Dapagliflozin in Chronic Kidney Disease
Dapagliflozin 10 mg once daily should be initiated in patients with CKD who have eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g to reduce kidney failure, cardiovascular death, and heart failure hospitalization, regardless of diabetes status. 1, 2
Primary Indication and Evidence Base
The FDA has approved dapagliflozin to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression. 2 This approval was based on the DAPA-CKD trial, which demonstrated a 39% reduction in the primary composite outcome (≥50% sustained eGFR decline, ESKD, or renal/cardiovascular death) with hazard ratio 0.61 (95% CI 0.51-0.72, p<0.0001). 2, 3
Key Clinical Benefits
Kidney protection: Dapagliflozin reduced the kidney-specific composite outcome (≥50% sustained eGFR decline, ESKD, or renal death) by 44% (HR 0.56,95% CI 0.45-0.68). 2, 3
Cardiovascular protection: The drug reduced cardiovascular death or hospitalization for heart failure by 29% (HR 0.71,95% CI 0.55-0.92, p=0.0089). 2, 3
Mortality benefit: All-cause mortality was reduced by 31% (HR 0.69,95% CI 0.53-0.88, p=0.0035). 2, 3
Initiation Criteria: A Practical Algorithm
For Patients with UACR ≥200 mg/g:
eGFR ≥20 mL/min/1.73 m²: Initiate dapagliflozin 10 mg once daily for cardiovascular and renal protection (strong recommendation, 1A evidence). 1, 4
No diabetes required: Benefits are consistent in patients with and without type 2 diabetes (HR 0.64 vs 0.50 for primary outcome, p-interaction=0.24). 5
Continue if eGFR declines: If eGFR falls below 25 mL/min/1.73 m² during treatment, continue 10 mg daily until dialysis initiation. 1, 4
For Patients with UACR <200 mg/g:
eGFR 20-45 mL/min/1.73 m²: Consider dapagliflozin 10 mg daily, though evidence is rated 2B due to limited trial data in this specific population. 1 Real-world evidence suggests benefit with eGFR slope attenuation of 1.07 mL/min/1.73 m²/year compared to non-initiators. 6
eGFR ≥45 mL/min/1.73 m²: For glycemic control in diabetes, start 5 mg once daily, may increase to 10 mg if needed. 4 For cardiovascular/renal protection, use 10 mg once daily regardless of diabetes status. 4
Dosing Specifications
The dose is always 10 mg once daily for cardiovascular and renal protection, with no titration required and no dose adjustment based on eGFR at initiation (as long as eGFR ≥20 mL/min/1.73 m²). 4, 2
Important Dosing Distinction:
For glycemic control: Not recommended when eGFR <45 mL/min/1.73 m² as glucose-lowering efficacy is significantly reduced due to mechanism of action. 4, 2
For cardiovascular/renal protection: Effective down to eGFR 20 mL/min/1.73 m², as these benefits are independent of glycemic effects. 1, 4
Expected Initial eGFR Changes
Anticipate a transient, reversible eGFR decline of 3-5 mL/min/1.73 m² within the first 1-4 weeks. 1, 4 This hemodynamic effect does not require discontinuation and is followed by long-term eGFR stabilization. 1
Recheck eGFR within 1-2 weeks after initiation to document this expected dip and assess volume status. 4
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. 4
Critical Safety Precautions and Sick Day Management
Withhold Dapagliflozin During Acute Illness:
Temporarily discontinue dapagliflozin during any acute illness with fever, vomiting, diarrhea, or reduced food/fluid intake to prevent diabetic ketoacidosis and volume depletion. 1, 4
Hold at least 3 days before major surgery or procedures requiring prolonged fasting. 4
Resume only after patient has recovered 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. 1, 4
Volume Depletion Management:
Assess volume status before starting and correct any volume depletion. 4
Consider proactive dose reduction of concurrent diuretics in patients at high risk for volume depletion. 1, 4
If eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering dapagliflozin adjustment. 4
Monitoring for Adverse Events:
Genital mycotic infections occur in approximately 6% of patients versus 1% on placebo. 4 Daily hygiene to keep genital area clean and dry can mitigate this risk. 1, 4
Monitor for euglycemic diabetic ketoacidosis, which can occur even with normal blood glucose levels. 4 Check blood or urine ketones if patients develop malaise, nausea, or vomiting. 4
Watch for rare but serious necrotizing fasciitis of the perineum (Fournier gangrene), which requires prompt treatment if suspected. 4
Beneficial Side Effects and Drug Interactions
Dapagliflozin reduces the risk of hyperkalemia without causing hypokalemia, facilitating the use of other guideline-directed therapies such as RAS inhibitors, mineralocorticoid receptor antagonists, and endothelin antagonists. 1 This makes it particularly valuable in patients requiring multiple cardioprotective medications.
Common Pitfalls to Avoid
Do not discontinue dapagliflozin solely because eGFR falls below 45 mL/min/1.73 m², as cardiovascular and renal protective benefits persist even when glycemic efficacy is lost. 4
Do not withhold dapagliflozin in non-diabetic CKD patients, as the DAPA-CKD trial demonstrated consistent benefits regardless of diabetes status (HR 0.50 in non-diabetics vs 0.64 in diabetics for primary outcome). 5
Do not reduce insulin doses excessively when holding dapagliflozin during illness, as this combination significantly elevates ketoacidosis risk. 4
Do not assume lack of efficacy in patients with lower albuminuria (UACR <200 mg/g), as real-world evidence and eGFR slope analyses suggest potential benefit in this population. 1, 6
Integration with Other CKD Therapies
Dapagliflozin should be used as a first-line agent for kidney and heart protection in patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, prioritizing SGLT2 inhibitors with proven kidney and cardiovascular benefits over others without similar evidence. 1 It can be added to RAS inhibitors and used in combination with nonsteroidal mineralocorticoid receptor antagonists for patients with type 2 diabetes, eGFR >25 mL/min/1.73 m², and persistent albuminuria despite maximum tolerated RAS inhibitor therapy. 1
Dialysis Considerations
The FDA reviewed safety data on dapagliflozin in patients who initiated dialysis during the DAPA-CKD trial and found no safety signals, leading to removal of the recommendation to discontinue at dialysis initiation from the package insert. 1 However, there is insufficient evidence to suggest effectiveness in patients receiving kidney replacement therapy, and ongoing trials are exploring potential benefits in dialysis patients. 1