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, post-marketing studies have raised concerns that their use might be associated with an increased risk of liver injury. Accordingly, regulatory agencies have issued warning for liver injury 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 fatal nature of acute liver injuries, 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, hospitalization, and death registry data 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 SGLT-2 inhibitors, antidiabetic drugs used in the same stage of the disease, is associated with an increased risk of acute liver injury 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 SGLT-2 inhibitors, antidiabetic drugs used at a similar stage in the disease, is associated with an increased risk of acute liver injuries 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 SGLT-2 inhibitors from 1 January 2013 (the year of availability of the comparator drugs in the United Kingdom) until 31 December 2019, with follow-up until March 31, 2020. Propensity scores will be computed to determine the predicted probability of treatment with GLP-1 RAs or DPP-4 inhibitors versus SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting will then be used to estimate hazard ratios of acute liver injury, separately for GLP-1 RAs and DPP-4 inhibitors. Secondary analyses will be conducted to determine whether there is a duration-response relation, association with individual drugs, and whether the association varies by age, sex, and use of hepatotoxic 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.
Acute liver injury identified by using Read and SNOMED-CT codes as well as a liver-enzyme based definition in CPRD,1, 2 and ICD-10 codes3 in HES and ONS (definitions in Appendix 1).
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Richeek Pradhan - Collaborator - Sir Mortimer B Davis Jewish General Hospital
HES Admitted Patient Care;ONS Death Registration Data