Sulfonylureas are a class of medications that are commonly used in the management of type 2 diabetes. While they have several benefits, their safety is controversial. This drug class has been linked to low blood sugar levels (hypoglycaemia) and an increased risk of dying because of heart problems (cardiovascular death). This increased risk of death has been observed despite no observed increased risk of heart attacks with sulfonylureas. There is therefore a need to better understand what is causing this increased risk of dying from heart problems. The proposed study will examine the relationship between the use of sulfonylureas and heart-related rhythm disorders called arrhythmias among patients with type 2 diabetes using electronic health records that describe the use of these drugs in a real-clinical setting. We will create a cohort of all patients receiving sulfonylurea or metformin (another type of drug used to treat type 2 diabetes) as their first ever diabetes drug. We will then compare the occurrence of ventricular arrhythmias (rhythm disorders related to the heart’s ventricles) among patients prescribed sulfonylureas to that of patients prescribed metformin. We will also examine whether this relationship varies by duration of use, individual sulfonylurea drug, age, sex, severity of diabetes, and history of heart problems. Finally, we will compare the rate of cardiac arrest (when the heart stops beating), fatal ventricular arrhythmia, and sudden cardiac death (unexpected, sudden death typically caused by a rhythm problem with the heart) among patients using these two types of drugs.
Sulfonylureas are frequently used as a first‐line treatment in patients with type 2 diabetes who are intolerant or have a contraindication to metformin. While previous studies have identified an increased risk of cardiovascular death with sulfonylureas, the underlying cause of this increased risk remains unclear. Sulfonylureas are known to increase the risk of hypoglycaemia relative to other oral antidiabetic drugs. One possibility is an increased risk of fatal hypoglycaemia-induced ventricular arrhythmias. We will therefore conduct a retrospective, population-based cohort study. This cohort will include patients with type 2 diabetes in the Clinical Practice Research Datalink (CPRD) AURUM (linked to Hospital Episode Statistics and Office for National Statistics) receiving sulfonylureas or metformin as their first-ever antidiabetic drug prescription. In the primary analysis, exposure will be defined using an as-treated definition. Patients will be followed from cohort entry until an event, discontinuation of cohort entry medication, initiation of another antidiabetic drug, end of study period, or administrative censoring. For our first objective, the primary endpoint will be fatal or non-fatal ventricular arrhythmia. We will use Cox proportional hazards models to estimate hazard ratios for ventricular arrhythmia with current use of sulfonylureas relative to current use of metformin. To minimize confounding, Cox models will be inverse weighted by high-dimensional propensity scores. In secondary analyses, we will examine whether duration of use, sulfonylurea molecule, age, sex, history of cardiovascular disease, and haemoglobin (HbA1c) level modify the association between current use of sulfonylureas and the risk of ventricular arrhythmia, relative to metformin. We will also investigate rates of cardiac arrest, fatal ventricular arrhythmia, and sudden cardiac death between treatment groups. In addition, we will use a marginal structural model to examine potential mediation of the association between sulfonylurea versus metformin and the risk of ventricular arrhythmias by the occurrence of hypoglycaemia.
Our outcomes of interest include: Ventricular Arrhythmia (Fatal or Non-Fatal), Cardiac Arrest (Fatal or Non-Fatal), and Sudden Cardiac Death
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Antonios Douros - Collaborator - McGill University
Nehal Islam - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
HES Admitted Patient Care;ONS Death Registration Data