Dapagliflozin in combination with verinurad and febuxostat may be useful in the treatment of hyperuricemia, according to study results published in Journal of Clinical Endocrinology & Metabolism. In a randomized clinical trial of patients with asymptomatic hyperuricemia, dapagliflozin further reduced serum uric acid (sUA) levels without increasing urinary UA (uUA) secretion.
The optimal strategy and thresholds for reducing sUA has yet to be identified. Although clinical studies have shown that combining dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, with febuxostat and verinurad may enhance sUA lowering, it may also result in high uUA excretion rates, and therefore, affect kidney function.
Investigators conducted a randomized placebo-controlled phase 2 study (ClinicalTrials.gov Identifier: NCT03316131) of intense urate-lowering therapy with dapagliflozin to assess its effects on sUA levels and urinary UA excretion.
Patients with asymptomatic hyperuricemia (sUA, >6.0 mg/dL) were enrolled at 2 study sites in the United States. Participants were randomly assigned 1:1 to receive either oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days (dapagliflozin period), followed by crossover to once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo for 7 days (placebo period); or the same treatment regimens in reverse order. Urine samples were collected hourly for the first 12 hours after dosing, then once more 12 to 24 hours after dosing. The primary outcome was change between baseline and day 7 in peak uUA excretion during the dapagliflozin treatment period.
The study cohort included 36 patients (mean age, 42.3±12.0 years; 97.2% men; 47.2% Black). Mean estimated glomerular filtration rate was 84.5 mL/min/1.73 m2 and mean sUA levels at baseline were 7.3 mg/dL and 6.8 mg/dL during the dapagliflozin and placebo periods, respectively.
After 7 days of treatment, mean sUA concentrations were significantly lower in the dapagliflozin vs placebo group (1.17±0.45 vs 1.51±0.65 mg/dL). Mean sUA reduction was significantly greater in the dapagliflozin period compared to the placebo period (mean treatment difference, -0.7 mg/dL). Neither peak urinary excretion of UA nor total daily urinary excretion of UA were significantly different between the dapagliflozin and placebo periods. Mean change between baseline and day 7 in peak urinary UA excretion rates was -12.9 mg per hour in the dapagliflozin period and -13.2 mg per hour in the placebo period. Peak daily urinary excretion levels were also not significantly different between the dapagliflozin and placebo regimens.
These trial data demonstrate that the addition of dapagliflozin to verinurad and febuxostat does not increase urinary excretion rates of UA in patients with asymptomatic hyperuricemia. Dapagliflozin was also associated with increased sUA lowering capacity compared to verinurad and febuxostat only.
The primary study limitation is the small sample size and the exclusion of patients with symptomatic hyperuricemia. Further research in a larger cohort is necessary to better understand the benefits and safety of dapagliflozin.
“These findings suggest that combining dapagliflozin with a verinurad-based intensive UA-lowering strategy can further reduce sUA levels without adversely affecting kidney function,” the investigators wrote. “Given the potential adverse consequences of hyperuricemia on clinical outcomes and the likely substantial benefits of SGLT2 inhibitors in high-risk cardiorenal populations, strategies that combine an SGLT2 inhibitor with an intensive UA-lowering strategy may lead to greater clinical benefits.”
Disclosure: This clinical trial was supported by AstraZeneca. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Stack AG, Han D, Goldwater R, et al. Dapagliflozin added to verinurad plus febuxostat further reduces serum uric acid in hyperuricemia: the QUARTZ study. J Clin Endocrinol Metab. Published online October 19, 2020. doi:10.1210/clinem/dgaa748