Studies of the bodys role in breaking down medications suggest that obesity may alter the effectiveness (the extent to which a drug achieves its intended effect) of certain medications. However, since obese individuals are not usually included in drug safety trials due to their high risk of unintended medical problems, dosage indications for medications are not tailored to each individual according to their level of obesity. Specifically, sodiumglucose cotransporter 2 inhibitors (SGLT2i), might be affected by obesity because of decreased drug distribution within the tissues. Three recent randomized controlled trials of SGLT2i showed a lower risk of cardiovascular outcomes compared to placebo. However, when comparing obese and non-obese, their results were inconsistent. The aim of this project is to examine the effect of obesity on SGLT2i treatment efficacy in a real-world setting, within an observational cohort. To accomplish this, we will compare the rates of cardiovascular events among patients using SGLT2i and patients using dipeptidyl peptidase-4 (DPP-4) inhibitors, another class of antidiabetic drugs, between 2013 and 2018. We will further compare these results across sexes, age categories, history of heart disease and SGLT2i drug classes. Our main hypothesis is that, given the potential for obesity to affect drug movement within the body, SGLT2i will be less effective in obese individuals and result in a higher risk of cardiovascular outcomes. These results will be of great importance for the treatment of diabetes and will shed light on whether precision medicine and individualized treatment are required for obese individuals with diabetes.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new class of drugs used in the treatment of type 2 diabetes. Clinical trials have suggested that SGLT2i reduce the incidence of major adverse cardiac events (MACE) among patients with type 2 diabetes and either established cardiovascular disease or at high cardiovascular risk compared with placebo. However, when comparing obese and non-obese, their results were inconsistent. In addition, studies of drug metabolism suggest that obesity may alter the efficacy of certain medications. Nevertheless, the effect of obesity on the effectiveness of SGLT2 inhibitors in a real-world setting is unknown. Our objective is therefore to examine the effect of obesity on SGLT2 treatment effectiveness in a real-world setting. Using a new-user design, we will conduct a propensity score matched analysis comparing users of SGLT2i to users of dipeptidyl peptidase-4 (DPP-4) inhibitors for the following outcomes: MACE, the individual components of MACE (myocardial infarction, ischemic stroke, cardiovascular death), hospitalization for heart failure, arrhythmia, hypoglycaemia and all-cause mortality stratified by obesity level. Cox proportional hazards models will be used to estimate adjusted hazard ratios and corresponding 95% confidence intervals of the association between SGLT2i and DPP-4 inhibitor use and cardiovascular outcomes stratified by obesity. To reduce residual confounding, we will adjust for any imbalances between matched groups. In addition, we will adjust for history of outcome in the year prior to cohort entry. In addition to investigating the effects in stratified analyses by levels of obesity, we will also examine these with continuous BMI level using cubic splines. Secondary analyses will consist of comparison of our results across categories of sex, age, history of heart disease and SGLT2i drug classes.
Major adverse cardiac events including myocardial infarction, ischemic stroke, cardiovascular death
Hospitalization for heart failure
Arrhythmia
Diabetic ketoacidosis
Hypoglycaemia
All-cause mortality
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Samy Suissa - Corresponding Applicant - Sir Mortimer B Davis Jewish General Hospital
Antonios Douros - Collaborator - McGill University
Elisabetta Patorno - Collaborator - Brigham & Women's Hospital
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Karine Suissa - Collaborator - McGill University
Laurent Azoulay - Collaborator - McGill University
Sebastian Schneeweiss - Collaborator - Aetion, Inc
HES Admitted Patient Care;ONS Death Registration Data;Practice Level Index of Multiple Deprivation