Objectives: Amputation rates appear to be increased in people with diabetes taking canagliflozin, an SGLT2 inhibitor. The mechanism underlying this observation is unknown. To better understand the negative consequences of canagliflozin on limb salvage, we evaluated the effects of canagliflozin on ischemic hindlimb perfusion and angiogenesis in db/db mice (a murine model for type 2 diabetes).

Methods: Adult wild type (+/+) and db/db mice were maintained on 8 weeks of regular chow diet or chow diet containing canagliflozin (200mg/kg chow). All mice underwent unilateral hindlimb ischemia via femoral artery ligation.

The appearance, use, and Doppler perfusion of hindlimbs were evaluated post-ischemia. Hindlimb gastrocnemius muscle fiber size and microvessel density were evaluated 21 days post-ischemia. One-way ANOVA was used to evaluate differences in the study endpoints between mouse genotypes and diets.

Results: db/db mice ischemic hindlimbs demonstrated significantly worse appearance and use than +/+ mice on regular and canagliflozin diets (p<.05). db/db mice on canagliflozin diet had even worse appearance and use compared to db/db mice on a regular diet (p<.05), and +/+ mice on canagliflozin diet (p<.01). At day 21 following hindlimb ischemia, db/db mice on canagliflozin diet demonstrated decreased Doppler perfusion and gastrocnemius muscle fiber size compared to db/db mice on a regular diet as well as +/+ mice on canagliflozin diet (p=.04, p=.02 and p=.04, respectively). db/db mice had significantly decreased microvessel density compared to +/+ mice on canagliflozin diet (p<.001).

Conclusions: Canagliflozin significantly decreases perfusion and muscle angiogenesis in ischemic hind-limbs, and these deleterious effects are higher in the setting of diabetes. These findings may have direct clinical relevance, and suggest that this model will be useful for identifying additional mechanisms underlying the effects of canagliflozin in peripheral arterial disease.


M. Nalugo: None. N. Harroun: None. L. Belaygorod: None. X. Jin: None. C.F. Semenkovich: None. M.A. Zayed: None.


National Institutes of Health (K08HL132060)

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