Diabetes Distilled: More evidence that SGLT2 inhibitors slow CKD progression. Are we optimising care?

The EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) randomised controlled trial enrolled 6609 people with chronic kidney disease (CKD) who fitted one of two categories: either an eGFR of 20–45 mL/min/1.73 m² regardless of urinary ACR level, or an eGFR of 45 to <90 mL/min/1.73 m² plus an ACR of ≥200 mg/g (≥22.6 mg/mmol). Participants were randomised to empagliflozin 10 mg or placebo and were followed for a median of 2 years; the study was stopped early due to prespecified efficacy endpoints being met. The composite primary outcome was progression of renal disease (development of end-stage renal disease, sustained eGFR reduction to <10 mL/min/1.73 m², sustained eGFR reduction of ≥40% from baseline or death from renal causes) or death from cardiovascular causes.

Results

The primary endpoint occurred in 13.1% of empagliflozin and 16.9% of placebo recipients, a significant relative risk reduction of 28%. Importantly, the reductions were consistent across a wide variety of participants: those with and without diabetes and those in different eGFR ranges at baseline. Rates of hospitalisation for any cause were also reduced by a significant 14% in the empagliflozin group compared with placebo, but there were no between-group differences in two of the other endpoints examined: a composite of hospitalisation for heart failure or cardiovascular death, and all-cause mortality.

At baseline, 48% of participants had a urinary ACR of less than 300 mg/g. There was a limited number of primary composite outcome events in this subgroup, which was to be expected as these people would have had slower progression of their CKD than those with a higher ACR. Because of this, there were comparable rates of the primary outcome between empagliflozin and placebo within this subgroup. However, a pre-specified analysis of the annual rate of change in eGFR, which is an accepted surrogate for CKD progression, demonstrated that empagliflozin did slow the rate of eGFR decline even in these participants. Importantly, rates of serious adverse events were similar between the empagliflozin and placebo groups.

Since treatment with ACE inhibitors or angiotensin receptor blockers is recommended for people with CKD, significant numbers of participants were also receiving one of these drugs. Interestingly, there was less benefit in this study among participants who were not also receiving these renin–angiotensin system (RAS) blockers, which raises the question, asked in an accompanying editorial (August, 2023), of whether SGLT2 inhibitors are equally effective without RAS blockade.

Analysis

Beneficial effects of SGLT2 inhibitors on slowing the progression of renal disease in people with type 2 diabetes were initially identified in the cardiovascular outcome trials for agents within the class, resulting in specific studies being undertaken subsequently in people with CKD/diabetic kidney disease. In the case of empagliflozin and dapagliflozin, these studies have included people with and without type 2 diabetes.

Although the results of EMPA-KIDNEY are quantitatively similar to those in the other renal studies of SGLT2 inhibitors, there are differences in the inclusion criteria between the studies, which are important in expanding the range of people who are proven to benefit from SGLT2 inhibitors, and which can help us to understand which of our patients with CKD may benefit from empagliflozin. The CREDENCE trial of canagliflozin (Perkovic et al, 2019) enrolled only people with type 2 diabetes and a urinary ACR of ≥300 mg/g (≥33.9 mg/mmol) and excluded people with an eGFR <30 mL/min/1.73 m². This is reflected in the drug’s licence (see our recently updated need-to-know guide). The DAPA-CKD trial of dapagliflozin (Heerspink et al, 2020) included significant numbers of people with and without diabetes, and people with an eGFR <30 mL/min/1.73 m², as did the present EMPA-KIDNEY study.

This was a large study with good rates of adherence to therapy and follow-up. Despite the lower-than-expected number of cardiovascular events, the reduction in cardiovascular events was similar to that expected and in line with a recent meta-analysis which demonstrated that SGLT2 inhibitors significantly reduce the relative risk of cardiovascular death by 14% and the risk of hospitalisation for heart failure or death from cardiovascular causes by 23% (Baigent et al, 2022).

Even more recently, a pre-specified analysis from the DAPA-CKD study has confirmed that the benefits of dapagliflozin in reducing renal disease progression and cardiovascular events remain consistent irrespective of the types and number of other glucose-lowering treatments being used at baseline (Beernink et al, 2023).

The present study again reminds us we should review people with CKD (either eGFR <60 mL/min/1.73 m² or ACR >3 mg/mmol); assess their suitability for ACE inhibitor/ARB treatment; add an appropriate SGLT2 inhibitor if they fit a group likely to benefit; and ensure optimised control of blood pressure, glycaemia and lipids to slow progression of renal disease and reduce the risk of cardiovascular events. We will always find people whose treatment is not yet optimised or where management has lapsed and who would benefit from review.