What alternative medications can be used to replace Farxiga (dapagliflozin) in a patient with type 2 diabetes who discontinued it due to recurrent urinary tract infections (UTIs)?

Alternative to Farxiga After UTI-Related Discontinuation

Switch to a GLP-1 receptor agonist (such as liraglutide or semaglutide) as your next-line agent, as these medications provide comparable cardiovascular and renal benefits without the increased UTI risk associated with SGLT2 inhibitors. 1

Why GLP-1 Receptor Agonists Are the Preferred Alternative

GLP-1 RAs are the guideline-recommended second choice when SGLT2 inhibitors cannot be used. 1 The 2020 KDIGO guidelines explicitly state that when patients with type 2 diabetes and CKD cannot tolerate SGLT2 inhibitors like dapagliflozin (Farxiga), long-acting GLP-1 RAs should be added to metformin therapy. 1

Cardiovascular and Renal Benefits

• GLP-1 RAs reduce cardiovascular death, major adverse cardiovascular events, and stroke with evidence from large trials including LEADER (liraglutide) and SUSTAIN-6 (semaglutide). 1
• Liraglutide reduced the risk of new or worsening nephropathy by 22%, and semaglutide reduced this risk by 36% in cardiovascular outcomes trials. 1
• These agents provide cardiovascular mortality reduction comparable to SGLT2 inhibitors, with semaglutide showing a 49% reduction in CV death in the PIONEER-6 trial. 1

No Increased UTI Risk

• GLP-1 RAs do not increase urinary glucose excretion, eliminating the mechanistic link to UTIs that exists with SGLT2 inhibitors. 2, 3
• The most common adverse effects are gastrointestinal (nausea, vomiting), not genitourinary infections. 1

Understanding Why Farxiga Caused UTIs

SGLT2 inhibitors like dapagliflozin increase urinary glucose excretion, creating a glucose-rich environment in the urinary tract that promotes bacterial growth. 2, 3

• Pooled safety data from 12 trials showed UTI rates of 4.3-5.7% with dapagliflozin versus 3.7% with placebo. 2
• While the absolute increase is modest, patients with recurrent UTIs represent a clear contraindication to continuing SGLT2 inhibitor therapy. 2, 4
• A case report documented E. coli septicemia in a patient on dapagliflozin with bladder outlet obstruction, emphasizing the real clinical risk. 4

Treatment Algorithm When SGLT2 Inhibitors Are Not Tolerated

Step 1: Ensure Metformin Is Optimized

• Continue or initiate metformin (if eGFR ≥30 mL/min/1.73 m²) as first-line therapy, as it remains the foundation of type 2 diabetes management. 1
• Metformin should be dosed at 1,000 mg twice daily if tolerated, with dose reduction when eGFR falls below 45 mL/min/1.73 m². 1

Step 2: Add a GLP-1 Receptor Agonist

• Initiate a long-acting GLP-1 RA such as:
  • Liraglutide 1.8 mg daily (or maximum tolerated dose) 1
  • Semaglutide 0.5-1 mg weekly (subcutaneous) or 14 mg daily (oral) 1
  • Dulaglutide 1.5 mg weekly 1

Step 3: Consider Additional Agents If Needed

If glycemic targets are not met with metformin plus GLP-1 RA:

• DPP-4 inhibitors (sitagliptin, linagliptin) can be added, though they lack the cardiovascular and mortality benefits of GLP-1 RAs. 1
• Insulin therapy may be necessary for patients with more advanced disease or eGFR <30 mL/min/1.73 m². 1
• Avoid sulfonylureas when possible due to hypoglycemia risk, especially in patients with CKD. 1

Important Clinical Considerations

When NOT to Use Another SGLT2 Inhibitor

• Do not switch to empagliflozin or canagliflozin if the patient had recurrent UTIs with dapagliflozin, as all SGLT2 inhibitors share the same mechanism and UTI risk. 2, 5
• Canagliflozin data showed similar UTI patterns with small increases versus placebo. 5

Special Populations Requiring Extra Caution

• Patients with bladder outlet obstruction or incomplete bladder emptying should absolutely avoid SGLT2 inhibitors due to urinary stasis promoting infection. 4
• Elderly patients and those with recurrent UTI history are at higher baseline risk and should preferentially receive GLP-1 RAs. 4

Monitoring on GLP-1 RA Therapy

• Monitor for gastrointestinal side effects (nausea, vomiting, diarrhea), which typically improve over 4-8 weeks. 1
• Assess for pancreatitis symptoms (severe abdominal pain), though this is rare. 1
• Check renal function periodically, as GLP-1 RAs have direct beneficial effects on the kidney. 1

Cost and Access Considerations

If cost is prohibitive for GLP-1 RAs, the treatment hierarchy becomes:

1. Optimize metformin dosing first 1
2. Add a DPP-4 inhibitor (less expensive, though inferior cardiovascular benefits) 1
3. Consider basal insulin if glycemic control remains inadequate 1

However, the long-term cost savings from preventing cardiovascular events and CKD progression with GLP-1 RAs often justify the upfront medication expense. 1