The mechanisms by which SGLT‐2 inhibitors lower albuminuria are incompletely understood. We assessed in a post‐hoc analysis of a cross‐over trial the effects of the SGLT2 inhibitor dapagliflozin on glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM‐1, NGAL and LFABP) and inflammatory markers (urinary MCP‐1 and IL‐6) to provide more insight into kidney protective effects. Dapagliflozin decreased albuminuria by 43.9% (95% CI, 30.3%‐54.8%) and eGFR by 5.1 (2.0‐8.1) mL/min/1.73m ² compared to placebo. Dapagliflozin did not change glomerular charge or size selectivity index compared to placebo. Dapagliflozin decreased urinary KIM‐1 excretion by 22.6% (0.3%‐39.8%; P = .05) and IL‐6 excretion by 23.5% (1.4%‐40.6%; P = .04) compared to placebo, whereas no changes in NGAL, LFABP and MCP‐1 were observed. During dapagliflozin treatment, changes in albuminuria correlated with changes in eGFR (r = 0.36; P = .05) and KIM‐1 (r = 0.39; P = .05). In conclusion, the albuminuria‐lowering effect of 6 weeks of dapagliflozin therapy may be the result of decreased intraglomerular pressure or reduced tubular cell injury.

Aims: To compare the effects of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor dapagliflozin on estimated (ePV) and measured plasma volume (mPV) and to characterize the effects of dapagliflozin on ePV in a broad population of patients with type 2 diabetes. Materials and methods: The Strauss formula was used to calculate changes in ePV. Change in plasma volume measured with ¹²⁵ I‐human serum albumin (mPV) was compared with change in ePV in 10 patients with type 2 diabetes randomized to dapagliflozin 10 mg/d or placebo. Subsequently, changes in ePV were measured in a pooled database of 13 phase 2b/3 placebo‐controlled clinical trials involving 4533 patients with type 2 diabetes who were randomized to dapagliflozin 10 mg daily or matched placebo. Results: The median change in ePV was similar to the median change in mPV (−9.4% and −9.0%) during dapagliflozin treatment. In the pooled analysis of clinical trials, dapagliflozin decreased ePV by 9.6% (95% confidence interval 9.0 to 10.2) compared to placebo after 24 weeks. This effect was consistent in various patient subgroups, including subgroups with or without diuretic use or established cardiovascular disease. Conclusions: ePV may be used as a proxy to assess changes in plasma volume during dapagliflozin treatment. Dapagliflozin consistently decreased ePV compared to placebo in a broad population of patients with type 2 diabetes.

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.

Purpose of Review Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have emerged as a promising drug class for the treatment of diabetic kidney disease. Developed originally as glucose-lowering drugs by enhancing urinary glucose excretion, these drugs also lower many other renal and cardiovascular risk factors such as body weight, blood pressure, albuminuria, and uric acid. Results from the EMPA-REG OUTCOME and CANVAS trials show that these salutary effects translate into a reduction in cardiovascular outcomes and have the potential to delay the progression of kidney function decline. This review summarizes recent studies on the mechanisms and rationale of renoprotective effects. Recent Findings Effects of SGLT-2 inhibitors on the kidney are likely explained by multiple pathways. SGLT-2 inhibitors may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT-2 inhibitors are associated with a reduction in glomerular hyperfiltration, an effect which is mediated through increased natriuresis and tubuloglomerular feedback and independent of glycemic control. Analogous to diabetic kidney disease, various etiologies of non-diabetic kidney disease are also characterized by single nephron hyperfiltration and elevated albuminuria. This offers the opportunity to reposition SGLT-2 inhibitors from diabetic to non-diabetic kidney disease. Clinical trials are currently ongoing to characterize the efficacy and safety of SGLT-2 inhibitors in patients with diabetic and non-diabetic kidney disease. Summary The glucose-independent hemodynamic mechanisms of SGLT-2 inhibitors provide the possibility to extend the use of SGLT-2 inhibitors to non-diabetic kidney disease. Ongoing dedicated trials have the potential to change clinical practice and outlook of high-risk patients with diabetic (and non-diabetic) kidney disease.

This year the medical community was pleasantly surprised by the results of the first large outcome trial that primarily examined the renal effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) in subjects with diabetes and impaired kidney function. The Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial showed that CANA, relative to placebo, reduces the risk for end-stage renal disease, doubling of creatinine or renal death by 34% [hazard ratio 0.66 (95% confidence interval 0.53–0.81]. These effects were consistent across baseline estimated glomerular filtration rate (eGFR) and haemoglobin A1c subgroups. In this review we combine the results of the CREDENCE trial with those of several cardiovascular outcome trials with SGLT2 inhibitors and show that, unexpectedly, patients with lower eGFR levels may have greater benefit with respect to cardiovascular outcome than patients with normal kidney function. The cardio- and renoprotective effects of SGLT2 inhibitors seem to be independent of their glucose-lowering effects, as shown in several post hoc analyses. In this review we discuss the alleged mechanisms of action that explain the beneficial effects of this novel class of drugs. Moreover, we discuss whether these findings indicate that this class of drugs may also be beneficial in non-diabetic chronic kidney diseases.

Aims: To assess the effect of sodium‐glucose cotransporter‐2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. Materials and methods: We performed a mechanistic open‐label study (DAPASALT) to evaluate the effects of dapagliflozin on 24‐hour sodium excretion, 24‐hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo‐controlled double‐blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. Results: In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m ² , median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24‐hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24‐hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24‐hour systolic BP decreased by −9.3 (95% confidence interval [CI] −19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash‐out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m ² , median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI −5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). Conclusions: During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24‐hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra‐renal compensatory mechanisms to prevent excessive water loss.