Dapagliflozin in combination with verinurad and febuxostat led to a substantial decline in serum uric acid without influencing urinary uric acid excretion and thus appears to be useful in the treatment of  gout/hyperuricemia.

A randomized, phase II, placebo-controlled, two-way crossover study (QUARTZ) aimed to determine the effect of adding dapagliflozin (sodium/glucose cotransporter 2 inhibitor)  to verinurad (selective urate transporter 1 inhibitor) and febuxostat (xanthine oxidase inhibitor) on urinary uric acid excretion and serum uric acid levels in patients with asymptomatic hyperuricemia.

Overall, 36 subjects were randomly allocated to (i) oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin (dapagliflozin group) for seven days, and then cross-over to (ii) oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo (placebo group) for seven days with an intervening 7 to 21-day washout period.

The difference in peak urinary uric acid excretion between the cohorts from baseline to day 7 was the primary outcome while alterations in serum uric acid levels and 24-hour urinary uric acid elimination were the secondary endpoints.

Both the therapies reduced mean peak urinary uric acid excretion (least-squares mean alteration from baseline: −12.9 mg/h, dapagliflozin; −13.2 mg/h, placebo). The serum uric acid decline in the dapagliflozin arm was substantially greater compared to the placebo arm, with a mean treatment difference of −62.3 µmol/L, as shown in the following figure:

Neither the peak urinary excretion of uric acid nor the total daily urinary excretion of uric acid differed considerably at the end of each therapy period. Dapagliflozin did not affect the pharmacokinetics of verinurad, its major metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. No clinically relevant alteration in safety parameters was witnessed. 

Combining dapagliflozin with verinurad and febuxostat remarkably lowers uric acid levels in serum. This was attained without any detectable rise in total urinary uric excretion rates and without adversely affecting the kidney function.