Canagliflozin is associated with an increased risk of lower limb amputations compared to other SGLT2 inhibitors. The proposed mechanism involves:

• A Unique SGLT1 intestinal inhibition reducing glucose absorption and causing hyperosmolar peripheral vasoconstriction
• B Canagliflozin-specific carbonic anhydrase inhibition causing acidosis in peripheral tissues
• C Greater hemoconcentration effect, increased LDL-C, and possible direct effects on sympathetic tone in peripheral vasculature ✓
• D Off-target inhibition of eNOS in peripheral endothelium reducing vasodilatory nitric oxide

Explanation

CANVAS trial with canagliflozin showed an approximately 2-fold increased risk of amputations vs. placebo, which was not seen to the same degree in EMPA-REG (empagliflozin) or DECLARE-TIMI (dapagliflozin). The exact mechanism remains under investigation. Proposed contributors include: greater hemoconcentration (raised hematocrit) increasing blood viscosity in already compromised peripheral vessels, adverse effects on sympathetic nervous system activity affecting peripheral vascular tone, and volume-related reductions in perfusion pressure in patients with peripheral arterial disease. Additionally, canagliflozin has dual SGLT1/SGLT2 inhibition which may have additional effects.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.