A real-world study on SGLT2 inhibitors and diabetic kidney disease progression

Abstract

Background: Randomized controlled trials have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, real-world data on CKD progression and the development of end-stage kidney disease (ESKD) remains scarce. Our aim was to study renal outcomes of people with diabetic kidney disease (DKD) using SGLT2is in a highly prevalent DKD population.

Methods: Between 2016 and 2019 we recruited T2DM patients in the renal and diabetic clinics in a regional hospital in Singapore. Patients prescribed SGLT2is were compared with those on standard anti-diabetic and renoprotective treatment. The outcome measures were CKD progression [a ≥25% decrease from baseline and worsening of estimated glomerular filtration rate (eGFR) categories according to the Kidney Disease: Improving Global Outcomes guidelines] and ESKD (eGFR <15 mL/min/1.73 m²).

Results: We analysed a total of 4446 subjects; 1598 were on SGLT2is. There was a significant reduction in CKD progression {hazard ratio [HR] 0.60 [95% confidence interval (CI) 0.49-0.74]} with SGLT2is. The HR for eGFR ≥45 mL/min/1.73 m² and 15-44 mL/min/1.73 m² was 0.60 (95% CI 0.47-0.76) and 0.43 (95% CI 0.23-0.66), respectively. There was also a reduction in risk for developing ESKD for the entire cohort [HR 0.33 (95% CI 0.17-0.65)] and eGFR 15-44 mL/min/1.73 m² [HR 0.24 (95% CI 0.09-0.66)]. Compared with canagliflozin and dapagliflozin, empagliflozin showed a sustained risk reduction of renal outcomes across CKD stages 1-4.

Conclusions: This real-world study demonstrates the benefits of SGLT2is on CKD progression and ESKD. The effect is more pronounced in moderate to advanced CKD patients.

Keywords: CKD progression; ESKD; SGLT2is; diabetes mellitus; diabetic kidney disease; real-world study.

Graphical Abstract

FIGURE 1:

Patient selection.

FIGURE 2:

Kaplan–Meier survival curves for the event-free survival of CKD progression (defined by α ≥25% decrease in eGFR from baseline and worsening of eGFR categories according to KDIGO guidelines) in (a) the whole cohort, (b) patients with eGFR ≥45 mL/min/1.73 m² and (c) patients with eGFR 15–44mL/min/1.73 m². (a) Log-rank test statistics = 58.64, P < .001; (b) log-rank test statistics = 1.59, P = .207; (c) log-rank test statistics = 12.59, P = < .001.

FIGURE 2:

Kaplan–Meier survival curves for the event-free survival of CKD progression (defined by α ≥25% decrease in eGFR from baseline and worsening of eGFR categories according to KDIGO guidelines) in (a) the whole cohort, (b) patients with eGFR ≥45 mL/min/1.73 m² and (c) patients with eGFR 15–44mL/min/1.73 m². (a) Log-rank test statistics = 58.64, P < .001; (b) log-rank test statistics = 1.59, P = .207; (c) log-rank test statistics = 12.59, P = < .001.

FIGURE 3:

Funnel plot of the HR for CKD progression based on eGFR categories with different adjustment models. Model 1 adjusted for age, gender and ethnicity. Model 2 adjusted for age, gender, ethnicity, HbA1c, baseline eGFR, natural log-transformed uACR and use of RAS antagonists.

FIGURE 4:

Kaplan–Meier survival curves for the event-free survival of ESKD in (a) the whole cohort, (b) patients with an eGFR ≥45 mL/min/1.73 m² and (c) patients with an eGFR of 15–44 mL/min/1.73 m². (a) Log-rank test statistics = 150.95, P < .001; (b) log-rank test statistics = 0.02, P = .881; (c) log-rank test statistics = 36.46, P < .001.

FIGURE 4:

Kaplan–Meier survival curves for the event-free survival of ESKD in (a) the whole cohort, (b) patients with an eGFR ≥45 mL/min/1.73 m² and (c) patients with an eGFR of 15–44 mL/min/1.73 m². (a) Log-rank test statistics = 150.95, P < .001; (b) log-rank test statistics = 0.02, P = .881; (c) log-rank test statistics = 36.46, P < .001.

FIGURE 5:

Funnel plot of the HR for ESKD based on CKD categories with different adjustment models. Model 1 adjusted for age, gender and ethnicity. Model 2 adjusted for age, gender, ethnicity, HbA1c, baseline eGFR, natural log-transformed uACR and use of RAS antagonists.