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Sabe et al. Vessel Plus 2024;8:2  https://dx.doi.org/10.20517/2574-1209.2023.95  Page 9 of 12

               compared to sitagliptin therapy; the latter, in fact, may result in somewhat diminished cardiac systolic
               function compared to control.

               We also investigated the differential effects of canagliflozin and sitagliptin on microvascular collateralization
               and perfusion in chronically ischemic myocardium. We found that sitagliptin, compared to canagliflozin
               therapy, improved capillary and arteriolar collateralization. Interestingly, despite these differences in
               collateralization, no notable changes were noted in myocardial coronary perfusion within ischemic
               myocardial regions between treatment groups. These findings are consistent with findings from a
               randomized clinical trial by Oh et al., who investigated the effects of empagliflozin, an SGLT2i, with
               sitagliptin on myocardial perfusion reserve in patients with coronary disease and diabetes using single-
                                                         [16]
               photon emission computed tomography imaging . Their study demonstrated improvement in myocardial
                                                                                            [16]
               perfusion reserve with both agents, but no significant difference between treatment groups . Similar to the
               limitations of comparative studies of SGLT2i and DPP4i with regard to cardiac function, there is a lack of
               studies exploring the impact of these medications in the absence of diabetes. Within the current study, our
               direct perfusion measurements using isotope-labeled microspheres demonstrated improved perfusion with
               both sitagliptin and canagliflozin therapy without notable differences between groups. We have previously
               demonstrated  improved  perfusion  with  canagliflozin  therapy  despite  a  lack  of  microvessel
                             [9]
               collateralization , which may be secondary to improvements in vasodilatory function in the coronary
               microvasculature with these agents. We have recently demonstrated that canagliflozin improves coronary
               microvascular vasodilation and decreases vasoconstriction independent of angiogenesis, possibly via
               increased pro-vasodilatory metabolite availability and gene expression . These findings may explain why
                                                                           [30]
               canagliflozin has similar improvements to perfusion as collateral-dependent improvements in perfusion
               seen with sitagliptin therapy [Figure 5].


               We utilized immunoblotting experiments to investigate some preliminary molecular pathways in order to
               determine how SGLT2i and DPP4i differentially affect chronically ischemic myocardium. Interestingly,
               though there was a trend towards increased activation of angiogenic marker eNOS in sitagliptin-treated
               compared to canagliflozin-treated swine, there were no differences in activation of angiogenic marker
               ERK1/2, or in expression of VE-cadherin between treatment groups. Therefore, there are likely alternative
               mechanisms involved in the differential collateralization response between these two agents. One important
               finding was the decreased activation of AMPK in the sitagliptin group compared to the canagliflozin group.
               AMPK plays a major role in a variety of cardiovascular functions, including metabolism, transcription,
               mitochondrial function, and contractility [31,32] . Decreased AMPK activation may, in part, contribute to
               reduced cardiac function with sitagliptin therapy compared to canagliflozin, which may offset the beneficial
               effects on perfusion.

               In this study, we focused on the effects of SGLT2i and DPP4i on myocardial function, the coronary
               microvasculature, and related molecular mechanisms. However, there are likely other mechanisms involved
               in the cardioprotective effects of these agents that have been demonstrated previously, including effects on
               inflammation, fibrosis, and metabolism [9,13,33] . All of these effects are likely independent of glucose control,
               given that these experiments were performed in animals receiving a normal diet. We have reported some of
               these effects in SGLT2i and DPP4i independently [9,13,33] , but further investigative studies comparing the
               effects of these agents on those and other pathways may provide further insight into the differential effects
               of SGLT2i and DPP4i in chronically ischemic myocardium.
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