Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors

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.

Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial

“…As a result of mild diuretic effects, SGLT2 inhibitors increase copeptin, a surrogate marker of vasopressin. 30 In experimental settings of anaemia, vasopressin stimulates EPO release and red cell mass production providing another explanation for the observed increase in haemoglobin and haematocrit in our study. 31 Furthermore, SGLT2 inhibitors restore impaired tubuloglomerular feedback and reduce hyperfiltration in diabetes, which could preserve long-term kidney function and reduce hypoxia.…”

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

“…In the current study, glycosuria was consistently increased, although we did not observe a clear effect on urine volume, which contrasts the findings from in silico models ( 21 ). A previous study showed that dapagliflozin caused a larger increase in urine compared with plasma osmolality, making it less likely that osmotic diuresis explains the observed hemodynamic effects in our study ( 24 ). Given that glycosuria is persistent during treatment with dapagliflozin while the actual fluid balance of the participants was negative, the kidney likely uses other mechanisms to concentrate the urine and enhance water reabsorption.…”

Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure

“…Loss of chloride is sensed by the macula densa in the distal convoluted tubule and leads to release of adenosine, causing afferent vasoconstriction and a decreased renal blood flow, in order to spare salt. If we assume that the established drop in glomerular filtration rate is indeed the result of activation of the macula densa, there should still be high levels of sodium and chloride present in the distal convoluted tubule in order for juxtaglomerular feedback mechanism to be activated 19 . This would mean that although we do not find increased concentrations of sodium in the urine, proximal tubular sodium resorption is indeed diminished.…”