Graduation Year
2024
Document Type
Thesis
Degree
M.S.
Degree Name
Master of Science (M.S.)
Degree Granting Department
Pharmacy
Major Professor
Feng Cheng, Ph.D.
Committee Member
Vijaykumar Sutariya, Ph.D.
Committee Member
Sheeba Varghese Gupta, Ph.D.
Keywords
Pharmacovigilance, Reporting Odd Ratio, SGLT2 inhibitors, Transcriptome data
Abstract
In this thesis, we explored the differential effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiovascular and renal health, utilizing both clinical data and molecular insights. Focusing on three commonly prescribed SGLT2 inhibitors—Dapagliflozin, Canagliflozin, and Empagliflozin—we employed the Food and Drug Administration Adverse Event Reporting System (FAERS) database to assess adverse events, including myocardial infarction, cardiac failure, tachycardia, acute kidney injury (AKI), renal failure, urinary tract infections, and fungal infections. This analysis was complemented by transcriptomic data from kidney cell lines treated with these drugs, processed through NCBI’s GEO2R and Limma programs, to reveal the gene expression profiles linked to these adverse outcomes. Together, this approach provided an integrative view of the cellular mechanisms and clinical risks associated with SGLT2 inhibitors, uncovering potential biomarkers and therapeutic targets such as interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α).
FAERS data revealed distinct adverse event patterns among the three drugs, suggesting that Dapagliflozin may pose a higher risk of myocardial infarction compared to Canagliflozin and Empagliflozin, raising considerations for cardiovascular safety in patient selection. On the other On the other hand, Canagliflozin showed a comparatively lower risk of cardiac failure and hypotension, but an elevated risk of AKI and renal failure, underscoring its potential impact on renal health. Additionally, Canagliflozin’s association with increased risks of urinary tract and fungal infections hints at unique genitourinary effects that may contribute to patient susceptibility to infections. This differentiation in adverse events highlights the importance of individualized treatment plans, particularly for patients with underlying cardiovascular or renal conditions.
The transcriptomic analysis provided insight into the molecular effects of SGLT2 inhibitors. particularly in relation to IL-6 and HIF-1α expression. IL-6, strongly correlated with AKI and inflammatory responses, emerged as a potential biomarker for kidney injury, especially with Canagliflozin, which showed the highest AKI risk in FAERS data. Increased IL-6 expression in Canagliflozin-treated kidney cells aligns with clinical observations, suggesting that SGLT2 Inhibitors may amplify renal inflammatory responses, contributing to AKI risk. Meanwhile, HIF- 1α, associated with hypoxic responses and cardiovascular adaptation, was upregulated following myocardial stress and ischemia, offering a mechanistic link to the observed lower cardiac failure risk with Canagliflozin. These findings support the role of HIF-1α in vascular remodeling and provide a basis for exploring it as a therapeutic target to mitigate cardiac complications from SGLT2 inhibitors. This dual-approach study ultimately underscores the value of personalized therapy in SGLT2 inhibitor prescription, balancing benefits with potential adverse effects at both the molecular and clinical levels.
Scholar Commons Citation
Ali, Rahinatu Bawah, "Analysis of Adverse Events Associated with SGLT2 Inhibitors and Molecular Mechanisms Using FAERS Database and Transcriptome Data" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10589
