What are alternative medications to Jardiance (empagliflozin) for a patient with impaired renal function?

Alternative Medications to Jardiance (Empagliflozin) for Patients with Impaired Renal Function

Primary Alternative: Dapagliflozin (Farxiga)

Dapagliflozin 10 mg once daily is the preferred alternative to Jardiance for patients with impaired renal function, as it can be initiated down to eGFR ≥25 mL/min/1.73 m² for cardiovascular and renal protection, with identical benefits to empagliflozin in reducing mortality and kidney disease progression. 1

Evidence Supporting Dapagliflozin as First Alternative

• The DAPA-CKD trial demonstrated that dapagliflozin 10 mg daily reduced the primary composite outcome (≥50% sustained eGFR decline, end-stage kidney disease, or renal/cardiovascular death) by 39% (HR 0.61,95% CI 0.51-0.72) in patients with CKD and eGFR 25-75 mL/min/1.73 m² 1, 2
• Dapagliflozin reduced kidney-specific outcomes by 44% (HR 0.56,95% CI 0.45-0.68) and cardiovascular death or heart failure hospitalization by 29% (HR 0.71,95% CI 0.55-0.92) 1, 2
• All-cause mortality was significantly reduced (HR 0.69,95% CI 0.53-0.88, P<0.004) with dapagliflozin 1

Dosing Algorithm for Dapagliflozin Based on Renal Function

• eGFR ≥45 mL/min/1.73 m²: Start dapagliflozin 5 mg once daily for glycemic control, may increase to 10 mg once daily if needed; or start 10 mg once daily for cardiovascular/renal protection 1, 3
• eGFR 25-44 mL/min/1.73 m²: Initiate dapagliflozin 10 mg once daily for cardiovascular and renal protection only (not for glycemic control, as glucose-lowering efficacy is significantly reduced) 1, 3
• eGFR <25 mL/min/1.73 m²: Do not initiate dapagliflozin; however, if already on treatment, may continue 10 mg daily until dialysis is required 1

Key Advantages of Dapagliflozin Over Other Alternatives

• Fixed 10 mg once daily dosing for cardiovascular/renal protection requires no titration or adjustment 1
• Benefits are preserved even when glycemic efficacy is lost at lower eGFR levels 1
• Can be continued if eGFR falls below 25 mL/min/1.73 m² during treatment 1

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Alternative Class: GLP-1 Receptor Agonists

For patients with eGFR <25 mL/min/1.73 m² or those who cannot tolerate SGLT2 inhibitors, GLP-1 receptor agonists (liraglutide or semaglutide) are the preferred alternative, as they provide cardiovascular benefits and can be used with eGFR >30 mL/min/1.73 m². 4, 1

Specific GLP-1 RA Options by Renal Function

• Liraglutide 1.8 mg subcutaneous daily: Can be used with eGFR ≥30 mL/min/1.73 m², provides cardiovascular mortality benefit 4
• Semaglutide 1 mg subcutaneous weekly or 14 mg oral daily: Can be used with eGFR ≥30 mL/min/1.73 m², reduces major adverse cardiovascular events 4
• Dulaglutide 4.5 mg subcutaneous weekly: Can be used with eGFR ≥30 mL/min/1.73 m², provides cardiovascular protection 4

Evidence for GLP-1 RAs in Renal Impairment

• The 2022 ADA Standards recommend GLP-1 receptor agonists for additional glucose lowering in patients with eGFR <45 mL/min/1.73 m² 4
• GLP-1 RAs provide complementary cardiovascular and renal benefits when combined with SGLT2 inhibitors 4

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Alternative SGLT2 Inhibitor: Canagliflozin

Canagliflozin is a reasonable alternative to empagliflozin, but has more restrictive renal dosing requirements and increased amputation risk compared to dapagliflozin. 4

Canagliflozin Dosing and Limitations

• Canagliflozin 300 mg daily is the maximum dose, but requires dose reduction or discontinuation at lower eGFR thresholds than dapagliflozin 4
• The 2018 ADA/EASD consensus states that SGLT2 inhibitors including canagliflozin have not been approved for use by regulators at eGFR below 45 mL/min/1.73 m² for initiation 4
• Canagliflozin has been associated with increased risk of lower limb amputation in clinical trials 4

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Traditional Alternatives for Glycemic Control Only

DPP-4 Inhibitors (When SGLT2 Inhibitors Cannot Be Used)

• Linagliptin 5 mg once daily: Requires no dose adjustment regardless of renal function, including severe renal impairment 1
• Sitagliptin: Requires dose reduction to 50 mg once daily if eGFR 30-44 mL/min/1.73 m², and to 25 mg once daily if eGFR <30 mL/min/1.73 m² 1

Insulin Therapy

• Insulin remains effective regardless of kidney function and can be dose-adjusted based on clinical response 1
• Insulin is the most reliable option for glycemic control in advanced CKD (eGFR <30 mL/min/1.73 m²) 1

Metformin (With Caution)

• Metformin should not be used in patients with eGFR <30 mL/min/1.73 m² 4
• Dose reduction should be considered when eGFR is <45 mL/min/1.73 m² 4

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Clinical Decision Algorithm

Step 1: Assess Renal Function

• Check eGFR and UACR before selecting alternative 1

Step 2: Select Alternative Based on eGFR

eGFR ≥45 mL/min/1.73 m²:

• First choice: Dapagliflozin 10 mg once daily for cardiovascular/renal protection 1
• Alternative: GLP-1 RA (liraglutide, semaglutide, or dulaglutide) if SGLT2 inhibitor contraindicated 4

eGFR 25-44 mL/min/1.73 m²:

• First choice: Dapagliflozin 10 mg once daily for cardiovascular/renal protection (not for glycemic control) 1
• For glycemic control: Add GLP-1 RA if eGFR ≥30 mL/min/1.73 m², or insulin if eGFR <30 mL/min/1.73 m² 1

eGFR <25 mL/min/1.73 m²:

• Do not initiate dapagliflozin 1
• Use GLP-1 RA if eGFR ≥30 mL/min/1.73 m², or insulin for glycemic control 1

Step 3: Monitor and Adjust

• Recheck eGFR within 1-2 weeks after initiation, then every 3-6 months 1
• Expect initial eGFR dip of 3-5 mL/min/1.73 m² within first 1-4 weeks with dapagliflozin, which is transient and reversible 1

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Critical Safety Considerations

When to Hold SGLT2 Inhibitors

• Withhold dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting 1
• Temporarily discontinue during acute illness, fever, vomiting, or diarrhea 1
• Hold during any intercurrent illness requiring hospitalization 1

Volume Depletion Risk

• Assess volume status before starting dapagliflozin and consider reducing concurrent diuretic doses 1
• Elderly patients and those on loop diuretics are at higher risk for volume depletion 1

Genital Mycotic Infections

• Genital mycotic infections occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo 1
• Educate patients about daily hygienic measures to reduce risk 1

Euglycemic Diabetic Ketoacidosis

• Monitor for DKA even with normal blood glucose levels, particularly in insulin-requiring patients 1
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held during illness 1

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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 1
• Do not reduce dapagliflozin dose below 10 mg daily for heart failure or CKD indications, as all cardiovascular and renal outcome trials used this fixed dose 1
• Do not combine sulfonylureas with dapagliflozin without reducing sulfonylurea dose, as this increases hypoglycemia risk without additional cardiovascular benefit 1