What is the cross-sensitivity between gliflozins (sodium-glucose cotransporter 2 inhibitors), such as canagliflozin, dapagliflozin, and empagliflozin?

Cross-Sensitivity Between SGLT2 Inhibitors (Gliflozins)

The primary cross-sensitivity concern between SGLT2 inhibitors is serious hypersensitivity reactions, which are a contraindication for using any other medication in this class if a patient has previously experienced such a reaction to one SGLT2 inhibitor. 1

Hypersensitivity Reactions

• Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with SGLT2 inhibitors 1
• These reactions are listed as a contraindication in FDA labeling, meaning patients who experience a serious hypersensitivity reaction to one SGLT2 inhibitor should not receive another medication from this class 1
• In glycemic control trials, serious anaphylactic reactions, severe cutaneous adverse reactions, and angioedema were reported in 0.3% of dapagliflozin-treated patients 1

SGLT2 Inhibitor Selectivity Differences

• Different SGLT2 inhibitors have varying degrees of selectivity for SGLT2 versus SGLT1 receptors 2
• Dapagliflozin, empagliflozin, and ertugliflozin are the most selective inhibitors for SGLT2 2
• Canagliflozin has greater potential for inhibiting SGLT1 receptors compared to other agents 2
• Sotagliflozin is considered a "dual SGLT1/SGLT2 inhibitor" with the highest affinity for SGLT1 receptors 2

Common Adverse Effects Across Class

• Genital mycotic infections are consistently reported across all SGLT2 inhibitors, with higher rates in females and in patients with prior history of such infections 1
• Urinary tract infections are less common but still reported across the class 1, 3
• Volume depletion effects (particularly in patients with renal impairment, elderly patients, or those on diuretics) 2
• Euglycemic ketoacidosis risk exists with all agents in this class 2, 4

Agent-Specific Adverse Effects

• Canagliflozin has been associated with increased risk of:

  • Bone fractures 2
  • Lower limb amputations (particularly in patients with prior amputation, severe peripheral vascular disease, neuropathy, or diabetic foot ulcers) 2
  • Osteoporosis concerns 2

• No increased risk of amputation has been observed with empagliflozin or dapagliflozin to date 2

Clinical Implications

• If a patient experiences a serious hypersensitivity reaction to one SGLT2 inhibitor, all other SGLT2 inhibitors should be avoided 1
• For non-hypersensitivity adverse effects (such as genital infections or volume depletion), switching between agents within the class may be reasonable as these represent class effects rather than true cross-sensitivity 3, 5
• When considering switching between SGLT2 inhibitors due to side effects, consider the specific safety profiles:
  • Patients with history of fractures or osteoporosis may benefit from avoiding canagliflozin 2
  • Patients with peripheral vascular disease or at risk for amputation may benefit from empagliflozin or dapagliflozin rather than canagliflozin 2

Cardiovascular and Renal Benefits

• All SGLT2 inhibitors demonstrate similar cardiorenal benefits, suggesting a class effect rather than agent-specific effects 6
• The magnitude of benefit appears to correlate most strongly with baseline renal function and degree of albuminuria rather than which specific agent is used 6
• Empagliflozin, canagliflozin, and dapagliflozin all demonstrate cardiovascular benefit in patients with established cardiovascular disease 2

Practical Recommendations

• Document any hypersensitivity reactions to SGLT2 inhibitors clearly in the patient's medical record 1
• For patients who tolerate one SGLT2 inhibitor well but require switching for insurance or other reasons, cross-sensitivity for non-hypersensitivity adverse effects appears low 5, 7
• When initiating any SGLT2 inhibitor, counsel patients about class-wide adverse effects including genital mycotic infections, volume depletion, and risk of euglycemic ketoacidosis 1, 4