Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are drugs commonly prescribed for the treatment of type 2 diabetes, a chronic condition marked by elevated blood glucose levels. Despite their favourable clinical effects, these drugs have been the subject of safety concerns since their introduction to the market, including concerns with thyroid cancer, a diseased marked by uncontrolled cell growth in the thyroid gland, the hormone-producing gland in the neck. These concerns were brought on by animal studies using rodent models that showed that exposure to GLP-1 RAs induced thyroid cancer formation. Given the biological differences between human and rodent thyroids, however, it is unclear if this effect seen in rodents can be applied to humans. To date, only two observational studies have investigated the potential association between GLP-1 RAs and thyroid cancer. However, these studies have methodological limitations and the relationship between these drugs and thyroid cancer remains unclear. Thus, the aim of this study is to assess the potential association between the use of GLP-1 RAs and the risk of thyroid cancer among patients with type 2 diabetes, using a large population-based cohort. This information will be important to better understand the safety profile of the GLP-1 RAs.
The objective of this study is to assess whether GLP-1 RAs is associated with an increased risk of thyroid cancer, compared to DPP-4 inhibitors, among patients with type 2 diabetes.
The primary analysis will be conducted with a new-user, active comparator cohort, which will consist of new users of GLP-1 RAs and new users of DPP-4 inhibitors. Cohort entry will be the date of the first prescription for a GLP-1 RA or DPP-4 inhibitor during the study period, whichever came first. Patients will be followed from cohort entry until an incident diagnosis of thyroid cancer, switch or add-on of one of the study drugs, death from any cause, end of registration with the general practice, or the end of the study period, whichever occurs first. A one-year lag period will be imposed, where thyroid cancer events occurring in the first year of follow-up will be censored as non-events.
In a secondary analysis, we will use the prevalent new-user design, which will allow us to capture all the GLP-1 RA users during the study. We will match new GLP-1 RA users to DPP-4 inhibitor users on time-conditional propensity scores in a 1:3 ratio. Patients who switched from a DPP-4 inhibitor to a GLP-1 RA will be matched to DPP-4 inhibitor users on duration of previous DPP-4 inhibitor use and propensity score. Patients in this cohort will be followed from cohort entry until an incident diagnosis of thyroid cancer, switch or add-on of a GLP-1 RA among DPP-4 inhibitor users, death from any cause, end of registration with the general practice, or the end of the study period, whichever occurs first. A one-year lag period will also be imposed.
Cox proportional hazards models will be fitted to estimate hazard ratios with 95% confidence intervals for thyroid cancer.
The primary outcome will be an incident diagnosis of thyroid cancer. It will be identified using the CPRD using Read and SNOMED-CT codes, and in the HES APC using ICD-10 codes (Appendix 1).
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
Karine Suissa - Collaborator - Brigham & Women's Hospital
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Sally Lu - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation