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

  • Author / Creator
    Abdelmoneim, AS
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.