The impact of the use of immunotherapy and risk of type I diabetes mellitus (TIDM) and other immune related adverse events: a population-based observational cohort study

Date of Approval
Application Number
Technical Summary

In the last twenty years, the treatment-options for multiple cancer types, have increased considerably. A group of drugs that has become a serious treatment-option for several cancer types is immunotherapy. Those drugs block specific checkpoints within the immune system, thereby increasing the activity of the body’s own immune system against the tumour. Unfortunately, this form of therapy does not come without the drawback of adverse events, mainly immune-related adverse events (for example: TIDM, hypothyroidism and hyperthyroidism). TIDM is normally diagnosed early on in life. In the literature, multiple case-reports and case-series have been published that report the occurrence of TIDM after the start of immunotherapy. In this study we will evaluate the incidence of TIDM in patients that receive immunotherapy, compared to patients with the same condition that are not exposed to immunotherapy and were diagnosed between 01-07-2011 and 31-12-2018 with non-small cell lung cancer (NSCLC), melanoma or renal cell carcinoma (RCC). This will be the primary outcome. Hypothyroidism and hyperthyroidism will be used as secondary outcome. The number of patients with a specific adverse event and the incidence rate per 1000 person years will be determined and Cox proportional hazards models and cause specific proportional hazards models will be used to calculate hazard ratios (HRs) for patients treated with immunotherapy, compared to patients that have not (yet) been exposed to immunotherapy. Furthermore, this will be evaluated for every type of immunotherapy independently. Sensitivity analyses will be performed to evaluate the influence of adjusting specific assumptions in the primary analysis.
To put the results of the primary analysis into more perspective, we also will perform data quality checks and evaluate the similarities and differences in the collected data in multiple databases in the United Kingdom, such as CPRD GOLD, CPRD Aurum, hospital episode statistics (HES) and the cancer registry.

Health Outcomes to be Measured

For the primary analysis (objective 1), the incidence of TIDM will be the primary outcome of interest, thyroid specific adverse events (hypothyroidism and hyperthyroidism) will serve as secondary outcome. For the secondary analyses (objective 2), we will evaluate concordance in registration of patient- and disease-related characteristics in multiple databases.


Patrick Souverein - Chief Investigator - Utrecht University
Patrick Souverein - Corresponding Applicant - Utrecht University
Ard van Veelen - Collaborator - Utrecht University
Frank de Vries - Collaborator - Utrecht University
Hans Petri - Collaborator - Maastricht University Medical Centre
Johanna Driessen - Collaborator - Utrecht University
Judith Gulikers - Collaborator - Utrecht University
Lizza Hendriks - Collaborator - Maastricht University Medical Centre
Olaf Klungel - Collaborator - Utrecht University
Robin van Geel - Collaborator - Maastricht University Medical Centre
Sander Croes - Collaborator - Maastricht University Medical Centre


HES Admitted Patient Care;NCRAS Cancer Registration Data;NCRAS Systemic Anti-Cancer Treatment (SACT) data