The impact of empagliflozin on kidney injury molecule-1: a subanalysis of the Effects of Empagliflozin on Cardiac Structure, Function, and Circulating Biomarkers in Patients with Type 2 Diabetes CardioLink-6 trial

Sodium–glucose cotransporter-2 (SGLT2) inhibitors are now well established as important oral glucose-lowering therapies for type 2 diabetes (T2D), with added value in the context of both cardiovascular and diabetic kidney disease (DKD). Landmark cardiovascular outcome trials including the EMPAgliflozin Removal of Excess Glucose (EMPA-REG OUTCOME) trial, the Canagliflozin Cardiovascular Assessment Study (CANVAS) program and the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial, as well as the primary renal outcome, Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE) trial, uniformly demonstrated renoprotective efficacy of SGLT2 inhibitors in T2D [1–4]. Secondary analyses from the cardiovascular outcome trials indicate a cumulative 45% reduction in the composite of worsening estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD) and renal death across a spectrum of patients with established cardiovascular disease or with multiple cardiovascular risk factors [5]. In subjects with T2D and DKD, CREDENCE similarly reported a 34% reduction in the composite outcome of ESRD, doubling of serum creatinine or death from renal causes [4]. While the clinical benefits are evident, the mechanisms responsible for this remarkable and robust improvement in renal function and the consequent delay in progression to ESRD remain incompletely understood. Tubulointerstitial injury is a primary pathway implicated in the early stages of DKD development that may be mitigated through SGLT2 inhibition [6]. Due to increased reabsorptive and metabolic demands fueled by hyperglycemia, the proximal tubule of the nephron is particularly vulnerable to hypoxic injury [6]. Therefore tubular protection may be an important pathway leading to improved renal outcomes with SGLT2 inhibition. Various markers of tubular injury, which have emerged as early and noninvasive measures of DKD progression, may be useful to assess potential changes induced by SGLT2 inhibitors. In a prespecified subanalysis of the Effects of Empagliflozin on Cardiac Structure, Function, and Circulating Biomarkers in Patients with Type 2 Diabetes (EMPA-HEART) CardioLink-6 Trial, we evaluated the effects of empagliflozin on urinary markers of tubular injury and renal function in individuals with T2D and established cardiovascular disease [7]. Study participants received either empagliflozin 10 mg or matching placebo once daily for 6 months, during which time urine samples were collected at random times and the 6-month visit. Multiplex assays (EMD Millipore, Mississauga, ON, Canada) were used to assess changes in kidney injury markers, and the analysis of covariance was performed to determine the mean percentage difference between groups at Month 6, adjusting for baseline values. From the 97 participants enrolled in the study, data for 78 participants (n = 40 empagliflozin, n = 38 placebo) for whom laboratory values were available were included in the renal subanalysis. Baseline characteristics for both groups were comparable [overall mean age 63 ± 9 years, 94% male, 11-year history of T2D and glycated haemoglobin 61.3 ± 13.6 mmol/mol (7.9 ± 0.9%)]. At baseline, participants had a mean eGFR of 87.2 ± 17.7 mL/min/1.73 m2, evidence of microalbuminuria [median urinary albumin:creatinine ratio (UACR) of 49.9 (25.1–160.3) mg/g], a mean systolic blood pressure of 139 ± 15 mmHg and a mean diastolic blood pressure of 80 ± 8 mmHg. Approximately 95% of the study participants were on background metformin and 96% were on angiotensin II receptor blockers and/or angiotensin-converting enzyme inhibitors (Supplementary data, Table S1). Following 6 months of treatment, empagliflozin reduced levels of urinary kidney injury molecule-1 (KIM-1) by 34% (95% confidence interval −65 to −3; P = 0.03) compared with placebo (Figure 1A). No differences were observed between groups in the other measured kidney injury markers, including UACR and eGFR, over the same period. As expected, urinary glucose excretion increased by ∼300% in patients administered with empagliflozin compared with placebo (Figure 1E), while no significant difference was observed in the fractional excretion of sodium (FENa) between groups (Figure 1D). Dot plot graphs are provided as Supplementary data, Figure S1 to provide further information on individual variability in treatment response within this study population. Mean change in kidney injury markers from