Concomitant Use of Sulfonylureas and Warfarin and the Risk of Severe Hypoglycemia: A Population-based Cohort Study

Background: Sulfonylurea-induced severe hypoglycemia constitutes a major safety concern during antidiabetic therapy. Warfarin can interact with sulfonylureas via different pharmacokinetic mechanisms and potentially increase their risk of hypoglycemia.

Objectives: To determine whether concomitant use of sulfonylureas and warfarin is associated with an increased risk of severe hypoglycemia compared to the use of sulfonylureas alone among patients with type 2 diabetes.

Methods: We conducted a retrospective cohort study using the United Kingdom's Clinical Practice Research Datalink, which was linked to hospitalization and vital statistics data. We included patients who initiated treatment with a second-generation sulfonylurea between April 1998 and June 2020. Severe hypoglycemia was defined as hospitalization with or death due to hypoglycemia. Using a time-varying exposure definition, we compared current concomitant use of sulfonylureas and warfarin to current use of sulfonylureas alone. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycemia, adjusted for potential confounders at cohort entry. In supplementary analyses, we used active comparators (concomitant use of sulfonylureas and antiplatelet agents; concomitant use of sulfonylureas and direct oral anticoagulants [DOACs]) as reference categories to account for residual confounding. In sensitivity analyses, we assessed the potential impact of exposure misclassification, time-dependent confounding, and competing risk due to death.

Results: Overall, 325,549 patients initiated treatment with a second-generation sulfonylurea during the study period. During a mean (standard deviation) follow-up of 8.4 (5.7) years, there were 23,039 events of severe hypoglycemia (crude incidence rate, 8.42 [95% CI, 8.31 to 8.53] per 1000 person-years). Compared with current use of sulfonylureas alone, current concomitant use of sulfonylureas and warfarin was associated with a 25% increased risk of severe hypoglycemia (HR, 1.25; 95% CI, 1.16 to 1.35). When using concomitant use of sulfonylureas and antiplatelet agents as an active comparator, the increase in the risk was slightly attenuated (HR, 1.20; 95% CI, 1.11 to 1.30). Moreover, when using concomitant use of sulfonylureas and DOACs as the active comparator, the increase in the risk disappeared entirely (HR, 1.01; 95% CI, 0.67 to 1.52). The sensitivity analyses yielded findings consistent with those of the primary analysis.

Conclusions: Compared with current use of sulfonylureas alone, current concomitant use of sulfonylureas and warfarin was associated with a modest increase in the risk of severe hypoglycemia. However, the increase in the risk is likely a result of bias.