What can replace Farxiga (dapagliflozin) for a patient experiencing increased urination?

Replacing Farxiga Due to Increased Urination

If increased urination from Farxiga (dapagliflozin) is intolerable, switch to a GLP-1 receptor agonist (such as semaglutide or liraglutide) as the preferred alternative, particularly if the patient has cardiovascular disease, heart failure, or chronic kidney disease. 1

Understanding Why Farxiga Causes Increased Urination

• Farxiga works by blocking glucose reabsorption in the kidney's proximal tubules, forcing glucose excretion in urine—this mechanism inherently increases urinary volume and frequency 2, 3
• The increased urination is not a side effect but rather the primary mechanism of action, making it unavoidable with any SGLT2 inhibitor 2
• This osmotic diuresis effect also contributes to modest blood pressure reduction and volume depletion risk 1, 4

Primary Replacement Strategy: GLP-1 Receptor Agonists

GLP-1 receptor agonists are the preferred replacement because they provide comparable or superior cardiovascular and renal protection without causing increased urination. 1

Specific GLP-1 RA Options:

• Semaglutide (injectable) is recommended for patients with eGFR >30 mL/min/1.73 m² who need cardiovascular protection, as it has demonstrated cardiovascular risk reduction in large trials 1
• Liraglutide can be used with eGFR >30 mL/min/1.73 m² and has proven cardiovascular benefits 1
• These agents work through insulin-dependent mechanisms (enhancing insulin secretion and suppressing glucagon) rather than increasing urinary losses 1

Advantages of GLP-1 RAs Over SGLT2 Inhibitors:

• No increased urination or genital mycotic infections 1, 4
• Comparable cardiovascular death and heart failure hospitalization reduction 1
• Weight loss benefits similar to or greater than SGLT2 inhibitors 1
• Can be used in patients with recurrent urinary tract infections or urinary incontinence where SGLT2 inhibitors should be avoided 1

Alternative Replacement Options Based on Clinical Context

For Heart Failure with Reduced Ejection Fraction (HFrEF):

• Do not replace Farxiga if possible—SGLT2 inhibitors are foundational therapy for HFrEF with a 26% reduction in cardiovascular death or worsening heart failure 1
• If urination is truly intolerable, consider reducing concurrent loop diuretic doses first rather than stopping Farxiga, as the SGLT2 inhibitor's diuretic effect may allow lower traditional diuretic requirements 1, 5
• If replacement is absolutely necessary, optimize other guideline-directed medical therapy: ARNI (sacubitril/valsartan), beta-blockers, and mineralocorticoid receptor antagonists 1

For Chronic Kidney Disease with Albuminuria:

• GLP-1 receptor agonists are the clear alternative for patients with eGFR >30 mL/min/1.73 m² who cannot tolerate SGLT2 inhibitors 1, 6
• The ongoing FLOW trial is evaluating semaglutide's renal outcomes, with preliminary data suggesting renal protection 1
• Continue ACE inhibitors or ARBs for blood pressure control and albuminuria reduction if not already on these agents 1

For Type 2 Diabetes Without Heart Failure or Advanced CKD:

• GLP-1 receptor agonists remain first choice for cardiovascular protection and weight loss without increased urination 1
• DPP-4 inhibitors (such as sitagliptin or linagliptin) are an alternative if injectable therapy is refused, though they lack cardiovascular mortality benefit and provide less robust glycemic control 1
• Pioglitazone can be considered if the patient needs insulin sensitization, though it causes weight gain and fluid retention (contraindicated in heart failure) 1

Critical Pitfalls to Avoid

• Never switch from an SGLT2 inhibitor to a sulfonylurea or insulin alone in patients with established cardiovascular disease or heart failure, as you lose critical cardioprotective benefits 1
• Do not assume all SGLT2 inhibitors cause the same degree of urinary symptoms—while the mechanism is identical, individual patient tolerance varies, but switching between SGLT2 inhibitors (empagliflozin, canagliflozin) is unlikely to resolve urinary complaints 2, 3
• Assess whether urinary symptoms are truly from Farxiga or from underlying conditions such as uncontrolled diabetes with glucosuria, urinary tract infection, or benign prostatic hyperplasia before discontinuing a beneficial medication 1, 4

Practical Management Algorithm

1. First, optimize the situation before switching:

   • Reduce loop diuretic doses if patient is on concurrent diuretics 1, 5
   • Ensure patient is not volume depleted (check orthostatic vital signs) 1
   • Rule out urinary tract infection or genital mycotic infection as the primary complaint 1, 4
   • Counsel patient that urinary frequency often improves after 2-4 weeks as osmotic adaptation occurs 2

2. If symptoms persist and replacement is necessary:

   • For patients with ASCVD, heart failure, or CKD: Switch to GLP-1 receptor agonist (semaglutide or liraglutide) 1
   • For patients with HFrEF specifically: Maximize other GDMT (ARNI, beta-blocker, MRA) before considering GLP-1 RA as partial replacement 1
   • For patients with diabetes alone: GLP-1 RA remains preferred; DPP-4 inhibitor is acceptable if injections refused 1

3. Monitor after switching:

   • Check HbA1c in 3 months to ensure glycemic control maintained 1
   • Monitor cardiovascular symptoms closely in heart failure patients 1
   • Reassess eGFR and albuminuria in CKD patients within 3 months 1, 6

Special Considerations for Older Adults

• Older adults are at higher risk for volume depletion and orthostatic hypotension with SGLT2 inhibitors 1
• Urinary incontinence symptoms may worsen with SGLT2 inhibitors and should be specifically queried before and after initiation 1
• GLP-1 receptor agonists are generally well tolerated in older adults but may cause more gastrointestinal side effects (nausea, vomiting) requiring slow titration 1