Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a new class of drugs used to treat type 2 diabetes. These drugs have been shown to decrease the risk of fatal and non-fatal cardiovascular outcomes (such as heart attacks, strokes, and death) in patients with type 2 diabetes in clinical trials. Despite their remarkable benefits, there have been concerns that these drugs might increase the risk of important adverse events including bladder cancer. To date, however, no studies have been conducted in the real-world setting to assess this possible association. To address this concern, we will conduct a large, international, multi-site population-based cohort study using five administrative, primary care, and insurance databases from Canada, the United Kingdom, and the United States. At each site, we will compare new users of SGLT-2 inhibitors with new users of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, two classes of drugs used at a similar stage of diabetes severity. The results from each site will then be pooled together for an overall estimate of the effect of SGLT-2 inhibitors on bladder cancer. As patients with type 2 diabetes are already at an increased risk of bladder cancer, this large international study will provide concerned stakeholders with much needed information on the safety profile of these drugs in a timely and cost-effective fashion.
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors represent the newest pharmacotherapy for the treatment of type 2 diabetes. These drugs were shown to reduce the risk of cardiovascular and mortality events in randomized controlled trials. However, their safety profile has been controversial, with evidence from pre- and post-marketing trials indicating that SGLT-2 inhibitors may be associated with an early increased risk of bladder cancer. The mechanism behind this risk may be explained by either an over-detection of prevalent bladder cancers or through tumour promotion of SGLT-2 inhibitors. To date, this possible association has not been investigated in the natural setting of clinical practice.
We will use four databases from the United States (US) and United Kingdom (UK). The UK databases will include the CPRD, which will be linked to HES APC and ONS. Linkage will allow the complete ascertainment of bladder cancer events and death, while keeping results generalizable to patients in England, Wales and across the UK. Addition of US data will increase study generalizability and power. At each site, we will identify patients newly-treated with either SGLT-2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (comparison #1), or SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors (comparison #2). We will use propensity score fine stratification to reweigh the study groups and balance study covariates. Patients will be followed from the date of their first prescription until an incident diagnosis of bladder cancer, death from any cause, end of coverage, or end of the study period, whichever occurs first. Cox proportional hazards models will be used to estimate hazard ratios of incident bladder cancer, comparing SGLT-2 inhibitors with GLP-1 receptor agonists and DPP-4 inhibitors, separately. We will conduct several analyses to assess the robustness of our findings. Site-specific estimates will be pooled using the DerSimonian and Laird random-effects models with inverse variance.
The outcome for this study is incident bladder cancer, which will be identified using Read codes (Appendix I), ICD-9 codes (Appendix II) or ICD-10 codes (Appendix III).
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Blánaid Hicks - Collaborator - Queen's University Belfast
Devin Abrahami - Collaborator - McGill University
Elisabetta Patorno - Collaborator - Brigham & Women's Hospital
Helen Tesfaye - Collaborator - Brigham & Women's Hospital
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Lysanne Campeau - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University
Sebastian Schneeweiss - Collaborator - Brigham & Women's Hospital
HES Admitted Patient Care;ONS Death Registration Data