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. Examples include warfarin, which is a blood thinner used to prevent stroke in patients with an abnormal heartbeat, beta-blockers, which are used to lower blood pressure and to slow the heart rate, dipeptidyl peptidase-4 inhibitors, which are used to lower blood sugar, and fluoroquinolones, which are antibiotics used to treat bacterial infections. 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, compared to the use of sulfonylureas alone. Second, we will describe the occurrence of severe hypoglycaemia when using sulfonylureas and beta-blockers together, compared to the use of sulfonylureas alone. Third, we will describe the occurrence of severe hypoglycaemia when using certain types of sulfonylureas and dipeptidyl peptidase-4 inhibitors together, compared to using other types of sulfonylureas and dipeptidyl peptidase-4 inhibitors together. Fourth, we will describe the occurrence of severe hypoglycaemia when using sulfonylureas and fluoroquinolones together, compared to using sulfonylureas and amoxicillin, which is another antibiotic, together.
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. Commonly used medications that interact with sulfonylureas and could potentially increase the risk of sulfonylurea-induced hypoglycaemia are warfarin, beta-blockers, and fluoroquinolones. Moreover, it is unclear whether the hypoglycaemic risk of the interaction between sulfonylureas and dipeptidyl peptidase-4 inhibitors is modified according to certain pharmacologic characteristics of sulfonylureas (duration of action) and dipeptidyl peptidase-4 inhibitors (peptidomimetic structure). To assess the risk of the respective drug-drug interactions, we will conduct several population-based cohort studies 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 confounder-adjusted hazard ratios and 95% confidence intervals of severe hypoglycaemia associated with (i) concomitant use of sulfonylureas and warfarin compared to use of sulfonylureas alone, (ii) concomitant use of sulfonylureas and beta-blockers compared to use of sulfonylureas alone, (iii) concomitant use of sulfonylureas and peptidomimetic dipeptidyl peptidase-4 inhibitors compared to concomitant use of sulfonylureas and non-peptidomimetic dipeptidyl peptidase-4 inhibitors, and (iv) concomitant use of long-acting sulfonylureas and dipeptidyl peptidase-4 inhibitors compared to concomitant use of short-acting sulfonylureas and dipeptidyl peptidase-4 inhibitors. Moreover, Cox proportional hazards models will estimate propensity score matched hazard ratios and 95% confidence intervals of severe hypoglycaemia associated with concomitant use of sulfonylureas and fluoroquinolones compared with concomitant use of sulfonylureas and amoxicillin. Sensitivity analyses will address different sources of bias including various approaches (marginal structural Cox proportional hazards model, prevalent new-user design, active comparator) to account for residual confounding.
Severe hypoglycaemia
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
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
Wanqi Wang - Collaborator - McGill University
Ying Cui - Collaborator - Sir Mortimer B Davis Jewish General Hospital
HES Admitted Patient Care;ONS Death Registration Data