By Reham Awad, PharmD, BCPS and Mukti Patel, PharmD
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally approved as glucose-lowering agents for persons with type 2 diabetes (T2D). More recently, large, randomized, placebo-controlled trials have shown SGLT2i therapy reduces the risk of CV events and kidney disease progression in persons with “albuminuric” diabetic kidney disease taking maximally-tolerated renin-angiotensin system inhibitor therapy. Overall, a large proportion of persons with chronic kidney disease (CKD) have low levels of albuminuria and do not have diabetes; therefore, studying this population is particularly important for public health.(1)
Introduction
In November 2022, the EMPA-KIDNEY trial was published.(2) The goal was to assess the effect of once-daily empagliflozin on the progression of kidney disease and cardiovascular (CV) disease and to examine the safety profile of the medication in a wide range of patients with CKD. The aim of the trial was to include large numbers of persons with CKD without diabetes, with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2, and with low levels of albuminuria.
Methods
Figure 1. Study Design, Intervention, and Patient Population
Outcome Measures:
● Primary: First occurrence of progression of kidney disease (defined as end-stage kidney disease (ESKD), sustained decrease in eGFR to <10mL/min/1.73m^2, sustained decrease from baseline in eGFR of ≥40%, or death from kidney causes) or CV death.
o Subgroup analyses performed and stratified according to diabetes status, eGFR, and urine albumin-to-creatinine ratio (UACR) at baseline.
● Secondary: Composite of hospitalization for heart failure (HHF) or death from CV causes, hospitalization for any cause, death from any cause, progression of kidney disease, death from CV causes, and a composite of ESKD or death from CV causes.
● Safety: Serious adverse events and select other adverse events.
Statistical Analysis: Primary outcome was assessed on a time-to-event analysis using a Cox proportional-hazards model and adjusted for baseline variables.
● Analysis performed on intention-to-treat population and the two conditions for recommending an early stop for efficacy were prespecified as a hazard ratio (HR) <0.778 for primary outcome and secondary outcome of ESKD or death from CV causes (at a two-sided alpha <0.0017 and <0.05, respectively).
● A total of 1070 patients would detect a risk of a primary outcome event that is 18% lower in the empagliflozin than the placebo group for 90% power (at a two-sided alpha of 0.05).
Results
Baseline Characteristics: Total of 8544 participants screened -> 8184 patients entered pre-randomization phase --> 6609 patients randomized to intervention groups. The demographics between groups were similar:
● Mean age 64 years, 33% female, 58% White, 54% did not have diabetes, mean eGFR 37ml/min/1.73m^2 with 34.5% of patients having an eGFR <30 ml/min/1.73m^2, and median UACR of 329 mg/g with 48% of patients having a UACR <300 mg/g.
Table 1. Primary Outcome
Secondary Outcomes:
● The composite of HHF or CV death was not significantly different between groups (HR 0.84, CI 0.67-1.07, p=0.15)
o Anticipated CV event rate was lower than expected which reduced statistical power to detect differences for secondary endpoints
● Hospitalization for any cause: lower in the empagliflozin group (HR 0.86, CI 0.78-0.95, p=0.003, NNT 23)
● Progression of kidney disease (HR 0.71, CI 0.62-0.81) as well as the composite of ESKD or CV death (HR 0.73, CI 0.59 - 0.89) indicated a benefit with empagliflozin
● Death from CV causes and death from any cause were similar in both groups
Safety Outcomes:
● The incidence of serious adverse events including urinary tract infection, genital infection, hyperkalemia, acute kidney injury, and dehydration were broadly similar in the two groups.
● Rates of ketoacidosis for the empagliflozin and placebo groups (0.2% and <0.1%, respectively), lower limb amputation (0.8% and 0.6%), and bone fracture (4% and 3.7%) were similar.
Discussion
The use of empagliflozin in persons with CKD with a wide range of eGFRs, levels of albuminuria, and causes of CKD was associated with a 28% reduction in the risk of kidney disease progression or death from CV causes. The results of the EMPA-KIDNEY trial build upon the results from the CREDENCE trial published in 2019 which compared canagliflozin 100 mg daily vs placebo and the DAPA-CKD trial published in 2020 which compared dapagliflozin 10 mg daily vs placebo advocating for the use of SGLT2i in persons with CKD.(3,4) CREDENCE studied canagliflozin 100 mg daily and included patients with an eGFR ≥30mL/min and required patients to have a UACR ≥300 mg/g. On the other hand, DAPA-CKD studied dapagliflozin 10 mg daily and included patients with or without T2D with an eGFR ≥25mL/min and required patients to have a UACR ≥200mg/g. The data from the EMPA-KIDNEY trial shows consistent benefits among patients without diabetes and among those with an eGFR <30mL/min and extends treatment eligibility to those with non-albuminuric CKD. It’s important to note that the trials’ protocols involved eligible patients to be started on SGLT2i or placebo and were continued despite decline eGFR <20mL/min, until initiation of maintenance dialysis, transplantation, or death. This was reflected in updated recommendations in both the KDIGO 2022 and ADA 2023 guidelines.(5,6) Overall, this trial reflects an opportunity to improve the treatment of CKD across a broad CKD population in clinical practice irrespective of diabetes status and prevent people from needing dialysis.
Author’s Conclusion
Among a broad range of patients with CKD who were at risk for disease progression, including patients without diabetes, an eGFR <30mL/min, and low UACR, empagliflozin treatment led to a lower risk of progression of kidney disease or death from CV causes than placebo.
United States Renal Data System. 2022 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2022.
The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233.
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744.
Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816.
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022;102(5S):S1- S127. doi:10.1016/j.kint.2022.06.008.
ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S140-S157. doi:10.2337/dc23-S009.
Reham Awad, PharmD, BCPS
PGY2 Ambulatory Care Resident
University of Illinois Chicago College of Pharmacy
Mukti Patel, PharmD
PGY2 Ambulatory Care Resident
University of Illinois Chicago College of Pharmacy
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