Lance Sloan, MD, MSE, FACE, FASN, FACP

A crucible is a situation that forces something to change. The EMPA-KIDNEY trial adds to the body of evidence that this class of medications will act as a crucible, changing the standard of care for the treatment of CKD and prevention of diabetic kidney disease (DKD) in individuals with diabetes who have other risk factors for progression.

The EMPA-KIDNEY trial was a randomized, double-blind, placebo-controlled international trial in 6,609 patients with eGFR of 20 mL/min/1.73 m² to 90 mL/min/1.73 m². If the eGFR was 45 mL/min/1.73 m² to 90 mL/min/1.73 m², the albumin-to-creatinine ratio (ACR) had to be 200 mg/g or greater. This additional ACR requirement was done to increase the risk for cardiorenal events in this lower-risk group of individuals with mild to moderate (stages 2-3a) CKD with albuminuria being a risk multiplier for cardiorenal disease progression.

Overall, 46% of the participants had diabetes (mostly type 2), but 31% had DKD. Average eGFR was 37 mL/min/1.73 m², with 34% having an eGFR of less than 30 and approximate mean ACR was 222 mg/g, with 48% being less than 300 mg/g. This trial had a lower average eGFR, but broader range of eGFR and albumin levels than previous CKD trials, making it more reflective of a real-world population.

The participants were randomized to either empagliflozin 10 mg/d or placebo, and the primary outcome was the usual composite of major adverse kidney events (MAKE), which is a GFR decline (40% or greater), ESKD or cardiorenal death.

The trial was stopped early, at a median of 2 years of follow-up, due to overwhelming significance of MAKE of a 28% relative risk reduction with a P < .000001. Unfortunately, this did not allow all the secondary single outcome events to reach statistical significance such as cardiovascular death that had reached statistical significance in other trials, most notably the EMPA-REG trial, but the EMPA-REG trial was in a higher-risk population with diabetes and atherosclerotic cardiovascular disease, and was 3.1 years in median follow-up. The other components of MAKE were significant, and MAKE was significant regardless of diabetes or eGFR status. All-cause hospitalizations were significantly reduced by 14%.

How albuminuria effects the primary outcome was of special interest to some even though the Cardiovascular Outcome Trial had shown reductions in kidney disease progression in individuals with eGFR of less than 30 mg/g and eGFR in the seventy to eighty range. Overall, only the participants with an ACR of greater than 300 mg/g had a significant reduction in MAKE, but this was predicted due to this being the highest-risk group for events, due to the linear increase in cardiorenal events, seen in other trials, with increasing albuminuria. The P value for heterogeneity was not significantly different for this outcome at P = .02. Importantly, the chronic steady state eGFR slope was reduced at all levels of albuminuria with the average reduction being greater than 50%. This is a more physiologic measure of kidney function decline considering all the patients in the study, not just the ones who had events predicted by increased risk factors. What this means to the individual with kidney disease is it would take conservatively twice as long to reach ESKD.

The safety outcomes were like what has been seen in other trials with a slight increase in ketoacidosis in the patients with diabetes. All other adverse events were not significantly different.

A meta-analysis published in The Lancet by the Nuffield Renal Studies Group in November shows SGLT2i to significantly reduce MAKE in patients with DKD, ischemic and hypertensive kidney disease, and glomerular diseases, particularly IgA nephropathy. EMPA-KIDNEY had the greatest number of patients in the non-DKD categories of any SGLT2i study. The paper also included a benefit-to-risk analysis in CKD patients treated with SGLT2i that highly favors the use of this class of drugs in treating CKD.

In summary, the EMPA-KIDNEY trial adds to the literature expanding and strengthening the use of SGLT2i as a crucible event in the management of CKD and prevention of DKD in patients with type 2 diabetes with risk factors for cardiorenal disease progression. One might conservatively predict that this class of medications might reduce CKD and its complications of ESKD and death by 40% or more. As I mentioned in my First Word in Nephrology News & Issues, none of these trials have been long enough to show us the inhibition of tubular interstitial glycation that these products would be predicted to have in the diabetic population, potentially increasing their long-term effects in preventing kidney damage in this population.

Those who have been involved in the development of this class from the beginning have expected an improvement in cardiorenal outcomes beyond glycemic control based on an understanding of cardiorenal pathophysiology. This did not happen by chance. We now await other trials with this class of drugs with mineral corticoid receptor antagonists and other medications to see if there are added benefits.

References:

The Nuffield Department of Population Health Renal Studies Group and the SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Lancet. 2022; https://doi.org/10.1016/S0140-6736(22)02074-8.

Sloan L. New drug therapy will change the CKD landscape. Available online: https://www.healio.com/news/nephrology/20210707/new-drug-therapy-will-change-the-ckd-landscape.