Comparative Effectiveness of the Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin Versus Other Antihyperglycemics on Risk of Major Adverse Kidney Events

Abstract

Objective: To examine the comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin and other non-SGLT2i antihyperglycemics on the risk of major adverse kidney events (MAKE) of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease, or all-cause mortality.

Research design and methods: In a cohort study of 379,033 new users of empagliflozin or other non-SGLT2i antihyperglycemics, predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. Weighted survival analyses were then applied to estimate the risk of MAKE.

Results: Compared with other antihyperglycemics, empagliflozin use was associated with 0.99 (95% CI 0.51, 1.55) mL/min/1.73 m² less annual reduction in eGFR, 0.25 (95% CI 0.16, 0.33) kg/m² more annual decrease in BMI, and reduced risk of MAKE (hazard ratio [HR] 0.68 [95% CI 0.64, 0.73]). Empagliflozin use was associated with reduced risk of MAKE in eGFR ≥90, ≥60 to <90, ≥45 to <60, and ≥30 to <45 mL/min/1.73 m² (HR 0.70 [95% CI 0.60, 0.82], 0.66 [0.60, 0.73], 0.78 [0.69, 0.89]), and 0.71 [0.55, 0.92], respectively), in participants without albuminuria, with microalbuminuria and macroalbuminuria (HR 0.65 [95% CI 0.57, 0.75], 0.72 [0.66. 0.79], and 0.74 [0.62, 0.88], respectively), and in participants with and without cardiovascular disease (HR 0.67 [95% CI 0.61, 0.74] and 0.76 [0.69, 0.83], respectively). The association was evident in per-protocol analyses, which required continuation of the assigned antihyperglycemic medication (empagliflozin or other antihyperglycemics) during follow-up (HR 0.64 [95% CI 0.60, 0.70]), and in analyses requiring concurrent use of metformin in at least the first 90 days of follow-up (HR 0.63 [0.57-0.69]).

Conclusions: Among people with type 2 diabetes, empagliflozin use was associated with eGFR preservation, a greater decline in BMI, and a reduced risk of MAKE compared with other non-SGLT2i antihyperglycemics.

Figure 1

Survival probability for MAKE of eGFR decline >50%, ESKD, or all-cause mortality in the empagliflozin group (blue) and the control group of other non-SGLT2i antihyperglycemics (red) in the weighted cohort.

Figure 2

A: eGFR trajectory during follow-up. Estimated eGFR values and 95% CIs at 90 days and at 1, 2, and 3 years were plotted for the empagliflozin group (blue) and the control group of other non-SGLT2i antihyperglycemics (red). eGFR change associated with empagliflozin at each time point represents the difference between the two trajectories where the control group served as the reference. B: BMI trajectory during follow-up. Estimated BMI values and 95% CIs at 90 days and at 1, 2, and 3 years were plotted for the empagliflozin group (blue) and the control group of other non-SGLT2i antihyperglycemics (red). BMI change associated with empagliflozin at each time point represents the difference between the two trajectories where the control group served as the reference.

Figure 3

A: HRs and event rate differences for the MAKE of eGFR decline >50%, ESKD, or all-cause mortality in the overall cohort and in subgroups. B: HRs and event rate differences for individual components of the MAKE of eGFR decline >50%, ESKD, or all-cause mortality. Albuminuria status defined as no albuminuria (albumin-to-creatinine ratio ≤30 mg/g), microalbuminuria (>30 to ≤300 mg/g), and macroalbuminuria (>300 mg/g).