Addendum. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;45(Suppl. 1): S175–S184

“11.3a For patients with type 2 diabetes and diabetic kidney disease, use of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated glomerular filtration rate ≥20 mL/min/1.73 m² and urinary albumin ≥200 mg/g creatinine is recommended to reduce chronic kidney disease progression and cardiovascular events. A”

“11.3b For patients with type 2 diabetes and diabetic kidney disease, use of a sodium–glucose cotransporter 2 inhibitor is recommended to reduce chronic kidney disease progression and cardiovascular events in patients with an estimated glomerular filtration rate ≥20 mL/min/1.73 m² and urine albumin ranging from normal to 200 mg/g creatinine. B”

“However, for patients with type 2 diabetes and diabetic kidney disease, use of an SGLT2 inhibitor in patients with eGFR ≥20 mL/min/1.73 m²and UACR ≥200 mg/g creatinine is recommended to reduce CKD progression and cardiovascular events. This an A-level recommendation. This is a change in eGFR from previous recommendations that suggested an eGFR level >25 mL/min/1.73 m². The reason for the lower limit of eGFR is as follows. The major clinical trials for SGLT2 inhibitors that showed benefit for patients with diabetic kidney disease are CREDENCE and DAPA-CKD (27,117). CREDENCE enrollment criteria included eGFR >30 mL/min/1.73 m² and UACR >300 mg/g. DAPA-CKD enrolled patients with eGFR >25 mL/min/1.73 m² and UACR >200 mg/g. Analyses from the EMPEROR heart failure trials (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved] enrolled 5,998 participants [118], and Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction [EMPEROR-Reduced] enrolled 3,730 participants [119]; enrollment criteria included eGFR >60 mL/min/1.73 m², but efficacy was seen at eGFR >20 mL/min/1.73 m² in people with heart failure) as well as subgroup analyses from DAPA-CKD (120) suggest that SGLT2 inhibitors are safe and effective at eGFR levels of >20 mL/min/1.73 m². Hence, the new recommendation is to use SGLT2 inhibitors in patients with eGFR as low as 20 mL/min/1.73 m². In addition, SGLT2 inhibitors appear to be safe and effective in nonalbuminuric patients. The EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial (NCT03594110) was stopped early due to effectiveness of the study medication. The data have not been published, but the study enrolled 6,609 participants and enrolled normoalbuminuric participants. The preliminary reports are that the drug was safe and effective even in the absence of albuminuria. In addition, Dapagliflozin Effect on Cardiovascular Events–Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58) suggested effectiveness in participants with normal urine albumin levels (121). Hence, the American Diabetes Association is recommending the following at a B level for now: for patients with type 2 diabetes and diabetic kidney disease, use of an SGLT2 inhibitor is recommended to reduce CKD progression and cardiovascular events in patients with an eGFR ≥20 mL/min/1.73 m² and urine albumin ranging from normal to 200 mg/g creatinine.”

“Traditionally, eGFR is calculated from serum creatinine using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is preferred (2). eGFR is routinely reported by laboratories with serum creatinine, and eGFR calculators are available online at nkdep.nih.gov. An eGFR persistently <60 mL/min/1.73 m² in concert with a urine albumin value of >30 mg/g creatinine is considered abnormal, though optimal thresholds for clinical diagnosis are debated in older adults over age 70 years (2,16). Historically, a correction factor for muscle mass was included in a modified equation for African Americans; however, due to various issues with inequities, it was decided to revamp the equation such that it applies to all. Hence, a committee was convened, resulting in the recommendation for immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the U.S. Additionally, increased use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.”

“Finerenone In Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) assessed the safety and efficacy of finerenone in reducing cardiovascular events among patients with type 2 diabetes and CKD with elevated UACR (30 to <300 mg albumin/g creatinine), and eGFR 25–90 mL/min/1.73 m². The study randomized eligible subjects to either finerenone (n = 3,686) or placebo (n = 3,666). Patients with an eGFR of 25–60 mL/min/1.73 m² at the screening visit received an initial dose at baseline of 10 mg once daily, and if eGFR at screening was ≥60 mL/min/1.73 m², the initial dose was 20 mg once daily. An increase in the dose from 10 to 20 mg once daily was encouraged after 1 month, provided the serum potassium level was ≤4.8 mmol/L and the eGFR was stable. The mean patient age was 64.1 years (31% of patients were female), and the median follow-up duration was 3.4 years. The median A1C was 7.7%, mean systolic blood pressure was 136 mmHg, and mean GFR was 67.8 mL/min/1.73 m². Patients with heart failure with a reduced ejection fraction and uncontrolled hypertension were excluded.

The primary composite outcome was cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure. The finerenone group showed a 13% reduction in the primary endpoint: 12.4% vs. 14.2% (hazard ratio [HR] 0.87 [95% CI 0.76–0.98]; P = 0.03). This benefit was primarily driven by a reduction in heart failure hospitalizations: 3.2% vs. 4.4% (HR 0.71 [95% CI 0.56–0.90]).

Of the secondary outcomes, the most noteworthy was a 36% reduction in end-stage kidney disease: 0.9% vs. 1.3% (HR 0.64 [95% CI 0.41–0.995]). There was a higher incidence of hyperkalemia, 10.8% vs. 5.3%, although only 1.2% of the 3,686 patients on finerenone stopped the study due to hyperkalemia of 0.6% vs. 0.4% of the placebo group.

The FIDELITY prespecified pooled efficacy and safety analysis incorporated patients from both FIGARO and FIDELIO (N = 13,171) to allow for evaluation across the spectrum of severity of chronic kidney disease, since the populations were different (with a slight overlap) and the study designs were similar. The analysis showed a 14% reduction in composite cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, for finerenone vs. placebo: 12.7% vs. 14.4% (HR 0.86 [95% CI 0.78–0.95]; P = 0.0018).

It also demonstrated a 23% reduction in the composite kidney outcome, consisting of sustained ≥57% decrease in eGFR from baseline over ≥4 weeks, or renal death, for finerenone vs. placebo (5.5% vs. 7.1%; HR 0.77 [95% CI 0.67–0.88]; P = 0.0002).

The pooled FIDELITY analysis confirms and strengthens the positive cardiovascular and renal outcomes with finerenone across the spectrum of chronic kidney disease, irrespective of baseline ASCVD history (excluding those with reduced ejection fraction heart failure, as they were excluded from these trials).”