The weight loss effects of glucagon-like peptide-1 receptor agonists and the risk of breast cancer in women with type 2 diabetes

Date of ISAC Approval: 
11/02/2019
Lay Summary: 
Glucagon-like peptide-1 (GLP-1) receptor agonists are injectable drugs used in the treatment of type 2 diabetes. These drugs have been shown to have several beneficial effects, including reducing the risk of cardiovascular events, such as heart attacks, and promoting weight loss. However, there were early concerns that these drugs may be associated with an increased risk of breast cancer. While one hypothesis implicates a biological mechanism for this possible association, a competing hypothesis suggests a possible "over detection" of breast cancer by the rapid weight loss induced by these drugs. Indeed, significant weight loss might make it easier to feel a breast lump. It might also induce a behavioural change in some women, resulting in increased screening and detection of breast cancer. While the findings of a previous study supported the over detection hypothesis, it remains unknown whether the weight loss induced by GLP-1 receptor agonists is associated with an increased risk of breast cancer. Thus, this question will be investigated in a large group of women with type 2 diabetes identified in the Clinical Practice Research Datalink.
Technical Summary: 
The use of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes has markedly increased over the years, in part due to their favourable effects on cardiovascular outcomes. However, their association with breast cancer risk became a safety concern when they were initially introduced. Indeed, there were imbalances in breast cancer events with the GLP-1 receptor agonist, liraglutide, in premarketing trials which were typically of short duration. In contrast, this imbalance was no longer observed in the large LEADER trial of liraglutide that followed patients over a three-year period. While one hypothesis for these contradictory findings implicates a possible tumour promoting effect, another hypothesis implicates the rapid weight loss induced by GLP-1 agonists leading to a transient increased detection of breast cancers. Specifically, it has been shown that obese women are significantly less likely to undergo mammography screening or breast examination than women of normal weight. Thus, the rapid weight loss induced by GLP-1 receptor agonist may lead to a better detection of breast lumps and to an increased frequency and accuracy of screening. While the association between GLP-1 receptor agonists and breast cancer has been previously investigated in one observational study, it remains unclear whether the weight loss induced by these drugs has an effect on breast cancer incidence. To address this question, we will use the Clinical Practice Research Datalink to assemble a cohort of women who initiated antidiabetic drugs between January 1 2007 and December 31 2017, with follow-up until December 31 2018. Time dependent Cox proportional hazards models will be used to estimate hazard ratios and 95% confidence intervals of breast cancer, comparing GLP-1 receptor agonist maximal weight loss (<5%, 5%-10%, >10%) with dipeptidylpeptidase-4 inhibitors. Thus, this study will provide further insight on the potential weight loss effects of GLP-1 receptor agonists on the incidence of breast cancer.
Health Outcomes to be Measured: 
The primary outcome of interest is a diagnosis of breast cancer
Collaborators: 

Samy Suissa - Chief Investigator - McGill University
Blanaid Hicks - Collaborator - Queens University Belfast
Christina Santella - Collaborator - McGill University
Hui (Hoi) Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Dr Laurent Azoulay - Corresponding Applicant - McGill University
Nathaniel Bouganim - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital