#2638 SGLT2i in CKD with high albuminuria: an observational real-world study
Authors: Svensson Maria K , Bodegard Johan , Thuresson Marcus , Ambery Philip 
Published: May 2024

Abstract

Background and Aims
Dapagliflozin, a sodium–glucose co-transporter-2 inhibitor (SGLT2i), is indicated to treat chronic kidney disease (CKD). Clinical trials have shown that dapagliflozin significantly reduces albuminuria in patients with urine albumin-creatinine ratio (UACR) 200–5000 mg/g and has beneficial effects on estimated glomerular filtration rate (eGFR) decline and combined kidney outcomes. In the DAPA-CKD trial, dapagliflozin led to substantial reductions in the composite of sustained eGFR decline of ≥50%, end-stage kidney disease, and renal or cardiovascular death (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.51, 0.72; p &lt; 0.001), with similar reductions observed across UACR subgroups. Furthermore, compared with placebo, dapagliflozin reduced geometric mean UACR by 29.3% (95% CI: –33.1, –25.2; p &lt; 0.0001), with no difference in relative UACR reduction by baseline UACR above or below 1000 mg/g. In the ZENITH-CKD study, over 12 weeks the combination of zibotentan (a novel endothelin A receptor antagonist) and dapagliflozin showed a robust reduction in UACR of 47.7% vs 28.3% for dapagliflozin alone, with this effect maintained in patients with UACR &gt;700 mg/g. It is well known that renal disease progresses more quickly in patients with higher degree of albuminuria than in those with lower levels. We aimed to further characterize renal risk in patients with different levels of residual albuminuria despite standard of care treatment with renin–angiotensin system inhibitors (RASi) and SGLT2i.

Methods
We used a large USA claims database (Optum's de-identified Clinformatics® Data Mart Database [CDM]) to identify patients aged ≥18 years with CKD, defined as either two eGFR measurements ≤60 mL/min/1.73 m2 taken ≥90 days apart or a first eGFR ≤60 mL/min/1.73 m2 and a CKD diagnosis. Patients were indexed at the date of dapagliflozin 10 mg initiation between 30 April 2021 (date of approval for dapagliflozin in CKD) and March 2023. Patients with prior use of SGLT2i, immunosuppressive drugs, hydroxychloroquine, CKD stage 5 (based on eGFR &lt;15 mL/min/1.73 m2 or dialysis), polycystic kidney disease, or type 1 or gestational diabetes were excluded. Patients were indexed on 1st January 2022 and grouped into two UACR groups: ≥700UACR group (≥700 mg/g) and &lt;700UACR group (200–699 mg/g). Outcomes were UACR changes, eGFR slopes and CKD-associated hospitalizations within 1 year after dapagliflozin initiation. Hazard ratios were estimated using adjusted Cox survival regression. UACR follow-up analyses were restricted to patients with at least one follow-up measurement.

Results
In the 5908 patients with CKD, median UACRs at index in the ≥700UACR and &lt;700UACR groups were 1414 mg/g and 102 mg/g, respectively. Patients in the ≥700UACR group vs &lt;700UACR group had lower eGFR (40 vs 48 mL/min/1.73 m2), were younger (71 vs 74 years), and both groups had a high burden of comorbidities (heart failure: 38% vs 42%; type 2 diabetes: 74% vs 75%). RASi use was 81% and 74%, respectively. During follow-up, 22% of patients in the ≥700UACR group experienced a CKD-related hospitalization (25.1 events per 100 patient years) as compared to 19.5 events per 100 patient years in the &lt;700UACR group (HR 1.38 [95% CI: 1.16, 1.64, p &lt; 0.001]; Fig. panel A). The eGFR slope (95% Cl) of patients in the ≥700UACR group was –2.44 mL/min/1.73 m2 per year (–3.49, –1.65), compared with a flat eGFR trajectory in patients in the &lt;700UACR group (0.39 [–0.11, 0.96]). In the ≥700UACR group with at least one follow-up measurement (n = 431), UACR lowered from 2077 mg/g to 1674 mg/g (–36.3%) within 1 month of dapagliflozin initiation but remained above 1200 mg/g throughout the 12-month follow-up period (Fig. panel B).

Conclusions
While treatment with RASi and SGLT2i are associated with reduced risk of renal outcomes in patients with CKD, awareness and management of residual albuminuria remains an area of unmet clinical need. The novel combination of zibotentan/dapagliflozin currently under investigation in the ZENITH High Proteinuria phase III trial (NCT06087835) seeks to address this need.