Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

BackgroundDapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. Methods and ResultsHealthy subjects (n=42) receiving a fixed diet with approximate to 110mmold-1 of Na+ were randomized to bumetanide (1mgd-1), dapagliflozin (10mgd(-1)), or both for 7days, followed by 7days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (226mmold(-1); P<0.005) but by more (P<0.005) with the first dose of bumetanide (747mmold(-1); P<0.005), which was not significantly different from both diuretics together (80 +/- 5mmold(-1); P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1week of bumetanide (64 +/- 6mmold(-1)), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1week of dapagliflozin (101 +/- 8mmold-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05). ConclusionsFirst-dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. Clinical Trial RegistrationURL: . Unique identifier: NCT00930865.