Abstract
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin–angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by −885.3 mL/24 h (from −1156.2 to −614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.
Highlights
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the incidence of heart failure and renal events in type 2 diabetes patients at risk for cardiovascular disease, as well as in patients with diabetes and chronic kidney disease [1,2,3,4]
The present study examined effects of dapagliflozin on volume markers in type 2 diabetes patients with micro- or macroalbuminuria
What does this study add to the existing literature? The present data confirm previous studies on the diuretic and natriuretic effects of SGLT2 inhibitors and extend these to a placebo-controlled setting
Summary
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the incidence of heart failure and renal events in type 2 diabetes patients at risk for cardiovascular disease, as well as in patients with diabetes and chronic kidney disease [1,2,3,4]. A few studies reported acute increases in urinary volume and sodium levels, supporting the natriuretic/diuretic properties of this drug class [5,6]. Other studies reported a decrease in plasma volume and interstitial fluid volume during SGLT2 inhibition, which would be in line with their natriuretic/diuretic profile [8,9]. These effects may, at least in part, explain the observed risk reduction of heart failure events in patients with diabetes [1,2,3]
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