What are alternative medications to Farxiga (dapagliflozin) for a patient with impaired renal function and a history of cardiovascular disease?

Alternative Medications to Farxiga for Patients with Impaired Renal Function and Cardiovascular Disease

Empagliflozin (Jardiance) is the preferred alternative to dapagliflozin for patients with impaired renal function and cardiovascular disease, offering equivalent cardiovascular and renal protection with a superior safety profile—specifically no increased amputation or bone fracture risk. 1, 2

Primary Alternative: Empagliflozin (Jardiance)

Empagliflozin should be your first-line alternative because it provides identical cardiovascular and renal benefits to dapagliflozin while avoiding the amputation concerns associated with canagliflozin. 1, 2

Dosing and Initiation

• Start empagliflozin 10 mg once daily, taken in the morning with or without food, for patients with eGFR ≥45 mL/min/1.73 m². 3
• The dose may be increased to 25 mg once daily if additional glycemic control is needed. 3
• Do not initiate empagliflozin if eGFR is below 45 mL/min/1.73 m²—this is a critical difference from dapagliflozin, which can be initiated down to eGFR 25 mL/min/1.73 m². 3
• Discontinue empagliflozin if eGFR falls persistently below 45 mL/min/1.73 m². 3

Cardiovascular and Renal Benefits

• Empagliflozin demonstrated remarkable reductions in cardiovascular death, all-cause mortality, and hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial. 4, 2, 5
• The drug provides positive renal outcomes, including slowing of kidney disease progression. 2, 5
• These benefits occur independently of glycemic control, making empagliflozin valuable even when glucose-lowering efficacy is reduced at lower eGFR levels. 2

Safety Advantages Over Other SGLT2 Inhibitors

• Empagliflozin has not been associated with increased risk of amputation or bone fractures, unlike canagliflozin which carries FDA warnings for both. 1, 2
• The most common adverse effects are genital mycotic infections and urinary tract infections, similar to other SGLT2 inhibitors. 3, 5
• Monitor for volume depletion, particularly in elderly patients, those on diuretics, or those with low systolic blood pressure. 3

Critical Safety Precautions

• Assess and correct volume status before initiating empagliflozin in patients with renal impairment, elderly patients, those with low systolic blood pressure, or those on diuretics. 3
• Withhold empagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis. 6
• Educate patients to stop empagliflozin and seek immediate care if experiencing dyspnea, nausea, vomiting, or abdominal pain, as euglycemic diabetic ketoacidosis can occur even with normal blood glucose levels. 1, 3
• If the patient is on insulin, reduce the insulin dose by 10-20% when initiating empagliflozin to prevent hypoglycemia. 1
• If the patient is on a sulfonylurea, reduce the dose by 50% or discontinue if already on a minimal dose. 1

Second-Line Alternative: GLP-1 Receptor Agonists

If empagliflozin cannot be used due to eGFR <45 mL/min/1.73 m², switch to a GLP-1 receptor agonist, which provides cardiovascular protection and can be used at lower eGFR levels. 4, 1

Liraglutide (Victoza) - Preferred GLP-1 RA

• Liraglutide is the preferred GLP-1 receptor agonist because it has an FDA-approved cardiovascular indication and requires no dose adjustment with renal impairment. 4, 1
• Start liraglutide at 0.6 mg subcutaneously daily, then titrate slowly to 1.8 mg or the maximally tolerated dose to minimize nausea and vomiting. 4, 1
• Liraglutide reduces the risk of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal MI, and nonfatal stroke, independent of glucose control. 4
• No dose adjustment is necessary with renal or hepatic impairment, though data in end-stage renal disease are limited. 4

Semaglutide (Ozempic) - Alternative GLP-1 RA

• Injectable semaglutide showed numerically favorable cardiovascular results and reduces the risk of new or worsening nephropathy by 36%. 4
• Start semaglutide at 0.25 mg subcutaneously per week, then titrate slowly to the maximally tolerated dose. 4
• Use caution in patients with proliferative retinopathy, as this is a specific concern with semaglutide. 1
• No dose adjustment is necessary with renal or hepatic impairment, though data in end-stage renal disease are limited. 4

GLP-1 RA Safety Considerations

• Up-titrate slowly to reduce nausea and vomiting, which are the most common side effects. 4
• Discontinue if pancreatitis is suspected and do not restart if pancreatitis is confirmed. 4
• GLP-1 receptor agonists may be used at low eGFR for cardiovascular protection but may require dose adjustment. 4

Agents to Avoid in This Population

Do not use canagliflozin in patients with a history of prior amputations, significant peripheral artery disease, active lower extremity soft tissue ulcers or infections, or history of osteoporosis. 1

• Canagliflozin carries FDA warnings for increased risk of lower limb amputation and bone fractures. 4, 1
• The increased incidence of bone fractures and amputation risk makes canagliflozin inappropriate for patients with cardiovascular disease and impaired renal function who often have concurrent peripheral vascular disease. 4, 1

Clinical Decision Algorithm

1. Check eGFR first: This determines which alternative is appropriate.
2. If eGFR ≥45 mL/min/1.73 m²: Use empagliflozin 10 mg once daily as the preferred alternative. 1, 3
3. If eGFR 30-44 mL/min/1.73 m²: Use liraglutide or semaglutide, as empagliflozin cannot be initiated at this level. 4, 1, 3
4. If eGFR <30 mL/min/1.73 m²: Use liraglutide or semaglutide; SGLT2 inhibitors are contraindicated. 4, 3
5. Assess for peripheral vascular disease: If present, avoid canagliflozin entirely and use empagliflozin or a GLP-1 RA. 1
6. Correct volume depletion before initiating any SGLT2 inhibitor, particularly in elderly patients or those on diuretics. 1, 3

Common Pitfalls to Avoid

• Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m² if the patient is already on treatment—cardiovascular and renal protective benefits persist even when glycemic efficacy is lost, though FDA labeling requires discontinuation at this threshold. 3
• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors (like sitagliptin)—they have overlapping mechanisms and should not be used together. 4
• Do not use SGLT2 inhibitors during acute illness with reduced oral intake—hold the medication during fever, vomiting, diarrhea, or any intercurrent illness requiring hospitalization. 6
• Do not assume all SGLT2 inhibitors have the same safety profile—empagliflozin has distinct advantages over canagliflozin regarding amputation and fracture risk. 1, 2