Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are among the most used drugs in type 2 diabetes. While these treatments have been shown to have clinical benefits, findings from recent randomized controlled trials have raised concerns that their use might be associated with an increased risk of skin cancer. Accordingly, regulatory agencies have classified skin cancer as a potential risk among users of incretin-based drugs, warranting further research. Given the high prevalence of type 2 diabetes, the frequent use of incretin-based drugs, and the potentially aggressive nature of some skin cancers, studies are needed to address this concerning safety signal. To date, this association has not been examined in the real-world setting. To address this knowledge gap, we will conduct a large, population-based cohort study using primary care from the United Kingdom. We will determine whether the use of incretin-based drugs (GLP-1-RAs and DPP-4 inhibitors), when compared with the use of sulphonylureas, antidiabetic drugs used in the same stage of the disease, is associated with an increased risk of melanoma and keratinocyte carcinoma among patients with type 2 diabetes. This study will have important policy implications, providing physicians, patients, and regulatory agencies with much-needed information regarding this potential association.
We propose to conduct a study to assess whether the use of incretin-based drugs, in comparison with the use of sulphonylureas, antidiabetic drugs used at a similar stage in the disease, is associated with an increased risk of melanoma and keratinocyte carcinoma among patients with type 2 diabetes mellitus. We will assemble a cohort of patients, at least 18 years of age, who initiated incretin-based drugs or sulphonylureas from 1 January 2007 (the year of availability of the drugs in the United Kingdom) until 31 July 2019, with follow-up until 31 July 2020. Propensity scores will be computed to determine the predicted probability of treatment with GLP-1 RAs or DPP-4 inhibitors versus sulphonylureas. Cox proportional hazards models with standardized morbidity ratio weighting by the propensity scores and inverse probability of censoring weighting will then be used to estimate hazard ratios of melanoma and keratinocyte carcinoma, separately for GLP-1 RAs and DPP-4 inhibitors. Secondary analyses will be conducted to determine whether there is a duration-response relation, a dose-response relation, and whether the association varies by age, sex, use of immunosuppressive agents, and specific incretin-based drugs. Given the relatively high prevalence of type 2 diabetes, our study will address an important safety concern regarding the commonly used drugs in this patient population.
Melanoma and keratinocyte carcinoma (Read codes and SNOMED-CT concept IDs outlined in Appendix 1).
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Richeek Pradhan - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University