Addendum. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes—2021: Diabetes Care 2021;44(Suppl. 1):S151–S167

“A second trial in advanced diabetic kidney disease was the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) study. This trial examined a cohort similar to CREDENCE; however, the end points were a little different. The primary outcome was time to the first occurrence of any of the components of the composite: ≥50% sustained decline in eGFR or reaching ESRD or cardiovascular death or renal death. Secondary outcome measures included time to the first occurrence of any of the components of the composite kidney outcome (≥50% sustained decline in eGFR or reaching ESRD or renal death), time to the first occurrence of either of the components of the cardiovascular composite (cardiovascular death or hospitalization for heart failure), and lastly time to death from any cause. The trial had 4,304 patients with a mean eGFR at baseline of 43.1 ± 12.4 mL/min/1.73 m², the median UACR was 949 mg/g, and 67.5% of patients had type 2 diabetes. There was a significant benefit by dapagliflozin for the primary end point (hazard ratio 0.61 [95% CI, 0.51 to 0.72]; P < 0.001).

The hazard ratio for the kidney composite of a sustained decline in the eGFR of at least 50%, ESRD, or death from renal causes was 0.56 (95% CI 0.45 to 0.68; P < 0.001). The hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI 0.55 to 0.92; P = 0.009). Lastly, all-cause mortality was decreased in dapagliflozin group compared with placebo (P = 0.004).”

“Mineralocorticoid receptor antagonists have not been well studied in diabetic kidney disease because of the risk of hyperkalemia. However, data that do exist suggest benefit on albuminuria reduction that is sustained. Late in 2020, the results of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial testing a novel nonsteroidal mineralocorticoid receptor antagonist, finerenone, demonstrated a significant reduction in CKD progression and cardiovascular events in patients with advanced diabetic kidney disease. This trial had a primary end point of time to first occurrence of the composite end point of onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. A prespecified secondary outcome was time to first occurrence of the composite endpoint: cardiovascular death or nonfatal cardiovascular events (myocardial infarction, stroke, hospitalization for heart failure). Other secondary outcomes included all-cause mortality, time to all-cause hospitalizations, time to first occurrence of the following composite end point: onset of kidney failure, a sustained decrease in eGFR of ≥57% from baseline over at least 4 weeks or renal death and change in UACR from baseline to month 4.

The trial was a double-blind trial and randomized 5,734 patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a UACR of 30 to <300 mg/g, an eGFR of 25 to <60 mL/min/1.73 m², and diabetic retinopathy, or a UACR of 300 to 5,000 mg/g and an eGFR of 25 to <75 mL/min/1.73 m². Mean age of the patients was 65.6 years, and 30% were female. The mean eGFR was 44.3 mL/min/1.73 m². Mean albuminuria (interquartile range) was 852 (446–1,634) mg/g. The primary end point was reduced with finerenone compared with placebo (hazard ratio 0.82, 95% CI 0.73–0.93; P = 0.001), as was the key secondary composite outcome (hazard ratio 0.86, 95% CI 0.75–0.99; P = 0.03). Hyperkalemia resulted in 2.3% study discontinuation compared to 0.9% in the placebo group. No deaths occurred related to hyperkalemia.”

“Mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) in combination with ACE inhibitors or ARBs remain an area of great interest. Mineralocorticoid receptor antagonists are effective for management of resistant hypertension, have been shown to reduce albuminuria in short-term studies of CKD, and may have additional cardiovascular benefits (103–105). There has been, however, an increase in hyperkalemic episodes in those on dual therapy, and larger, longer trials with clinical outcomes are needed before recommending such therapy.”