Type 2 diabetes is a long-term condition which results in high levels of glucose (sugar) in the blood. The condition is often associated with a higher risk of heart disease, heart-damaging events (e.g., heart attack), kidney disease, and kidney events (e.g., dialysis). Type 2 diabetes can be treated with glucose-lowering drugs such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Despite the proven effectiveness of GLP-1 RAs and SGLT2 inhibitors on the reduction of both heart-damaging events and kidney events when used separately, there has been little research into the effects on the heart and kidneys when the two drugs are used in combination. In this study, we will use anonymised electronic healthcare records to assess the risk of heart-damaging events (such as a heart attack, heart failure, stroke or death caused by damage to the heart) and serious kidney events (such as dialysis, kidney transplantation, hospitalization for kidney events) when using the GLP-1 RA-SGLT2 inhibitor combination. This study will provide a more detailed understanding on the heart- and kidney-related safety of using GLP-1 RAs and SGLT2 inhibitors in combination. This information will enable clinicians to make a more informed decision when recommending glucose-lowering drug combination therapies to patients.
Use of the combination of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors is becoming an increasingly popular treatment among patients with type 2 diabetes. While there is evidence that GLP-1 RAs and SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes when used individually, there has been little research into their potential cardiovascular and renal benefits when used in combination. Thus, the objective of this population-based cohort study is to determine whether the combination of GLP-1 RAs and SGLT-2 inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal outcomes, compared with either agent (SGLT-2 inhibitors or GLP-1 RAs) alone or in combination with other antihyperglycaemic agents. To address this objective, we will use the CPRD and linked databases (Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics databases) to create two cohorts, one for patients who initiated SGLT-2 inhibitors and added on GLP-1 RAs and one for patients who initiated GLP-1 RAs and added on SGLT-2 inhibitors. We will identify all patients, at least 18 years of age, newly-treated with an SGLT-2 inhibitor (January 1, 2013 to December 31, 2020) or GLP-1 RA (January 1, 2013 to December 31, 2020), depending on the cohort. Using a prevalent new-user design, we will match patients initiating a GLP-1 RA-SGLT2 inhibitor combination with patients continuing their SGLT2 inhibitor or GLP-1 RA treatment (depending on the analysis) on time-conditional propensity scores and duration of SGLT-2 inhibitor or GLP-1 RA before the add-on of the other drug. Cox proportional hazards models will be used to assess the risk of cardiovascular and renal outcomes, separately, comparing patients using the GLP-1 RA-SGLT2 inhibitor combination with patients using SGLT-2 inhibitors or GLP-1 RAs (depending on the analysis) alone or in combination with other antihyperglycaemic agents.
Primary outcomes:
Major adverse cardiovascular events (MACE, including myocardial infarction, ischemic stroke, and cardiovascular mortality) and serious renal outcomes (see Appendix 1)
Secondary outcomes:
Myocardial infarction; Ischemic stroke; Heart failure; Cardiovascular mortality, and all-cause mortality.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Christel Renoux - Collaborator - McGill University
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Nikita Simms-Williams - Collaborator - University of Birmingham
Nir Treves - Collaborator - The Hebrew University of Jerusalem
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Richeek Pradhan - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Sally Lu - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data