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Page 10 of 12 Sabe et al. Vessel Plus 2024;8:2 https://dx.doi.org/10.20517/2574-1209.2023.95

Study limitations
There are important limitations to consider in this study. One important limitation is the small sample size
in our large animal model, which may have underpowered our study, particularly with statistical correction
for multiple comparisons. Another limitation is in the single-time point of analysis, five weeks after
therapeutic agent initiation, which limits our understanding of the differential effects of these agents with
short- and longer-term use and may underestimate the dynamic changes that occur with time.
Additionally, to increase clinical relevance, we dosed medications based on clinically used doses, given that
the weight of pigs at the time of harvest is similar to that of a normal adult patient. However, at the time
medications are initially administered, the pigs are smaller, and doses of medications at that time may be
physiologically higher per weight than clinically relevant, which may exaggerate the molecular and
functional effects of the medications. Additionally, our small animal model utilizes adolescent Yorkshire
swine, given practical and logistical limitations to using older and larger swine; however, studies into the
effects of these antihyperglycemic agents in animal models of aging, with its associated endothelial
[34]
dysfunction and neovascularization , may provide valuable insights particularly given some promising
trials in the setting of frailty [35,36] . Finally, there are several agents within the classes of SGLT2i and DPP4i,
and we only investigated one within each class. However, the mechanistic effects of these agents within each
class may vary, and the comparison of additional agents may yield interesting results.

In summary, in the setting of CI, canagliflozin is associated with improved cardiac function compared to
sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization. These
findings indicate that despite differing specific cardiovascular effects, canagliflozin therapy may result in an
overall greater benefit in the context of CMI compared to sitagliptin treatment, though further studies on
the comparative effects of these agents may be warranted.

DECLARATIONS
Acknowledgments
We would like to thank the veterinary and animal care staff at Rhode Island Hospital for their excellent care
of the animals used in this study.

Authors’ contributions
Conceptualization; resources: Sabe SA, Abid MR, Sellke FW
Methodology: Sabe SA, Harris DD, Broadwin M, Xu CM, Abid MR, Sellke FW
Formal analysis: Sabe SA, Harris DD, Broadwin M, Xu CM, Sabra M
Data curation: Sabe SA, Harris DD, Broadwin M, Xu CM, Sabra M, Banerjee D
Writing - original draft preparation; visualization: Sabe SA
Writing - review and editing, investigation: Sabe SA, Harris DD, Broadwin M, Xu CM, Sabra M,
Banerjee D, Abid MR, Sellke FW
Supervision: Abid MR, Sellke FW
Project administration: Sellke FW
Funding acquisition: Sabe SA, Xu CM, Harris DD, Broadwin M, Abid MR, Sellke FW
All authors have read and agreed to the published version of the manuscript.

Availability of data and materials
The data that support the findings of this study are available from the corresponding author upon
reasonable request.