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Building Evidence to Assess a Drug Safety Signal: the Association between Sulfonylureas and Adverse Cardiovascular Events Open Access


Other title
Troponin I
Ischemic preconditioning
Binding affinity
Bradford Hill considerations
Acute coronary syndrome
Type 2 diabetes mellitus
Major adverse cardiovascular events
Type of item
Degree grantor
University of Alberta
Author or creator
Abdelmoneim, AS
Supervisor and department
Simpson, Scot (Pharmacy and Pharmaceutical Sciences)
Seubert, John (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Eurich, Dean
Brately, Richard
Light, Peter
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmacy Practice
Date accepted
Graduation date
Doctor of Philosophy
Degree level
All drugs have the potential to cause adverse events that can result in hospitalization or death. In order to protect the public health, it is critical to employ methods to detect and assess adverse drug events in a timely manner. One of the most controversial and long standing drug safety issue is the association between sulfonylureas and adverse cardiovascular events in patients with type 2 diabetes. The overall objective of this program of research was to use the cardiovascular safety signal associated with sulfonylureas as a case study to examine the application of Bradford-Hill considerations in the assessment of causal relationships. This objective was achieved through four related studies: 1) a systematic review that examined “biological plausibility” by evaluating tissue selectivity characteristics of different sulfonylureas using data from electrophysiological studies and considering the steady state concentrations of these drugs; 2) a nested case-control study that investigated “strength of association” by using provincial administrative healthcare databases to compare the effect of two commonly used sulfonylureas, gliclazide and glyburide, on risk of acute coronary syndrome; 3) a retrospective cohort study that used the same databases to evaluate the “dose-response” relationship between gliclazide and glyburide use and major adverse cardiovascular events; and 4) an observational study that relied on data from a regional ST-elevation myocardial infarction registry and examined “coherence” by extending observations from animal studies to humans with regard to the effect of sulfonylureas on infarct size. We found that individual sulfonylureas differ with respect to tissue selectivity characteristics at usual therapeutic doses, with some sulfonylureas being more selective to pancreatic receptors; while, other sulfonylureas bind non-selectively to pancreatic and cardiac receptors. These observations imply that individual sulfonylureas might differ in their ability to abolish ischemic conditioning, a protective mechanism to protect myocardium at time of acute ischemia. To confirm these findings, we found in the nested case-control study that patients using glyburide, a sulfonylurea that binds non-selectively to cardiac and pancreatic receptors, had a small but significantly higher risk of acute coronary syndrome events than patients using gliclazide, a sulfonylurea that is more selective to pancreatic receptors. We also found that patients using higher doses of glyburide had a higher risk of major adverse cardiovascular events compared to patients using lower doses of the drug. In contrast, we did not observe a dose-related difference in cardiovascular risk for gliclazide users. Finally, we demonstrated that sulfonylurea users had a larger infarct size compared to non-sulfonylurea users. However, there was no difference on infarct size between glyburide and gliclazide users, likely due to lack of adequate power in our study. These findings add further evidence that there are important differences among sulfonylureas, with gliclazide appearing to be associated with a lower risk of adverse cardiovascular events compared to glyburide. Clinicians should consider these differences when initiating sulfonylureas in type 2 diabetes patients. Further, we approached this assessment of the cardiovascular safety of sulfonylureas by evaluating elements of the Bradford-Hill considerations for casual relationships. We provided a case study on using these elements to assess causality in pharmacoepidemiology studies.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Abdelmoneim S, Hasenbank SE, Seubert JM, Brocks DR, Light PE, Simpson SH. Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Diabetes Obes Metab. 2012 Feb;14(2):130–8.Abdelmoneim AS, Eurich DT, Gamble JM, Johnson JA, Seubert JM, Qiu W, Simpson SH. Risk of acute coronary events associated with glyburide compared with gliclazide use in patients with type 2 diabetes: a nested case-control study. Diabetes Obes Metab. 2014;16(1):22–9.Abdelmoneim AS, Welsh R, Eurich DT, Simpson SH. Sulfonylurea use is associated with larger infarct size in patients with diabetes and ST-elevation myocardial infarction. Int J Cardiol. 2016;202:126-130.

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