What alternative to Jardiance (Empagliflozin) can be used for a patient with type 2 diabetes without causing urinary or urinary tract infection (UTI) side effects?

Alternative to Jardiance (Empagliflozin) Without Urinary/UTI Side Effects

For patients with type 2 diabetes requiring an alternative to empagliflozin due to urinary or UTI concerns, GLP-1 receptor agonists (such as liraglutide, semaglutide, or dulaglutide) are the preferred choice, as they provide comparable cardiovascular and renal benefits without the genitourinary side effects inherent to SGLT2 inhibitors. 1

Why SGLT2 Inhibitors Cause Urinary/UTI Side Effects

• All SGLT2 inhibitors, including empagliflozin and dapagliflozin, increase urinary glucose excretion by blocking renal glucose reabsorption, which creates a glucose-rich urinary environment that promotes bacterial and fungal growth 2, 3
• Genital mycotic infections occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo, and urinary tract infections are consistently more frequent across all SGLT2 inhibitors 4, 2
• These adverse effects are mechanism-based and therefore unavoidable with any drug in this class 2, 3

Preferred Alternative: GLP-1 Receptor Agonists

GLP-1 receptor agonists should be the first-line alternative because they provide cardiovascular benefits without genitourinary side effects. 1

Cardiovascular and Renal Benefits

• GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide, exenatide once-weekly, albiglutide) have demonstrated cardiovascular benefits in outcomes trials without increasing risk of heart failure hospitalization 1
• These agents reduce major adverse cardiovascular events (MACE) and provide renal protection through mechanisms independent of urinary glucose excretion 1
• In youth with type 2 diabetes, GLP-1 receptor agonists are safe and effective for decreasing A1C and promoting weight loss at higher doses 1

Safety Profile

• The primary side effects are gastrointestinal (nausea, vomiting, diarrhea), which typically diminish over time and are unrelated to urinary tract issues 1
• GLP-1 receptor agonists should not be used in individuals with a family history of medullary thyroid cancer 1
• No increased risk of urinary tract infections or genital mycotic infections has been identified with GLP-1 receptor agonists 1

Alternative SGLT2 Inhibitor: Dapagliflozin

If an SGLT2 inhibitor is specifically required for heart failure or advanced CKD indications, dapagliflozin offers no advantage over empagliflozin regarding urinary/UTI side effects, as both share identical mechanism-based genitourinary risks. 4, 2

• Dapagliflozin has the same class-related adverse effects as empagliflozin, including genital mycotic infections and urinary tract infections 4, 3
• The frequency of these infections is comparable between all SGLT2 inhibitors due to their shared mechanism of increasing urinary glucose excretion 2, 3
• Switching from empagliflozin to dapagliflozin would not resolve urinary or UTI concerns 4, 2

DPP-4 Inhibitors as Secondary Alternative

DPP-4 inhibitors (sitagliptin, linagliptin) represent a reasonable but less preferred alternative when GLP-1 receptor agonists are contraindicated or not tolerated. 1

• DPP-4 inhibitors do not cause urinary tract infections or genital mycotic infections 1
• However, they provide neutral cardiovascular outcomes without the mortality or heart failure benefits seen with SGLT2 inhibitors or GLP-1 receptor agonists 1
• In the CARMELINA and TECOS trials, DPP-4 inhibitors showed no significant increase in heart failure hospitalization risk compared with placebo 1

Clinical Decision Algorithm

Step 1: Assess Primary Treatment Goals

• If cardiovascular risk reduction is the priority: Choose a GLP-1 receptor agonist (liraglutide, semaglutide, or dulaglutide) 1
• If heart failure with reduced ejection fraction is present: GLP-1 receptor agonists remain preferred over switching to another SGLT2 inhibitor 1
• If advanced CKD (eGFR 25-45 mL/min/1.73 m²) with albuminuria is present: GLP-1 receptor agonists can be used if eGFR >30 mL/min/1.73 m², though SGLT2 inhibitors have stronger renal-specific data 4, 5

Step 2: Evaluate Contraindications

• Check for family history of medullary thyroid cancer before prescribing GLP-1 receptor agonists 1
• Assess gastrointestinal tolerance as GLP-1 receptor agonists commonly cause nausea initially 1

Step 3: Initiate Alternative Therapy

• Start with once-weekly GLP-1 receptor agonist (semaglutide 0.25 mg weekly or dulaglutide 0.75 mg weekly) for better adherence 1
• Titrate gradually to minimize gastrointestinal side effects 1
• Continue metformin as background therapy unless contraindicated 1

Common Pitfalls to Avoid

• Do not switch to dapagliflozin or canagliflozin expecting reduced urinary/UTI side effects—all SGLT2 inhibitors share this class effect 4, 2, 3
• Do not use linagliptin as monotherapy replacement in patients with established cardiovascular disease, as it lacks the cardiovascular benefits of empagliflozin 1
• Do not overlook GLP-1 receptor agonists as the optimal alternative—they provide comparable or superior cardiovascular benefits without genitourinary risks 1