What is the role of dapagliflozin (SGLT2 inhibitor) in patients with Chronic Kidney Disease (CKD)?

Dapagliflozin in Chronic Kidney Disease

Dapagliflozin 10 mg once daily is strongly recommended for patients with CKD to reduce the risk of kidney failure, cardiovascular death, and heart failure hospitalization, and should be initiated in patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, regardless of diabetes status. 1, 2

Indications and Patient Selection

Primary Indication

• Dapagliflozin is FDA-approved to reduce the risk of sustained eGFR decline, end-stage kidney disease (ESKD), cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression. 2
• The drug provides benefit in patients both with and without type 2 diabetes—the DAPA-CKD trial included 67.5% with diabetes and 32.5% without diabetes, showing consistent efficacy across both groups. 1, 3

eGFR Thresholds for Initiation

• Initiate dapagliflozin when eGFR is ≥20 mL/min/1.73 m² based on evidence from DAPA-CKD and EMPEROR heart failure trials showing safety and efficacy at this threshold. 1
• The original DAPA-CKD trial enrolled patients with eGFR 25-75 mL/min/1.73 m², but subgroup analyses demonstrated benefit down to eGFR >20 mL/min/1.73 m². 1
• Do not initiate dapagliflozin if eGFR <25 mL/min/1.73 m², but if already on treatment when eGFR falls below 25 mL/min/1.73 m², continue 10 mg daily until dialysis is required. 4

Albuminuria Requirements

• Dapagliflozin is recommended for patients with UACR ≥200 mg/g creatinine based on DAPA-CKD enrollment criteria. 1
• Evidence from DECLARE-TIMI 58 suggests effectiveness even with normal urinary albumin levels, though the strongest evidence supports use in patients with albuminuria. 1

Clinical Efficacy: The DAPA-CKD Trial

Primary Outcomes

• Dapagliflozin reduced the primary composite endpoint (≥50% sustained eGFR decline, ESKD, or kidney/cardiovascular death) by 39% (HR 0.61,95% CI 0.51-0.72, p<0.001). 1, 2
• The kidney-specific composite (≥50% sustained eGFR decline, ESKD, or renal death) was reduced by 44% (HR 0.56,95% CI 0.45-0.68, p<0.001). 1, 2

Cardiovascular Benefits

• Dapagliflozin reduced cardiovascular death or hospitalization for heart failure by 29% (HR 0.71,95% CI 0.55-0.92, p=0.009). 1, 2
• All-cause mortality was reduced by 31% (HR 0.69,95% CI 0.53-0.88, p=0.0035). 1, 2

Consistency Across Subgroups

• Benefits were consistent regardless of diabetes status: HR 0.64 (95% CI 0.52-0.79) in patients with type 2 diabetes versus HR 0.50 (95% CI 0.35-0.72) in those without diabetes (p-interaction=0.24). 3
• Efficacy was maintained across all KDIGO risk categories, with no heterogeneity by age, sex, or baseline eGFR. 5, 6
• The drug was equally effective in patients with diabetic nephropathy (HR 0.63), chronic glomerulonephritides (HR 0.43), and ischemic/hypertensive CKD (HR 0.75). 3

Dosing and Administration

Standard Dosing

• The fixed dose is 10 mg orally once daily for cardiovascular and renal protection, regardless of eGFR level (as long as ≥20 mL/min/1.73 m²). 4, 2
• No dose adjustment is required based on kidney function for cardiovascular/renal indications. 4

Important Distinction: Glycemic Control vs. Organ Protection

• For glycemic control, dapagliflozin should not be initiated if eGFR <45 mL/min/1.73 m² as it is likely ineffective due to its mechanism of action. 4, 2
• However, for cardiovascular and renal protection, continue 10 mg daily even when eGFR is 20-44 mL/min/1.73 m², as these benefits are preserved independent of glucose-lowering effects. 1, 4

Monitoring and Safety

Expected eGFR Changes

• An initial reversible eGFR decline of 3-5 mL/min/1.73 m² typically occurs within the first 1-4 weeks of treatment—this is hemodynamic and expected. 4, 7
• Patients experiencing an acute eGFR reduction >10% at 2 weeks actually had better long-term renal outcomes with slower eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) compared to those without an initial dip. 7
• Check eGFR and creatinine within 1-2 weeks after initiation; if eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering dapagliflozin adjustment. 4

Adverse Events to Monitor

• Genital mycotic infections and urinary tract infections occur more frequently—educate patients on prevention and early recognition. 4, 2
• Volume depletion risk is increased, particularly in patients on diuretics, elderly patients, or those with low baseline blood pressure—assess volume status before initiation. 4
• Euglycemic diabetic ketoacidosis (DKA) is a rare but serious risk, particularly in insulin-requiring patients. 4

Sick Day Management

• Withhold dapagliflozin during acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake, to prevent DKA and volume depletion. 4
• Withhold at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis. 4
• Resume only after recovery and normal oral intake is re-established. 4
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held, as complete insulin cessation increases DKA risk. 4

Clinical Decision Algorithm

For Patients with CKD and eGFR ≥20 mL/min/1.73 m²:

1. If UACR ≥200 mg/g → Initiate dapagliflozin 10 mg daily for renal and cardiovascular protection. 1
2. If eGFR 20-44 mL/min/1.73 m² → Use dapagliflozin 10 mg daily for organ protection, NOT for glycemic control. 1, 4
3. If eGFR ≥45 mL/min/1.73 m² → Use dapagliflozin 10 mg daily for both organ protection AND glycemic control (if diabetic). 4

For Patients Already on Dapagliflozin:

• Continue 10 mg daily even if eGFR falls below 25 mL/min/1.73 m² until dialysis is initiated. 4
• Do not discontinue solely because eGFR declines, as cardiovascular and renal protective benefits persist. 4

Common Pitfalls to Avoid

• Do not withhold dapagliflozin in patients with eGFR 20-44 mL/min/1.73 m² thinking it won't work—the cardiovascular and renal benefits are preserved even when glucose-lowering efficacy is lost. 1, 4
• Do not panic about the initial eGFR dip in the first 2-4 weeks—this is hemodynamic, reversible, and actually predicts better long-term kidney outcomes. 4, 7
• Do not use dapagliflozin for glycemic control when eGFR <45 mL/min/1.73 m²—it is ineffective for this purpose, though still beneficial for organ protection. 4, 2
• Do not forget to educate patients about sick day rules—failure to withhold during acute illness significantly increases DKA risk. 4