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

Figure 5. Graphical abstract. All Yorkshire swine age 11 weeks had an ameroid constrictor placed to the left circumflex artery. Two
weeks later oral therapy was started with vehicle (“CON”, n = 8), sitagliptin (“SIT”, n = 5), or canagliflozin (“CANA”, n = 8) daily. Five
weeks after treatment cardiac functional analysis was performed and tissue was harvested for further analysis. Main findings included
improved cardiac function with CANA compared to SIT, similar improvements in perfusion with the two treatment agents, and
improved microvascular density with SIT. Possible mechanisms implicated in coronary perfusion and collateralization are also outlined.
CON: Control; SIT: sitagliptin; CANA: canagliflozin; MCP-1: monocyte chemoattractant protein 1; TGFß: tumor growth factor beta;
FGFR1: fibroblast growth factor receptor 1; ICAM 1: intercellular adhesion molecule 1.

of these agents on cardiac function and coronary microvasculature using a large animal model of chronic
myocardial ischemia.

Previous clinical trials have attempted to address the differential effects of SGLTi and DPP4i on
cardiovascular-related outcomes. Gonzalez and others retrospectively analyzed Medicare data to investigate
the differential effects of DPP4i, SGLT2i, and another class of antihyperglycemic agents, glucagon-like
peptide-1 receptor agonists, on clinical outcomes in patients with diabetes and heart failure with reduced
and preserved ejection fraction . They found that SGLT2i was associated with a reduced risk of heart
[14]
failure hospitalization compared to the other agents, with a reduced risk of MI and stroke compared to
[14]
DPP4i . This study, unfortunately, lacks clarity on the differential effects on myocardial function, an
important endpoint in evaluation of the effects of medical therapies on chronic coronary disease, given that
untreated myocardial ischemia leads to functional deterioration and heart failure. Others have attempted to
bridge this gap, with one retrospective study demonstrating improved left ventricular ejection fraction with
SGLT2i compared to DPP4i in patients with diabetes and cardiovascular disease , and another study
[29]
demonstrating concurrent SGLT2i use with metformin resulting in improved left ventricular ejection
fraction compared to concurrent DPP4i use with metformin . However, studies are lacking on the
[15]
differential effects of these agents in the absence of diabetes, an important consideration given the increased
use of these agents in non-diabetic patients given cardioprotective effects. The current study provides some
clarity in this regard with direct functional measurements using a PV catheter inserted into LV cavity. Our
findings highlight that even in non-diabetic animals, canagliflozin augments cardiac functional parameters