What are the side effects of canagliflozin (SGLT2 inhibitor)?

Canagliflozin Side Effects: Clinical Considerations

Canagliflozin is associated with several important side effects, most notably genital mycotic infections, urinary tract infections, risk of lower limb amputations, and volume depletion, which require careful monitoring and management. 1

Common Side Effects

Genitourinary Infections

• Genital mycotic infections: Most common side effect, affecting approximately 10% of women and occurring at lower rates in men 2

  • Primarily candida vaginitis in women and balanitis in men
  • Usually mild to moderate in severity
  • Typically resolve with standard antifungal therapy
  • Higher risk in patients with prior history 2

• Urinary tract infections: Occur in approximately 9% of women treated with canagliflozin compared to 7% with placebo 2

  • Generally respond to standard antibiotic therapy
  • Not significantly different from placebo in large clinical trials 1

Volume-Related Effects

• Volume depletion: Due to osmotic diuresis effect 3

  • Symptoms include orthostatic hypotension, dizziness, and dehydration
  • Higher risk in elderly patients, those on diuretics, or with renal impairment 1
  • May cause clinically significant volume depletion in older adults 1

• Blood pressure reduction: Typically 3-5 mmHg systolic reduction 1

  • Can be beneficial in patients with hypertension
  • May require adjustment of antihypertensive medications

Serious Side Effects

Amputation Risk

• Lower limb amputations: Significant black box warning specific to canagliflozin 1
  • Rate of 6.3 vs 3.4 amputations per 1,000 patient-years compared to placebo
  • FDA added black box warning in May 2017
  • Increased vigilance needed in patients with:
    • History of prior amputation
    • Peripheral arterial disease
    • Neuropathy
    • Diabetic foot ulcers 1

Metabolic Complications

• Euglycemic diabetic ketoacidosis: Rare but serious complication 1

  • Can occur with normal or only moderately elevated blood glucose
  • Risk factors include insulin deficiency, reduced caloric intake, alcohol use
  • Symptoms include dyspnea, nausea, vomiting, and abdominal pain
  • Requires immediate discontinuation and medical attention 1

• Bone fractures: Increased risk observed in clinical trials 1

  • Particular concern in older adults at high fracture risk 1
  • Consider minimizing use in patients with osteoporosis

Rare but Serious Infections

• Necrotizing fasciitis of the perineum (Fournier's gangrene): Very rare but potentially life-threatening 1
  • FDA warning added based on post-marketing reports
  • 12 cases reported over 5 years among 1.7 million patients
  • Causal relationship not definitively established

Special Population Considerations

Older Adults

• Higher risk of volume depletion and hypotension 1
• Should be used cautiously in frail elderly or those prone to orthostasis 1
• Increased risk of urinary incontinence due to increased urine volume 1
• Consider fracture risk when prescribing to older adults 1

Women vs Men

• Women experience higher rates of genital mycotic infections (10% vs 3% in placebo) 2
• Women also have slightly higher rates of UTIs compared to men 1

Renal Considerations

• Favorable effects on kidney function observed in clinical trials 1
• Reduces progression of albuminuria 1
• Dose should be reduced in moderate renal impairment and discontinued in severe renal impairment 1

Management of Side Effects

For Genital Mycotic Infections

• First-line treatment: Topical antifungal agents (clotrimazole, miconazole) for 7-14 days 4
• For moderate to severe cases: Oral fluconazole 150 mg single dose 4
• Preventive measures: Good genital hygiene, keeping area dry, wearing loose cotton underwear 4
• Consider temporary discontinuation of canagliflozin for severe or recurrent infections 4

For Volume Depletion

• Monitor for signs of dehydration, especially when initiating therapy
• Consider reducing doses of concurrent diuretics
• Ensure adequate fluid intake
• Temporary discontinuation during acute illness or dehydration

Risk Mitigation

• Proper patient selection is crucial
• Regular monitoring for early detection of side effects
• Patient education regarding symptoms requiring medical attention
• Foot care and regular foot examinations for patients at risk of amputation
• Discontinue medication before major surgery or during serious illness

Benefits vs Side Effects

Despite these side effects, canagliflozin has demonstrated significant benefits including:

• Reduction in HbA1c by 0.5-1.1% 5
• Weight loss benefits 3
• Cardiovascular risk reduction 1
• Renal protection with reduced progression of kidney disease 1
• Low risk of hypoglycemia when used as monotherapy 3

The decision to use canagliflozin should carefully weigh these benefits against the potential side effects for each individual patient.