In a multivariate regression analysis, gout patients were at 2.6-fold greater risk of septic arthritis ( Rheumatology [Oxford]. 2015 Nov;54:2095-9 ).
• Gout is associated with increased risk of new-onset atrial fibrillation. A cohort study conducted using a U.S. commercial health insurance database identified 70,015 patients with gout and 210,045 with osteoarthritis. During a mean 2 years of follow-up, newly diagnosed atrial fibrillation occurred at a rate of 7.19 cases per 1,000 person-years in the gout group and 5.87 per 1,000 in the osteoarthritis patients. In a multivariate regression analysis, patients with gout had a 13% increased risk of new-onset atrial fibrillation, compared with the osteoarthritis group ( Ann Rheum Dis. 2015 Aug 31. doi: 10.1136/annrheumdis-2015-208161 ).
• Genetic screening test enables patients to avoid allopurinol-induced severe cutaneous adverse reactions. In a prospective cohort study, Taiwanese investigators performed screening for the HLA-B*58:01 allele in 2,926 patients of Han Chinese descent who had an indication for treatment with allopurinol. Those who tested positive – 571 patients, or 19.6% – received some alternative drug, while those who were HLA-B*58:01-negative were placed on allopurinol. All subjects were interviewed once weekly for the next 2 months, and hospital admissions for adverse drug reactions were monitored nationwide. Not a single study participant developed an allopurinol-induced severe cutaneous adverse reaction. Based upon historical incidence, seven cases would have been expected in the study population ( BMJ. 2015 Sep 23;351:h4848. doi: 10.1136/bmj.h4848 ).
Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.