Canagliflozin impedes ischemic hind-limb recovery in the setting of diabetes.

Abstract

There is a reported increased incidence of lower extremity amputations in individuals with diabetes who are treated with canagliflozin (an SGLT2 receptor inhibitor). It is unclear whether this is an unintended consequence of therapy, or whether canagliflozin can affect peripheral limb perfusion in the setting of underling arterial malperfusion. To evaluate this we explored the effect of canagliflozin on tissue recovery following unilateral hind-limb ischemia (HLI). Adult wildtype (+/+) and diabetic (db/db) mice were maintained on 8 weeks of a regular chow diet, or a chow diet containing canagliflozin (200 mg/kg). Following HLI, hind-limb appearance, function, and Doppler perfusion were serially evaluated. Gastrocnemius muscle fiber size and microvessel density were also evaluated 21 days following HLI. We observed that db/db that received a diet containing canagliflozin had significantly worse hind-limb function and appearance scores compared to both db/db mice that received a regular diet and +/+ mice that received a canagliflozin diet. At post-HLI day 21, db/db mice that received a canagliflozin diet also had decreased Doppler perfusion, gastrocnemius muscle fiber size, and microvessel density compared to +/+ mice that received a canagliflozin diet. These findings indicate that canagliflozin appears to impede ischemic peripheral tissue recovery and warrant further clinical investigation in individuals with diabetes and a history of peripheral artery disease.