Drug-drug interactions and the risk of sulfonylurea-induced hypoglycaemia

Date of Approval: 
2020-09-16 00:00:00
Lay Summary: 
Sulfonylureas are drugs used to treat type 2 diabetes because they can lower blood sugar. A common side effect of these drugs is very low blood sugar (hypoglycaemia). This side effect can be severe and even fatal. Some drugs can interact with sulfonylureas. One example is warfarin, which is a blood thinner used to prevent stroke in patients with an abnormal heartbeat. Another example are beta blockers, which are used to lower blood pressure and to slow the heart rate. These interactions could add to the effects of sulfonylureas on lowering blood sugar. Our study will assess whether the interactions between these drugs increase the risk of hypoglycaemia among patients initiating treatment with sulfonylureas. First, we will describe the occurrence of severe hypoglycaemia when using sulfonylureas and warfarin together. The comparator will be use of sulfonylureas alone. Second, we will describe the occurrence of severe hypoglycaemia when using sulfonylureas and beta blockers together. Again, the comparator will be use of sulfonylureas alone.
Technical Summary: 
Hypoglycaemia due to the antidiabetic drug class of sulfonylureas is common and potentially severe. Drug-drug interactions involving sulfonylureas may modify the risk of this adverse event. Two commonly used medications that interact with sulfonylureas and could potentially increase the risk of sulfonylurea-induced hypoglycaemia are the oral anticoagulant warfarin and the cardiovascular drug class of beta blockers. Thus, the primary objectives of this study will be to assess (i) whether concomitant use of sulfonylureas with warfarin is associated with an increased risk of severe hypoglycaemia, and (ii) whether concomitant use of sulfonylureas with beta blockers is associated with an increased risk of severe hypoglycaemia. Secondary objectives will assess (i) the comparative risk of severe hypoglycaemia associated with concomitant use of different sulfonylureas with warfarin by classifying sulfonylureas based on their protein binding potential (relevant to the interaction with warfarin), and (ii) the comparative risk of severe hypoglycaemia associated with concomitant use of sulfonylureas with different beta blockers by classifying beta-blockers based on their cardioselectivity (relevant to their hypoglycaemic potential). We will conduct a population-based cohort study of new users of second-generation sulfonylureas using data from the Clinical Practice Research Datalink. The study period will be between April 1998 and June 2020. Severe hypoglycaemia will be defined as hospitalization with or death due to hypoglycaemia. Time-dependent Cox proportional hazards models will estimate hazard ratios and 95% confidence intervals of severe hypoglycaemia associated with concomitant use of sulfonylureas with warfarin or concomitant use of sulfonylureas with beta blockers compared with sulfonylurea use alone. The models will be adjusted for several potential confounders including proxies of disease severity of type 2 diabetes. Sensitivity analyses will address different sources of bias including various approaches (i.e., marginal structural Cox proportional hazards model, prevalent new-user design, active comparator) to account for residual confounding.
Health Outcomes to be Measured: 
Severe hypoglycaemia
Application Number: 
20_195
Collaborators: 

Samy Suissa - Chief Investigator - McGill University
Antonios Douros - Corresponding Applicant - McGill University
Christel Renoux - Collaborator - McGill University
Jenny Dimakos - Collaborator - McGill University
Kristian Filion - Collaborator - McGill University
Robert Platt - Collaborator - McGill University
Ying Cui - Collaborator - Sir Mortimer B Davis Jewish General Hospital

Linkages: 
HES Admitted Patient Care;ONS Death Registration Data