randomization to Month 6 in the empagliflozin (n = 40) and placebo-treated groups (n = 38): (A) urinary KIM-1, (B) UACR, (C) eGFR, (D) FENa, (E) urine glucose excretion, (F) urinary neutrophil gelatinase-associated lipocalin (NGAL), (G) urinary alpha-1 microglobulin (A1M), (H) urinary collagen type IV. Urinary KIM-1, NGAL, A1M, collagen IV and glucose were normalized to urine creatinine. The effect sizes and 95% confidence intervals (CIs) obtained from the analysis of covariance models are displayed above each graph. Error bars represent standard errors of measurement. Significant difference noted as *P < 0.05 and ***P < 0.001. As a marker of structural damage in the proximal tubule, urinary KIM-1 is normally undetectable in healthy individuals but is elevated following episodes of acute kidney injury and chronic kidney damage. The observed 34% decrease in urinary KIM-1 therefore suggests that empagliflozin reduces tubular injury pathways, improving the structural integrity and thereby the function of the proximal tubule. By partially inhibiting proximal glucose and sodium reabsorption, empagliflozin may reduce the metabolic load and oxygen demands needed for the basolateral extrusion of sodium by the energy-requiring sodium/potassium ATPase. This improvement in tubular energy expenditure may also contribute to the reduction in acute kidney injury seen in EMPA-REG OUTCOME, DECLARE-TIMI 58 and CREDENCE [1, 3, 4]. Our findings show both similarities and differences with a previous study by Dekkers et al. [8] that examined changes in tubular and glomerular markers over a 6-week period following treatment with dapagliflozin. Like the present study, a diminution in urinary KIM-1 was noted [8]. However, in contrast, a decrease in albuminuria was also reported [8]. Notably, the reduction in urinary albumin excretion was commensurate with the decrease in eGFR, suggesting that glomerular hemodynamic changes rather than a direct effect on the permselectivity barrier might be responsible [8]. Indeed, eGFR is known to decrease acutely and return to baseline levels with continued SGLT2 inhibitor therapy or by 6 months; as reported here, neither eGFR nor albuminuria was reduced with SGLT2 inhibition. The lack of change in UACR in our study is likely due to the relatively small sample size and fewer repeated measures compared with the EMPA-REG OUTCOME, DECLARE-TIMI 58 and CREDENCE study populations, and the preserved baseline renal function of the EMPA-HEART participants, particularly compared with participants of the CREDENCE and Dekkers’ studies. Data derived from the larger landmark trials indicate that patients with more progressive kidney disease (higher UACR and lower eGFR levels) responded to SGLT2 inhibition with a greater reduction in UACR. Given that the EMPA-HEART participants had relatively preserved eGFRs with low-grade albuminuria at baseline, it is less likely that they would have exhibited significant changes in UACR. This study suggests that, with longer observation duration, improved tubular integrity and function may be an important contributor to renal protection with SGLT2 inhibition. Furthermore, the lack of sustained natriuresis following 6 months of treatment with empagliflozin may suggest that compensatory sodium reabsorption occurs distally in the nephron, with osmotic (glucose) diuresis potentially playing a greater role in plasma volume contraction with SGLT2 inhibition. However, it should be noted that changes in the FENa may be influenced by inherent variability in dietary sodium intake and volume status, particularly over a 6-month observation period. Overall, in this cohort of individuals with preserved eGFR and microalbuminuria, at relatively low risk for DKD progression, empagliflozin treatment for 6 months reduced levels of the tubular injury marker KIM-1. The reduction in KIM-1 raises the possibility that SGLT2 inhibitors may protect the proximal tubule, a major site of diabetes-related kidney injury. Mechanistic clinical trials tailored toward the assessment of DKD are required to provide further insights into the precise molecular effects of SGLT2 inhibitors on tubular function and renal protection. Supplementary data are available at ndt online. This trial was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim to S.V. and B.Z. The study sponsor was not involved in the study design; data collection, analysis and interpretation; writing of this report or the decision to submit for publication. A detailed conflict of interest statement can be found in the Supplementary material.

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