What is the recommended dose of Empagliflozin (Empagliflozin) for an adult patient with type 2 diabetes and impaired renal function?

Empagliflozin Dosing in Type 2 Diabetes with Impaired Renal Function

For adult patients with type 2 diabetes and impaired renal function, empagliflozin should be initiated at 10 mg once daily if eGFR is ≥45 mL/min/1.73 m², and the dose may be increased to 25 mg once daily for additional glycemic control if needed. 1, 2

Standard Dosing Recommendations

• The FDA-approved starting dose is 10 mg orally once daily, taken in the morning with or without food. 2
• The dose may be increased to 25 mg once daily if additional glycemic control is required. 1, 2
• Both the 10 mg and 25 mg doses demonstrated cardiovascular benefit in the EMPA-REG OUTCOME trial, with no evidence of a graded dose-response for cardiovascular or renal protection. 1

Critical eGFR Thresholds for Initiation and Continuation

Do not initiate empagliflozin if eGFR is below 45 mL/min/1.73 m², as the medication is less effective for glucose lowering when renal function is impaired, though this limitation is due to reduced efficacy rather than safety concerns. 1, 2

• For eGFR ≥45 mL/min/1.73 m²: No dose adjustment is required; initiate at 10 mg daily and may increase to 25 mg daily. 1
• For eGFR <45 mL/min/1.73 m²: Do not initiate therapy. 1, 2
• If eGFR falls persistently below 45 mL/min/1.73 m² during treatment: Discontinue empagliflozin. 1, 2

Important Nuance: Cardiovascular Benefit Extends Below the Initiation Threshold

While the FDA label and ACC guidelines state not to initiate below eGFR 45 mL/min/1.73 m², the cardiovascular benefit of empagliflozin appears to be present down to eGFR of 30 mL/min/1.73 m². 1 This creates a clinical scenario where patients already on empagliflozin who experience declining renal function may still derive cardiovascular and renal protection even when glucose-lowering efficacy is lost. 1, 3

Renal Protection Evidence

Empagliflozin demonstrated significant renal benefits in the EMPA-REG OUTCOME trial:

• Reduced incident or worsening nephropathy by 39% (HR 0.61; 95% CI 0.53-0.70; P<0.001). 3
• Reduced doubling of serum creatinine by 44% (1.5% vs 2.6% in placebo group). 3
• Reduced initiation of renal-replacement therapy by 55% (0.3% vs 0.6% in placebo group). 3

Cardiovascular Outcomes by Dose

In the EMPA-REG OUTCOME trial, both doses showed cardiovascular benefit:

• Cardiovascular death was reduced by 38% (HR 0.62; 95% CI 0.49-0.77; P<0.001). 1, 4
• All-cause mortality was reduced by 32% (HR 0.68; 95% CI 0.57-0.82; P<0.001). 1, 4
• Heart failure hospitalization was reduced by 35% (HR 0.65; 95% CI 0.50-0.85). 1

Practical Dosing Algorithm

1. Assess eGFR before initiating empagliflozin. 2
2. If eGFR ≥45 mL/min/1.73 m²: Start empagliflozin 10 mg once daily. 1, 2
3. If additional glycemic control is needed after 4-12 weeks: Increase to 25 mg once daily. 1, 2
4. Monitor eGFR periodically during therapy. 2
5. If eGFR falls persistently below 45 mL/min/1.73 m²: Discontinue empagliflozin per FDA guidance. 2

Safety Considerations in Renal Impairment

• Assess volume status before initiating empagliflozin, particularly in patients with renal impairment, elderly patients, those with low systolic blood pressure, or those on diuretics. 2
• Consider temporarily discontinuing empagliflozin in settings of reduced oral intake or fluid losses to prevent acute kidney injury. 2
• Monitor for signs of volume depletion during therapy, as the risk is higher in patients with renal impairment. 2
• The adverse event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that in the overall trial population. 3

Common Pitfall to Avoid

Do not discontinue empagliflozin solely because glucose-lowering efficacy diminishes with declining renal function. The cardiovascular and renal protective benefits persist at lower eGFR levels (down to 30 mL/min/1.73 m²), even when glycemic efficacy is reduced. 1, 3 However, the FDA label requires discontinuation if eGFR falls persistently below 45 mL/min/1.73 m², creating a tension between regulatory guidance and clinical trial evidence. 2

Pharmacokinetic Considerations

• Empagliflozin exposure (AUC) increases by approximately 18-20% in mild to moderate renal impairment and by 48-66% in severe renal impairment or ESRD, but no dose adjustment is required based on pharmacokinetic data. 5, 6
• Urinary glucose excretion decreases with increasing renal impairment and correlates with decreased eGFR. 5, 6
• Maximum plasma concentrations remain similar across all degrees of renal function. 5, 6