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Page 6 of 12 Sabe et al. Vessel Plus 2024;8:2 https://dx.doi.org/10.20517/2574-1209.2023.95

Figure 2. Canagliflozin and sitagliptin therapy demonstrate comparable improvements in coronary perfusion to chronically ischemic
myocardium. Perfusion expressed as mL/min/g as measured by microsphere analysis shown at rest and during pacing to
150 beats/min in pigs receiving canagliflozin (CANA, eight animals), sitagliptin (SIT, five animals), or vehicle with no drug (CON, eight
animals). **signifies a P value of less than 0.01.

Sitagliptin is associated with improved coronary microvessel density compared to canagliflozin
Sitagliptin-treated swine had improved arteriolar density (P = 0.05) and capillary density (P = 0.015) in
chronically ischemic myocardium compared to control. Compared to canagliflozin-treated swine,
sitagliptin-treated swine had improved capillary density (P = 0.022) with a trend towards improved
arteriolar density (P = 0.14). (Figure 3, complete blots are shown in Supplementary Figure 1).

Sitagliptin treatment is associated with reduced AMPK activation compared to canagliflozin in
chronically ischemic myocardium
In the ischemic myocardium of the canagliflozin-treated pigs, immunoblot experiments showed decreased
activation of AMPK in SIT-treated pigs compared to CON pigs (P = 0.019) and CANA-treated swine
(P = 0.019) as determined by the p-AMPK to AMPK ratio. Compared to canagliflozin-treated swine,
sitagliptin trended towards increased activation of eNOS (P = 0.14), without difference in activation of
ERK1/2 (P = 0.67). Both canagliflozin and sitagliptin were associated with increased expression of VE-
Cadherin compared to control (P = 0.014 for both comparisons), without differences between treatment
groups (P = 0.62). [Figures 4 and 5].

DISCUSSION
In the present study, we utilized a large animal model of CMI to compare the cardiac effects of canagliflozin,
a SGLT2i, and sitagliptin, a DPP4i. We determined that in the setting of CMI, CANA improved cardiac
function compared to SIT, with similar effects on perfusion despite improved coronary microvessel
collateralization in SIT-treated pigs. Sitagliptin was associated with reduced AMPK activation compared to
canagliflozin in chronically ischemic myocardium. These findings together highlight the differing cardiac
effects of two important classes of antihyperglycemic agents in the absence of diabetes.