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Kenneth G. Saag, MD, from the University of Alabama at Birmingham, and colleagues published a proof-of-concept study in Arthritis & Rheumatology showing that one year after gout patients with moderate to severe renal insufficiency were treated, serum uric acid reached target levels without further deterioration in renal function. The study randomly divided patients into three groups, receiving febuxostat 30 mg twice a day, febuxostat 40/80 mg once a day, or placebo. After 12 months, compared with the placebo group, 68.8% of patients in the febuxostat 30 mg group had serum uric acid levels lower than 6 mg/dl; 45.2% in the 40/80 mg group. There was no significant difference in the changes in serum creatinine between the experimental group and the placebo group after 12 months: the least squares mean difference in serum creatinine in the 30 mg group was -0.10 (95% confidence interval -0.37-0.17, P = 0.459), the least squares mean difference in serum creatinine in the 40/80 mg group was 0.04 (95% confidence interval -0.23-0.30, P = 0.789).

"The important finding of this study is that most patients with moderate to severe renal failure can achieve target uric acid levels when they receive standard treatment with febuxostat (40 mg per day, for patients without tophi, and the dose can be increased to 80 mg if serum uric acid levels need to be controlled below 6 mg/dl)," said Dr. Michael Pillinger (NYU Langone Medical Center), who was independent of the study.

More than 70% of gout patients suffer from renal insufficiency. Uric acid-lowering treatment is a major problem for these patients and is also a common cause of persistent hyperuricemia. Allopurinol can be used to treat gout in patients with renal insufficiency, but strict dose titration is required. "However, most clinicians tend not to use this drug in all patients with chronic kidney disease or do not titrate it accurately when lowering blood uric acid levels." Saag and colleagues wrote. "Febuxostat is different from allopurinol," Pillinger told MedPage Today. "Febuxostat has a more complex metabolism and is less dependent on the kidneys. Therefore, at present, the drug appears to be the best treatment for gout patients with renal insufficiency. In fact, the U.S. FDA has approved the drug for the treatment of patients with mild to moderate renal insufficiency (estimated glomerular filtration rate as low as 30 ml/min/1.73) based on relatively limited research data. m2), no dose adjustment is required. "Long-term studies of allopurinol and febuxostat have shown that maintaining serum uric acid levels below 6 mg/dL may prevent disease progression in patients with mild to moderate renal impairment, but this study did not include patients with severe renal impairment. "Therefore, the efficacy, safety, and impact on renal function of febuxostat in the treatment of gout patients with severe renal insufficiency are unknown," the researchers wrote.

Pillinger said there are many challenges in treating gout patients with renal insufficiency. The first problem is that "certain drugs that lower uric acid are not effective in these patients," he told MedPage Today. "Drugs that lower uric acid through renal metabolism, including probenecid and losartan - are not first-line treatments for most patients, however, when the estimated glomerular filtration rate falls to 50 ml/min/1.73 When m2 or lower, second-line treatment drugs have no therapeutic effect. "Another problem is: "The safety of drugs for treating patients with renal insufficiency has always been a concern for doctors, resulting in the emergence of standard first-line treatment drugs-xanthine oxidase inhibitors allopurinol and febuxostat." "Currently, there are research data on the treatment of patients with moderate renal failure. There are relatively few and almost no data on treating patients with severe renal failure. Allopurinol is less effective in patients with moderate to severe renal failure because the drug can cause a rare and fatal allergy, and there is data suggesting that allopurinol increases the risk of renal failure," Pillinger explained.

Therefore, to evaluate the efficacy of febuxostat in patients with renal failure and an estimated glomerular filtration rate of 15-50 ml/min/1.73 m2, Saag and colleagues analyzed 95 patients with a mean age of 66 years and a mean baseline serum uric acid level of 10.5 mg/dl. Among them, patients with severe renal dysfunction accounted for 37.5%, and patients with moderate renal dysfunction accounted for 62.5%. 38.5% of patients had serum creatinine below 2 mg/dl, 30.2% had serum creatinine between 2 and 2.5 mg/dl, and 31.3% had serum creatinine above 2.5 mg/dl. The majority of patients are male, and most suffer from hypertension and hyperlipidemia. Nearly half of the patients had diabetes. In the 6th month of treatment, 65.6% of patients in the febuxostat 30 mg group, 51.6% in the 40/80 mg group, and 0 in the placebo group had serum uric acid lower than the target value of 6 mg/dl (P < 0.001). There was no significant difference in the baseline change in estimated glomerular filtration rate at 12 months, with a least squares mean of 2.38 mL/min/1.73 m2 (95% confidence interval: -0.97-5.73, P = 0.162) in the febuxostat 30 mg group and a least squares mean of 1.19 (95% confidence interval -2.18-4.57, P = 0.485). However, when 12-month glomerular filtration rate was assessed against baseline renal function, the 30 mg group showed some benefit in treating moderately ill patients. According to reports, the incidence rates of serious adverse events in the 30 mg group, 40/80 mg group, and placebo group were 15.6%, 25%, and 21.9% respectively. Most adverse events can worsen renal function and are not related to treatment. One patient in the 30 mg group had elevated alanine aminotransferase, which was three times the upper limit of normal. Five patients discontinued treatment due to renal function events (one in the 40/80 mg group and four in the placebo group). Overall, 15.6% of patients in the 30 mg group, 9.4% of the 40/80 mg group, and 28.1% of the placebo group withdrew due to adverse events. There were two cardiovascular deaths, one in the 40/80 mg group and one in the placebo group. Both patients suffered from multiple cardiovascular comorbidities and died of myocardial infarction. In addition, there was one nonfatal myocardial infarction and one nonfatal stroke in the placebo group.

"To our knowledge, this prospective study is the first to evaluate the impact of urate-lowering therapy in gout patients with moderate to severe renal impairment," said Saag and colleagues. The limitations of this study include: small sample size, short study time, and most patients with severe renal insufficiency were randomly assigned to the placebo group, which may lead to bias. "This study points out that it is currently the best treatment for patients with moderate and especially severe kidney disease - at least, the study results show that it is safe and effective." Pillinger said.