Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide...

Dapagliflozin 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.

Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d^-1 of Na⁺ were randomized to bumetanide (1 mg·d^-1), dapagliflozin (10 mg·d^-1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na⁺ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d^-1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d^-1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d^-1; P<0.005). However, Na⁺ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d^-1), and Na⁺ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d^-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05).

First-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.

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.