Incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are used to treat type-2 diabetes. While they have several benefits, their safety is controversial. The results of some clinical trials, but not others, suggest that these drugs may harm kidneys. Given these conflicting data, there is a need to study this potential side effect. It is important to do so using real-world data from patients seen as part of normal clinical practice. We will study the effects of incretin-based drugs on the kidneys using the Clinical Practice Research Datalink (CPRD), linked to hospitalization data and vital statistics. In the database, we will identify all patients receiving any new antidiabetic therapy other than insulin. We will then compare the rates of adverse kidney outcomes of patients taking incretin-based drugs to those of patients taking other antidiabetic drugs. The main adverse outcome will be hospitalization for acute kidney injury (AKI). Dialysis, death from kidney disease, doubling of blood creatinine level, and worsening of albuminuria will also be studied. Kidney disease is common in diabetic patients and has poor long-term consequences. The study of the effects of antidiabetic drugs on the kidneys is therefore needed.
Recent evidence regarding the safety of incretin-based drugs on renal outcomes is conflicting. The SAVOR-TIMI 53 trial of saxagliptin and the FIGHT trial of liraglutide implicated these drugs in adverse renal events and worsened renal function, respectively. However, these safety signals were not replicated in TECOS, the EXAMINE trial found no effect of alogliptin on glomerular filtration rate or initiation of dialysis and SUSTAIN-6 observed that semaglutide reduced the rates of new or worsening nephropathy. Given these conflicting data, there is an urgent need to address the renal effects of incretin-based drugs. To meet this need, we will conduct a retrospective, population-based cohort study. We will identify all type-2 diabetic patients in the CPRD receiving a new prescription for a non-insulin antidiabetic drug (from 2007-2016) and will assign them to time-dependent exposure categories: users of DPP-4 inhibitors, users of GLP-1 agonists, users of ≥2 oral hypoglycaemic agents (OHAs), or patients on other regimens. The rates of hospitalization for AKI and other adverse kidney outcomes (i.e., dialysis, death from kidney disease, doubling of creatinine, or increase in albuminuria category) will be compared between DPP-4 inhibitor users, GLP-1 agonist users, and users of ≥2 OHAs, stratified on chronic kidney disease (CKD) history.
• Hospitalization for acute kidney injury • Initiation of dialysis • Death from renal causes • Doubling of baseline creatinine values • Worsening of albuminuria category
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Brenda R Hemmelgarn - Collaborator - University of Calgary
Dana Attar - Collaborator - McGill University
Laurent Azoulay - Collaborator - McGill University
Matthew Secrest - 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
Richeek Pradhan - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University
Samuel Igweokpala - Collaborator - McGill University
Shahrzad Salmasi - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data;Practice Level Index of Multiple Deprivation