Page 63 - Read Online
P. 63

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

               groups. SIT pigs had decreased 5′ adenosine monophosphate-activated protein kinase activation compared to CON
               and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group
               compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across
               groups.

               Conclusions: In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac
               function  compared  to  sitagliptin,  with  similar  effects  on  perfusion  despite  differences  in  microvascular
               collateralization.

               Keywords: Sodium-glucose cotransporter-2 inhibitor, dipeptidyl peptidase-4 inhibitor, coronary disease



               INTRODUCTION
               Longstanding coronary disease is a leading contributor to morbidity and mortality, and unfortunately,
               many patients with this disease process have poor revascularization options, leading to progressive tissue
                                                                                  [1,2]
               ischemia and subsequent myocardial adverse remodeling and heart failure . Thus, it is important to
               identify cardioprotective medical therapies that reduce and/or reverse the deleterious effects of chronic
               coronary disease and ischemia.


               There is a growing body of research and interest in antihyperglycemic drugs as cardioprotective agents
               independent of glucose control.  Two antihyperglycemic drug classes that have been investigated include
               sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i). SGLT2i
               have been shown in clinical trials to reduce the risk of cardiovascular death, stroke, and non-fatal
                                                              [3-5]
               myocardial infarction, irrespective of glucose control . These findings prompted further exploration,
               which included small animal non-diabetic animal models of acute myocardial ischemia/infarction which
                                                                             [6-8]
               showed that these agents reduce infarct size and improve cardiac function . Building on these studies, our
               lab recently demonstrated that canagliflozin, an SGLT2i, improves cardiac function and perfusion in a non-
               diabetic swine study of ameroid constrictor-induced chronic myocardial ischemia (CMI) . Likewise,
                                                                                               [9]
               another class of antihyperglycemic agents commonly used in clinical practice, DPP4i, may also have
               cardioprotective effects. Studies in murine models have shown that these agents improve infarct size and
               cardiac function [10-12] . Additionally, our lab recently demonstrated that sitagliptin, a DPP4i, improves cardiac
               perfusion via increased collateralization to chronically ischemic myocardium .
                                                                                [13]
               While previous studies have demonstrated cardiovascular benefits of SGLT2i and DPP4i individually, it is
               important to understand the comparative effects of these agents given that they are typically clinically used
               for similar indications. Some clinical trials have attempted to address this area with varied results,
               highlighting the need for more direct mechanistic studies. For example, one clinical study showed that
               among patients with diabetes and heart failure, SGLT2i was associated with reduced risk of heart failure
               hospitalization, myocardial infarction, and stroke compared to DPP4 inhibitors . Another trial comparing
                                                                                  [14]
               these agents in patients with diabetes and acute myocardial infarction found no differences in major adverse
               composite events, with improved left ventricular ejection fraction in patients receiving SGLT2i compared to
                     [15]
               DPP4i . Finally, one trial compared the effects of empagliflozin, an SGLT2i, and sitagliptin on myocardial
               perfusion reserve in patients with diabetes and coronary disease, demonstrating similarly improved
               perfusion reserve across groups . Unfortunately, direct functional and perfusion measurements are limited
                                          [16]
               in these clinical studies, with unclear mechanisms of differential cardiovascular effects. Further, all of the
               aforementioned studies focused on patients with diabetes, though the comparative effects of these agents on
               non-diabetic subjects are still poorly investigated, an important consideration given that SGLT2i are
               increasingly prescribed to non-diabetic patients with cardiovascular disease . These limitations in the
                                                                                  [17]
   58   59   60   61   62   63   64   65   66   67   68