The year 2019 proved an incredibly important year for the treatment of patients with diabetic kidney disease (DKD). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was a game changer; it demonstrated impressive cardiovascular- and kidney-protective effects of the sodium glucose co-transporter-2 (SGLT2) inhibitor canagliflozin in patients with DKD (1). CREDENCE was important because it was the first trial of SGLT2 inhibitors to include kidney endpoints as primary targets of the trial and led to the US Food and Drug Administration (FDA) extending the indication for canagliflozin specifically for reducing the risk of end-stage kidney disease (ESKD) in patients with type 2 diabetes. SGLT2 inhibitors quickly became a cornerstone of the treatment of diabetic nephropathy. Reflecting this, SGLT2 inhibitors were enshrined in the 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. It recommended that patients with type 2 diabetes, chronic kidney disease (CKD), and an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 should be treated with metformin and an SGLT2 inhibitor (2).
The year 2020 continued to raise the bar for therapeutics in kidney disease and extended the use of SGLT2 inhibitors to patients without diabetes. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial showed that the heart- and kidney-protective effects of dapagliflozin occurred in those with, and importantly without, diabetes mellitus (3). Dapagliflozin resulted in a 5% absolute risk reduction of ESKD, death from cardiovascular or kidney causes, or a sustained 50% fall in eGFR compared to placebo.
The bigger news from DAPA-CKD was that the benefit of SGLT2 inhibitors extended to those even without diabetes. Of the 4304 randomized participants, 33% did not have diabetes. Importantly, the safety profile of dapagliflozin in patients without diabetes was impressive. The recent Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) showed that in a study of 3730 patients with heart failure and an ejection fraction of <30%, cardiovascular death and admissions with heart failure were lower in those taking empagliflozin compared to placebo. A decline in eGFR was a secondary outcome of the study, and those on empagliflozin showed a slower rate of decline in eGFR over a median of 16 months of the study. Only 50% of enrolled patients in EMPEROR-Reduced had diabetes mellitus (4). We await the results of The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY), which aims to assess the effect of empagliflozin on kidney disease progression or cardiovascular death. EMPA-KIDNEY is also enrolling patients without diabetes and pushing the eGFR inclusion criteria to 20 mL/min/1.73 m2 without the need for albuminuria if eGFR is between 20 and 45 mL/min/1.73 m2. These trials are paving the road for use of SGLT2 inhibitors in DKD and non-diabetic proteinuric CKD and in patients with congestive heart failure and kidney disease.
This year also saw the introduction of another new agent for use in patients with DKD. Finerenone is a non-steroidal mineralocorticoid receptor antagonist. It functions similarly to other mineralocorticoid receptor antagonists, such as spironolactone or eplerenone, but without appreciable effects on the glucocorticoid, androgen, and progesterone receptors (5). In November 2020, the results from the Efficacy and Safety of Finerenone in Subjects with Type 2 Diabetes Mellitus and DKD (FIDELIO-DKD) trial were published. The study showed that compared to placebo, finerenone led to a 3% absolute risk reduction in a composite endpoint, consisting of death from kidney causes or kidney failure or a decrease of eGFR by 40% from baseline (6). The majority of this outcome was driven by patients who experienced a sustained decrease in eGFR. As with other mineralocorticoid receptors, hyperkalemia is a concern with finerenone. In FIDELIO-DKD, hyperkalemia-related events were seen in twice as many people in the finerenone group as in the placebo group (18% vs. 9%), and 2.3% of the finerenone group discontinued treatment due to hyperkalemia, compared to 0.9% of the placebo group.
It is truly a remarkable time for the treatment of individuals with DKD, and with more major trials expected in the coming years, we are hopeful that these therapies will be widely used to diminish the need for kidney replacement therapy.
Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295−2306. doi: 10.1056/NEJMoa1811744
de Boer IA, et al. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2020; 98:S1−S115. doi: 10.1016/j.kint.2020.06.019
Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383:1436−1446. doi: 10.1056/NEJMoa2024816
Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383:1413−1424. doi: 10.1056/NEJMoa2022190
Haller H, et al. Finerenone: A new mineralocorticoidreceptor antagonist without hyperkalemia: An opportunity in patients with CKD? Curr Hypertens Rep 2016; 18:41. doi: 10.1007/s11906-016-0649-2
Bakris GL, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383:2219−2229. doi: 10.1056/NEJMoa2025845