Kidney Week

Abstract: SA-PO140

Dapagliflozin Added to Verinurad plus Febuxostat Reduces Serum Uric Acid Without Increasing Urinary Uric Acid Excretion in Subjects with Hyperuricemia

Session Information

• Diabetic Kidney Disease: Clinical - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Stack, Austin G., Graduate Entry Medical School, University of Limerick, Limerick, Ireland

Austin G. Stack,

• Erlandsson, Fredrik, AstraZeneca, Mölndal, Sweden

Fredrik Erlandsson,

• Han, David S., PAREXEL International, California, California, United States

David S. Han,

• Oscarsson, Jan, AstraZeneca, Mölndal, Sweden

Jan Oscarsson,

• Goldwater, Ronald, PAREXEL International, Baltimore, Maryland, United States

Ronald Goldwater,

• Dronamraju, Nalina, AstraZeneca, Mölndal, Sweden

Nalina Dronamraju,

• Johansson, Susanne, AstraZeneca, Mölndal, Sweden

Susanne Johansson,

• Johnsson, Eva K.A., AstraZeneca, Mölndal, Sweden

Eva K.A. Johnsson,

Background

Hyperuricemia is associated with gout, kidney stones and CV events. An intensive urate lowering strategy combines a xanthine oxidase inhibitor (febuxostat [FEB]) and a URAT-1 inhibitor (verinurad [VER]) to maximize serum uric acid (sUA) reduction. Dapagliflozin (DAPA, SGLT2 inhibitor) reduces sUA by an unknown mechanism(s). Excessive UA excretion may damage renal tubules due to crystallization at high levels, so any DAPA-mediated effect on urinary UA (uUA) should be explored. We examined effects of DAPA on sUA and uUA excretion on top of VER+FEB in hyperuricemia.

Methods

A randomized, placebo-controlled, 2-way crossover study was conducted in adults with asymptomatic hyperuricemia over 7-d periods after washout. Groups (1:1) received oral VER 9mg+FEB 80mg+DAPA 10mg (Gp1), or VER+FEB+placebo (Gp2). Urine was collected hourly and for 24h on D–1 (baseline [BL]) and D7 of each period. Primary endpoint was difference from D7 to D–1 in peak uUA excretion between groups (△Gp1–△Gp2). Secondary measures were change in serum levels and 24-h urinary excretion of UA, Cr, and Na. AEs were monitored. Data are shown as mean (SD) and LSM (95% CI).

Results

Enrolled subjects (n=24) were male, mean age 43y. At BL (D–2), median BMI and eGFR were 29 kg/m² and 85 mL/min/1.73m² with mean (SD) sUA 445.3 (60.8) µmol/L. BL levels of sCr and sNa were (Gp1/Gp2) 93.8/95.8 µmol/L and 138/139 mmol/L, respectively. Peak uUA was available for 13 subjects and 24h urine for all. After DAPA, subjects showed no increase in peak UA excretion on D7 (mg/h); Grp1 –5.33 (–15.04, 4.37), Gp2 –7.20 (–16.91, 2.51); mean difference 1.87 (–7.63, 11.36). No difference was seen in total 24h UA excretion. After DAPA, subjects showed significantly reduced sUA levels; mean difference (Gp1 vs Gp2) on D7 was –76.35 (–104.02, –48.68) µmol/L (p<0.01). No between-group differences were seen in sCr or sNa. 8 subjects had 9 AE (Gp1 n=5; Gp2, n=4), all mild, no inter-group differences. DAPA did not affect VER or FEB PK.

Conclusion

Addition of DAPA to an intensive UA lowering strategy with VER+FEB provides additional sUA lowering without increase in urinary UA excretion, or changes in sCr; suggesting a DAPA+VER+FEB combination will not adversely affect kidney function (NCT03316131).

Funding

• Commercial Support – AstraZeneca