Kidney outcomes of SGLT2 inhibitors among older patients with diabetic kidney disease in real-world clinical practice: the Japan Chronic Kidney Disease Database Ex

Abstract

Introduction: We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria.

Research design and methods: Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease.

Results: At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m² and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was -0.80 mL/min/1.73 m²/year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m²/year (95% CI -2.08 to -1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m²/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria.

Conclusions: The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years.

Keywords: Diabetes Mellitus, Type 2.

Figure 1

Change in eGFR over time prior and after initiation of SGLT2 inhibitors or other diabetes drugs (on-treatment analyses). Error bars show mean±SEs. Numbers below the graph refer to the number of patients at each time point. Each monthly interval displayed the eGFR value closest to the relevant time point within a set period. Time zero denoted the estimated intercept of the preindex slopes. Analyses for eGFR slope were conducted from the index date and thereafter, accounting for the acute dip in eGFR in the SGLT2 inhibitor group. P values were calculated using a linear-mixed regression model. eGFR, estimated glomerular filtration rate; SGLT2, sodium-glucose cotransporter 2.

Figure 2

Annual rate of eGFR change in various subgroups (on-treatment analyses). (A) overall and with versus without proteinuria at the index date, (B) with versus without rapid decline in eGFR before initiating treatments, (C) eGFR<60 vs ≥60 mL/min/1.73 m² at the index date, (D) with versus without use of ACE inhibitors or ARBs at the index date, and (E) age<80 vs ≥80 years. Change in eGFR was calculated from the postindex eGFR measurements using a linear-mixed regression model. ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; eGFR, estimated glomerular filtration rate; SGLT2, sodium-glucose cotransporter 2.

Figure 3

Cumulative incidence of kidney events among the SGLT2 inhibitors group and other glucose-lowering drugs group (on-treatment analyses). The cumulative probability of (A) composite kidney events, (B) a ≥40% eGFR decline, and (C) ESKD among the SGLT2 inhibitors group and the other glucose-lowering drugs group was calculated using the Kaplan-Meier method. Composite kidney events included a sustained reduction in eGFR of 40% or more and ESKD (ie, an eGFR<15 mL/min/1.73 m²). The log-rank test was used to calculate the p value. The median (IQR) length of follow-up for each group was as follows: for composite kidney events analyses, 30 (17–43) months in the SGLT2 inhibitors group and 25 (14–44) months in the other glucose-lowering drugs group; for eGFR reduction≥40% analyses, 30 (17–43) months in the SGLT2 inhibitors group and 26 (15–44) months in the other glucose-lowering drugs group; and for ESKD analyses, 31 (18–45) months in the SGLT2 inhibitors group, and 27 (16–46) months in the other glucose-lowering drugs group. eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; SGLT2, sodium-glucose cotransporter 2.

Figure 4

The frequency of events, the corresponding incidence rates, and HR for composite kidney events among the SGLT2 inhibitors group and other glucose-lowering drugs group Composite kidney events included a sustained reduction in eGFR of 40% or more and ESKD (ie, an eGFR of less than 15 mL/min/1.73 m²). The incidence rate is per 1000 person-years. Time-to-first event for the SGLT2 inhibitors group and the other glucose-lowering drugs group was compared by use of Cox proportional-hazard models and presented as the HR and 95% CI for composite kidney events, separately by the subgroups. We tested for heterogeneity in the associations between SGLT2 inhibitor use and outcomes by each subgroup with the inclusion of multiplicative interaction terms. A statistically significant interaction was defined as p value<0.05. ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; SGLT2, sodium-glucose cotransporter 2.