Dapagliflozin (Farxiga) Dosing and Management in Type 2 Diabetes with Moderate CKD
Starting Dose and Indication-Based Dosing
For an adult with type 2 diabetes on metformin with elevated A1C and eGFR 45–59 mL/min/1.73 m², initiate dapagliflozin 10 mg once daily for cardiovascular and renal protection, not for glycemic control. 1, 2, 3
At eGFR 45–59 mL/min/1.73 m², dapagliflozin's glucose-lowering efficacy is significantly reduced due to its mechanism of action (inhibiting renal glucose reabsorption), but cardiovascular and renal protective benefits remain fully intact. 1, 2, 3
The FDA label explicitly states that dapagliflozin is "not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m²" and is "likely to be ineffective in this setting based upon its mechanism of action." 3
For cardiovascular/renal protection indications, the recommended dose is 10 mg once daily when eGFR ≥25 mL/min/1.73 m²—no titration is required or recommended. 2, 3
If the primary goal were glycemic control and eGFR were ≥45 mL/min/1.73 m², you could start at 5 mg once daily and increase to 10 mg if additional glucose lowering is needed. 3 However, at eGFR 45–59 mL/min/1.73 m², prioritize the 10 mg dose for cardiorenal protection rather than glycemic efficacy. 2, 4
Renal Dose Adjustments
No dose reduction is required at eGFR 45–59 mL/min/1.73 m²; continue 10 mg once daily. 2, 3
Initiation threshold: Do not start dapagliflozin if eGFR <25 mL/min/1.73 m². 2, 3
Continuation threshold: If eGFR falls below 25 mL/min/1.73 m² while already on treatment, you may continue 10 mg once daily until dialysis is required. 2, 3
At eGFR 30–44 mL/min/1.73 m², the 10 mg dose remains appropriate for cardiovascular and renal protection, though glucose-lowering efficacy will be minimal. 2, 4
Metformin adjustment: If eGFR is 45–59 mL/min/1.73 m², consider reducing metformin to half the maximum dose; if eGFR is 30–44 mL/min/1.73 m², limit metformin to ≤1000 mg/day; stop metformin entirely if eGFR <30 mL/min/1.73 m². 1
Contraindications
Absolute contraindications:
History of serious hypersensitivity reaction (anaphylaxis, angioedema) to dapagliflozin or any excipient. 3
Dialysis or eGFR <25 mL/min/1.73 m² for new initiation (though continuation is permitted if eGFR falls below this threshold during treatment). 2, 3
Relative contraindications and precautions:
Volume depletion: Correct hypovolemia before starting dapagliflozin; assess volume status in elderly patients, those on loop diuretics, or those with low systolic blood pressure. 2, 3
Pregnancy and breastfeeding: Not recommended. 2
Type 1 diabetes mellitus: Not indicated; significantly increases risk of diabetic ketoacidosis. 3
Polycystic kidney disease or recent immunosuppressive therapy for kidney disease: Not expected to be effective. 3
Monitoring
Before initiation:
Check baseline HbA1c, fasting glucose, blood pressure, and weight. 2
Assess for history of genital mycotic infections or recurrent urinary tract infections. 2
After initiation:
Recheck eGFR within 1–2 weeks: An acute, reversible eGFR decline of 2–5 mL/min/1.73 m² is expected and should not prompt discontinuation. 2
Monitor glucose closely for 2–4 weeks, especially if the patient is on insulin or sulfonylureas; reduce doses of these agents to prevent hypoglycemia. 2
Reassess eGFR every 3–6 months if eGFR is 45–59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m². 2
Monitor for genital mycotic infections (occur in ~6% of patients vs. 1% with placebo); counsel on daily hygiene. 2, 5
Watch for signs of euglycemic diabetic ketoacidosis (malaise, nausea, vomiting, abdominal pain even with normal blood glucose). 2, 5
Critical Safety Precautions
Sick-day rules:
Withhold dapagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea to prevent volume depletion and euglycemic ketoacidosis. 2
Stop dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting. 2, 3
If the patient is on insulin, maintain at least a low-dose insulin regimen even when dapagliflozin is held. 2
Medication adjustments:
Consider reducing concurrent loop or thiazide diuretic doses at initiation to avoid excessive volume depletion, especially in elderly patients. 2
If the patient is on a sulfonylurea (e.g., glipizide, gliclazide), stop it completely when starting dapagliflozin to reduce hypoglycemia risk without losing cardiovascular benefit. 2
Continue ACE inhibitors or ARBs unchanged; do not withhold these agents when starting dapagliflozin. 2
Common Pitfalls to Avoid
Do not discontinue dapagliflozin when eGFR falls below 45 mL/min/1.73 m²; cardiovascular and renal benefits persist even though glycemic efficacy is lost. 2, 4
Do not stop dapagliflozin because of the expected early eGFR dip in the first 2–4 weeks; this change is hemodynamic and reversible. 2
Do not reduce the dose below 10 mg for cardiovascular or renal indications, even at lower eGFR levels; all outcome trials used the fixed 10 mg dose. 2, 4
Do not combine dapagliflozin with sulfonylureas if HbA1c is well-controlled; the combination increases hypoglycemia risk without additional cardiovascular benefit. 2
Evidence-Based Clinical Benefits at eGFR 45–59 mL/min/1.73 m²
Dapagliflozin reduces the composite of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death by 39% (HR 0.61,95% CI 0.51–0.72). 2
Kidney-specific outcomes improve by 44% (HR 0.56,95% CI 0.45–0.68). 2
Cardiovascular death or heart failure hospitalization decreases by 29% (HR 0.71,95% CI 0.55–0.92). 2
All-cause mortality is reduced by 31% (HR 0.69,95% CI 0.53–0.88). 2
These benefits are consistent regardless of diabetes status (67.5% of trial participants had type 2 diabetes, 32.5% did not). 2