A cohort study on the risk of major adverse kidney events for new patients initiated on empagliflozin versus other non-SGLT2I antihyperglycemics.
There is a gap in evidence from previous studies that address the effectiveness of sodium-glucose cotransport 2 inhibitors (SGLT2I) versus other antihyperglycemics in patients with and without cardiovascular disease and with a range of kidney function. Previous studies have shown that the use of SGLT2I reduced the risk of end-stage kidney disease (ESKD) and death. However, these studies had patients with an established or at high risk of cardiovascular disease, with limited patients with reduced kidney functions. The only exception to this was the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study, which enrolled patients with albuminuria and an eGFR of 30 to < 90 mL/min/1.73m2. This study aims to fill in the gap and complement the previous RCT evidence to aid in selecting antihyperglycemic therapy for patients with T2DM.
This study utilizes the U.S. Department of Veterans Affairs (VA) data to assess the effectiveness of empagliflozin versus other antihyperglycemics on the risk of major adverse kidney events. These adverse kidney events were defined as a composite endpoint of eGFR decline of > 50%, ESKD, or all-cause mortality. The outcome of interest was defined as the time till the first occurrence of an eGFR decline in > 50% from baseline, ESKD described as the first occurrence of eGFR < 15 mL/min/1.73m2, or all-cause mortality. A cohort study was implemented from the VA Health Care System, in which patients from October 1, 2015, through September 30, 2019, were enrolled. This resulted in 1,406,662 patients being initially enrolled in the cohort study. Patients were excluded from the initial enrollment if they had received an SGLT2I within the study’s past year. This resulted in 63,208 patients selected as the empagliflozin group, and 438,127 patients in the control group. The control group consisted of patients who were switched to or had an additional antihyperglycemic medication except for SGLT2I.
All analysis conducted was done by per-protocol. To allow for a comparison between the two groups, a weighted pseudo-cohort was generated where both groups had similar baseline characteristics. During a 3-year follow-up, there were 2,305 (4.39%) outcomes of major adverse kidney events in the empagliflozin group versus 3,642.17 (6.89%) in the control group (34.80 per 1000 person-years in empagliflozin vs. 51.18 per 1000 person-years in the control group). Empagliflozin was also associated with reduced risk of major adverse kidney events in patients with varying eGFR ranges, including eGFR < 60 mL/min/1.73m2, and in patients with no albuminuria, microalbuminuria, and macro-albuminuria.
Additionally, there was a decrease in the estimated eGFR trajectory in the empagliflozin and the control group. Within three years of the treatment, patients in the empagliflozin group achieved a 5.30 mL/min/1.73m2 decline (95% CI: 4.62-5.97), and patients enrolled in the control exhibited an 8.27 mL/min/1.73m2 decline (95% CI: 6.80-9.92). Among the two groups, the empagliflozin group’s patients experienced a rapid decrease in the eGFR within the first 90 days after treatment initiation. However, annual eGFR preservation of 0.99 mL/min/1.73m2, as well as net preservation of 2.97 mL/min/1.73m2 at three years, was observed in the empagliflozin group (P < 0.001). Patients in both groups experienced a decline in BMI, but patients in the empagliflozin group had a more significant reduction. At the three-year follow-up, the empagliflozin group had a BMI decline of 1.68 kg/m2 (95% CI: 1.50–1.83), while the control had a BMI decline of 0.95 kg/m2 (95% CI: 0.76-1.09).
In conclusion, patients initiated on empagliflozin versus other non-SGLT2I experienced a reduced risk of major adverse kidney events, a higher eGFR preservation, a higher decline in BMI, and reduced composite eGFR decline > 50%, ESKD, or death. Empagliflozin was shown to be effective in patients with a reduced eGFR of 45 to < 60 and ≥30 to < 45 mL/min/1.73m2 and was associated with a reduced risk of major adverse kidney events. This study utilized data from the VA, allowing for a large population size and generalizing real-world experiences. Although this study had patient follow-ups at 90 days and 1, 2, and 3 years, further studies with longer follow up period should be implemented to determine the long term association of empagliflozin.
- Compared to non-SGLT2I, the use of empagliflozin may reduce major adverse kidney events in patients without albuminuria, or who have microalbuminuria.
- Empagliflozin is shown to be effective in patients with a reduced eGFR of 45 to < 60 and ≥30 to < 45 mL/min/1.73m2.
- Empagliflozin was associated with a reduced risk of major adverse kidney events in patients with an eGFR of < 60 mL/min/1.73m2.
Heerspink, Hiddo J L, et al. “Kidney Outcomes Associated with Use of SGLT2 Inhibitors in Real-World Clinical Practice (CVD-REAL 3): a Multinational Observational Cohort Study.” The Lancet Diabetes & Endocrinology, vol. 8, no. 1, 2020, pp. 27–35., doi:10.1016/s2213-8587(19)30384-5.
Xie, Yan, et al. “Comparative Effectiveness of the Sodium–Glucose Cotransporter 2 Inhibitor Empagliflozin Versus Other Antihyperglycemics on Risk of Major Adverse Kidney Events.“ Diabetes Care, vol. 43, no. 11, 2020, pp., 2785–2795., doi:10.2337/dc20-1231.
Shana Indawala, PharmD Candidate, University of South Florida Health, Taneja College of Pharmacy