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Sari et al. | Journal of Clinical and Translational Research 2024; 10(4): 246-255 253
ability to suppress β-MHC expression in wild-type rats without healthy controls in this study. Hence, we are unable to compare
Vitamin D deficiency [35]. the obtained reverse remodeling effects with those of a normal
Our study demonstrated a novel investigation into the control.
combined administration of Vitamin D and EMPA, revealing This study serves as a pilot study, establishing the groundwork
enhanced antihypertrophic and antifibrotic effects on the for future studies that will focus on specific pathways or
myocardium of diabetic rats, an area that has not been previously the activation of proteins that were not investigated in this
explored. These synergistic effects might occur because each study, namely SERCA2a/PLN, NHE1, β-hydroxybutyrate,
monotherapy targets different mechanisms of action in reducing NLRP3 inflammasome, and sirtuins. These pathways are
cardiac fibrosis and hypertrophy. Furthermore, lower Vitamin D speculated to drive the mechanism responsible for the observed
levels were observed in the DM population compared to those cardioprotective effect resulting from the combined therapy of
without it and were associated with increased HbA1c levels [11]. SGLT-2i and Vitamin D.
It is hypothesized that the accumulation of Vitamin D in the
adipose tissue of patients with T2DM reduces its availability in 5. Conclusion
circulation, whereas Vitamin D is required for facilitating gene Administration of EMPA, Vitamin D, and combination
transcription and insulin exocytosis [36,37]. therapy improved cardiac hypertrophy and fibrosis in T2DM
EMPA treatment in patients with T2DM has been reported rats. Compared to monotherapy, the combination therapy of
to transiently increase FGF-23 and decrease 1,25-dihydroxy EMPA and Vitamin D led to significantly better parameter
Vitamin D levels [38]. This observation may reflect a temporary reductions.
increase in sodium-driven phosphate reabsorption in the proximal
tubule of the kidney in response to SGLT-2 inhibition [38] After Acknowledgments
initiating the SGLT-2i, changes in fluid status have also been
observed, which is accompanied by elevated plasma renin None.
activity and serum aldosterone concentration after 30 days, Funding
suggesting increased RAAS activity, with normalization after
6 months [39]. The administration of Vitamin D was previously All authors claim no external funding or grants are associated
reported to reduce renin levels and inhibit FGF-23, both of with this research.
which contribute to cardiac hypertrophy and fibrosis [30]. Conflicts of Interest
Hence, we hypothesize that the combination of Vitamin D with
SGLT-2i administration will yield improved outcomes. The authors declare that there are no conflicts of interest
Our study concluded that the administration of EMPA, regarding the publication of this paper.
Vitamin D, and combination therapy of EMPA and Vitamin D
significantly reduced the expression of cardiac fibrosis and Ethics Approval and Consent to Participate
hypertrophy compared to untreated diabetic groups. However, This research was approved by the Ethics Commission of the
a significant reduction in parameters of cardiac hypertrophy and Faculty of Medicine, Udayana University (approval number:
fibrosis was observed (but not to the normal healthy baseline) 2395/UN14.2.2.VII.14/LT/2022).
in comparison to the untreated diabetic group. Thus, while the
treatments demonstrated efficacy in reducing these parameters Consent for Publication
relative to the diabetic control, it remains uncertain whether the
levels achieved are comparable to those in healthy subjects. Not applicable.
Further research is warranted to determine if the treatments can Availability of Data
restore cardiac health to normal levels.
We did not objectively measure the appetite, water intake, Data are available from the corresponding author on
urine output, and blood pressure of our experimental animal. reasonable request.
Hence, we were unable to evaluate the diuretic and blood
pressure-lowering effect of SGLT-2i and Vitamin D. Our References
study did not examine Vitamin D levels in rats before and [1] Bertoni AG, Hundley WG, Massing MW, Bonds DE,
after induction of DM, and after administration of treatment. Burke GL, Goff DC Jr. Heart Failure Prevalence,
Therefore, it cannot be concluded whether T2DM impacts Incidence, and Mortality in the Elderly with Diabetes.
Vitamin D blood levels and leads to secondary Vitamin D Diabetes Care 2004;27:699-703.
deficiency as the disease advances. doi: 10.2337/diacare.27.3.699
Our study also did not assess cardiac function due
to the limitation of our animal laboratory to conduct [2] Kannel WB, Hjortland M, Castelli WP. Role of Diabetes
proper echocardiographic procedures and measurements. in Congestive Heart Failure: The Framingham Study.
Consequently, we are unable to determine whether the Am J Cardiol 1974;34:29-34.
improvements in structural changes correspond to functional doi: 10.1016/0002-9149(74)90089-7
cardiac improvements. In addition, we did not include normal [3] Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M,

DOI: http://doi.org/10.36922/jctr.24.00010