Effects of Empagliflozin in Patients With Chronic Kidney Disease
Pooling results from 13 large trials including 90,000 participants have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of progression of chronic kidney disease (CKD) and acute kidney injury in a broad range of patients, including those with heart failure, CKD, or type 2 diabetes.1 The pooled analyses were published in parallel with the latest large SGLT2 inhibitor trial called EMPA-KIDNEY, which was designed, conducted and analyzed by the University of Oxford. EMPA-KIDNEY assessed the effects of the SGLT2 inhibitor, empagliflozin, on patients with CKD who are at risk for disease progression.2 The editors from Consultant360 asked Chief Investigator William Herrington, MA, MBBS, MD, to answer questions on behalf of the EMPA-KIDNEY Collaborative Group about the results of the trial.
Consultant360: What was the impetus for the study Empagliflozin in Patients With Chronic Kidney Disease?2
William Herrington MA, MBBS, MD: The trial was envisaged by nephrology trialists at Oxford Population Health in 2016 when they saw the results of the first large trial to report effects of SGLT2 inhibitors on the kidney outcomes by Wanner, et al.2 These results raise the hypothesis that SGLT2 inhibitors could substantially modify the risk of kidney disease progression, and we set out to design a trial that would include a broad range of patients at risk of kidney disease progression.
C360: How does this study fill gaps in the research of empagliflozin in patients with CKD?
Dr Herrington: EMPA-KIDNEY is the largest of the kidney progression trials testing SGLT2 inhibitors, and it included the broadest range of patients, including just more than one-half without diabetes and just fewer than one-half with low (ie, A1 - A2) levels of albuminuria. These groups of patients were understudied in previous trials.
C360: How do the results of this study contribute to clinical practice?
Dr Herrington: EMPA-KIDNEY demonstrated that, in the studied population, empagliflozin is safe and well tolerated and will reduce risk of kidney disease progression irrespective of diabetes status or level of kidney function. It also reduces risk of hospitalization. Licensed SGLT2 inhibitors should be initiated in patients with CKD at risk of progression and continued until need for kidney replacement therapy.
C360: What is next for research on empagliflozin in patients with CKD?
Dr Herrington: We identified benefits on the kidney, which appeared to be smaller in patients with lower levels of albuminuria. Exploratory analyses suggested such patients would benefit importantly if they were treated longer term. We are performing long-term follow-up of trial participants to facilitate reliable health economic analyses which will assess which patients can be treated and save costs for health services, and in which patients with CKD treatment is cost-effective.
C360: What are the overall take-home messages from this study?
Dr Herrington: The bottom line is that the EMPA-KIDNEY trial randomly assigned a broad range of 6609 patients with CKD at risk for disease progression. Empagliflozin reduced the composite primary outcome of kidney disease progression or cardiovascular death by 28% compared with placebo, with broadly similar effects in patients with and without diabetes and across the full spectrum of eGFR (down to an eGFR of 20 ml/min/1.73m3 and with some data to an initiating eGFR of 15). There was evidence for larger effects in patients with higher levels of albuminuria, but the annual rate of change in eGFR showed that empagliflozin slowed the rate of long-term eGFR decline in all albuminuria subgroups. The safety data were generally similar to the known safety profile of empagliflozin.
C360: Is there anything else you’d like to add?
Dr Herrington: The trial was published in the NEJM in Nov 2022, but there is also a comprehensive meta-analysis to accompany the publication in The Lancet with other important conclusions, including how SGLT2 inhibitors reduce risk of acute kidney injury.1
- Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788-1801. doi:10.1016/S0140-6736(22)02074-8
- Herrington WG, Staplin N, Wanner C, et al; The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
- Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 8;375(4):323-34. doi:10.1056/NEJMoa1515920