Empagliflozin in Diabetic CKD Stage 2 Without Albuminuria
Direct Recommendation
Empagliflozin 10 mg once daily is recommended for patients with type 2 diabetes and CKD stage 2 (eGFR 60-89 mL/min/1.73 m²) even without albuminuria, as it provides cardiovascular and renal protection that extends beyond glycemic control. 1
Evidence-Based Rationale
Guideline Support for Use Without Albuminuria
The 2022 ADA/KDIGO consensus explicitly recommends SGLT2 inhibitors for patients with type 2 diabetes and CKD with eGFR ≥20 mL/min/1.73 m² and urine albumin ranging from normal to 200 mg/g creatinine (Class I, Level A recommendation). 1
The EMPA-KIDNEY trial specifically enrolled patients with lower levels of albuminuria, including 20% of participants without pathological albuminuria, and demonstrated a 28% reduction in the composite outcome of CKD progression or cardiovascular death (p<0.001). 2
Post-hoc analysis from EMPA-REG OUTCOME demonstrated consistent cardiovascular and kidney benefits in patients with "non-overt DKD" (eGFR <60 mL/min/1.73 m² without overt albuminuria) and in those with eGFR ≥60 mL/min/1.73 m² without overt albuminuria (P-values for interaction >0.05). 3
Cardiovascular and Renal Protection Mechanisms
The 2023 ACC Chronic Coronary Disease Guideline gives a Class I recommendation for SGLT2 inhibitors in patients with CKD and type 2 diabetes to reduce the risk of major adverse cardiovascular events. 1
Empagliflozin reduces the risk of incident or worsening nephropathy by 39% (HR 0.61; 95% CI 0.53-0.70; p<0.001), including a 44% reduction in doubling of serum creatinine and 55% reduction in need for renal-replacement therapy. 4
The nephroprotective effect occurs through hemodynamic mechanisms (reducing intraglomerular pressure) that are independent of albuminuria status, explaining why benefits persist even without baseline proteinuria. 3, 4
Dosing and Initiation in CKD Stage 2
Start empagliflozin 10 mg once daily, taken with or without food, in the morning. 5
For patients tolerating the 10 mg dose who need additional glycemic control, the dose may be increased to 25 mg once daily. 5
At CKD stage 2 (eGFR 60-89 mL/min/1.73 m²), no dose adjustment is required, and the full glucose-lowering efficacy is preserved. 5, 6
The FDA label states that empagliflozin should not be initiated if eGFR is <45 mL/min/1.73 m², but CKD stage 2 is well above this threshold. 5
Safety Considerations and Monitoring
Volume Status Assessment
Before initiating empagliflozin, assess for volume contraction and correct volume status if indicated, particularly in elderly patients or those on concurrent diuretics. 5
Monitor for signs and symptoms of hypotension after initiating therapy, as empagliflozin causes intravascular volume contraction through osmotic diuresis. 5
Consider reducing concurrent diuretic doses proactively in patients at high risk for volume depletion. 1
Hypoglycemia Risk Management
If the patient is on insulin and HbA1c is well-controlled at baseline, reduce total daily insulin dose by approximately 20% when initiating empagliflozin. 7
Consider weaning or stopping sulfonylureas or glinides to prevent hypoglycemia, as empagliflozin adds glucose-lowering effect. 7
The combination of empagliflozin with metformin or DPP-4 inhibitors has low hypoglycemia risk and typically requires no preemptive dose adjustment. 8
Ketoacidosis Prevention
Educate patients to withhold empagliflozin during acute illness, particularly with reduced oral intake, fever, vomiting, or diarrhea. 1, 8
Maintain at least low-dose insulin in insulin-requiring patients even when empagliflozin is held during illness, as complete insulin cessation increases diabetic ketoacidosis risk. 1
Withhold empagliflozin at least 3 days before major surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis. 1, 7
Monitor for euglycemic diabetic ketoacidosis, which can occur even with normal blood glucose levels (often <250 mg/dL). 5
Infection Monitoring
Counsel patients about genital mycotic infections, which occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo. 1
Daily hygienic measures may reduce infection risk, and most genital mycotic infections are easily treated. 1
Rare but serious: necrotizing fasciitis of the perineum (Fournier gangrene) requires prompt treatment if suspected. 8
Renal Function Monitoring Algorithm
Assess eGFR before initiating empagliflozin and periodically thereafter. 1, 5
For CKD stage 2 (eGFR 60-89 mL/min/1.73 m²), recheck eGFR within 1-2 weeks after initiation to assess for the expected transient dip of 3-5 mL/min/1.73 m². 8
Continue monitoring eGFR at least annually when ≥60 mL/min/1.73 m², increasing to every 3-6 months if eGFR falls below 60 mL/min/1.73 m². 7
Do not discontinue empagliflozin if eGFR falls below 60 mL/min/1.73 m² during treatment, as cardiovascular and renal protective benefits persist even when glycemic efficacy is reduced. 1, 8
Continue empagliflozin even if eGFR falls below 45 mL/min/1.73 m² during treatment, unless the patient is not tolerating therapy or requires kidney replacement therapy. 1
Common Clinical Pitfalls to Avoid
Do not wait for albuminuria to develop before initiating empagliflozin, as the EMPA-KIDNEY trial demonstrated benefits in patients without pathological albuminuria. 2
Do not discontinue empagliflozin solely because eGFR declines during treatment, as the initial dip is hemodynamically mediated and associated with better long-term renal outcomes. 1, 8
Do not reduce empagliflozin dose based on eGFR decline alone in CKD stage 2, as the standard 10 mg dose provides optimal cardiovascular and renal protection. 7
Do not overlook sick day management education, as failure to hold empagliflozin during acute illness is a major contributor to diabetic ketoacidosis risk. 8