Dose-response relationship between sulfonylureas and major adverse cardiovascular events in elderly patients with type 2 diabetes

Pharmacoepidemiol Drug Saf. 2016 Oct;25(10):1186-1195. doi: 10.1002/pds.4014. Epub 2016 Apr 22.


Purpose: The objective of this study was to determine if there is a dose-response relationship between sulfonylureas and major adverse cardiovascular events (MACE).

Methods: We conducted a retrospective cohort study among elderly patients with no history of acute coronary syndrome or stroke who initiated gliclazide or glyburide therapy between 1998 and 2010. Gliclazide and glyburide users were evaluated separately, and a high-dimensional propensity score (HDPS) was used to match patients initiating therapy with a low or high dose. A time-dependent variable was used to further characterize exposure, which can change during follow-up. Cox proportional hazard regression models were used to compare the risk of MACE between low (reference) and high doses.

Results: We identified 14,213 new users of gliclazide or glyburide (mean age, 74.7 (standard deviation 6.4) years; males, 52.8%; and mean follow-up duration, 2.7 (standard deviation 2.9) years). Among gliclazide users, there was a higher risk of MACE with high compared with low dose (crude rates: 32.8 and 28.2 per 1000 person-years, respectively), but this did not reach statistical significance (HDPS-matched hazard ratio) 1.15; 95% confidence interval (0.96-1.38). For glyburide users, however, MACE occurred more frequently in the high compared with low dose (crude rates: 38.9 and 31.5 per 1000 person-years, respectively; HDPS-matched hazard ratio 1.24; 95% confidence interval 1.02-1.50).

Conclusions: Among new users of sulfonylureas, there appears to be a dose-response relationship between glyburide and MACE, but not for gliclazide. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: dose-response; major adverse cardiovascular events; pharmacoepidemiology; sulfonylureas; type 2 diabetes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / epidemiology
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Gliclazide / administration & dosage
  • Gliclazide / adverse effects*
  • Glyburide / administration & dosage
  • Glyburide / adverse effects*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects*
  • Male
  • Propensity Score
  • Proportional Hazards Models
  • Retrospective Studies
  • Sulfonylurea Compounds / administration & dosage
  • Sulfonylurea Compounds / adverse effects
  • Time Factors


  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Gliclazide
  • Glyburide