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Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes
  1. Anupam Kotwal1,
  2. Candace Haddox2,
  3. Matthew Block3,
  4. Yogish C Kudva1
  1. 1 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  2. 2 Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  3. 3 Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  1. Correspondence to Dr Yogish C Kudva; kudva.yogish{at}


Objective Insulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes.

Research design and methods We reviewed 1444 patients treated with ICIs over 6 years at our cancer center, and from the 1163 patients who received programmed cell death protein 1 (PD-1) inhibitors, we identified 21 such cases, 12 of which developed new-onset insulin-dependent diabetes and 9 experienced worsening of pre-existing type 2 diabetes.

Results ICI-induced diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The median age was 61 years, and body mass index was 31 kg/m2, which are both higher than expected for spontaneous type 1 diabetes. Other immune-related adverse events occurred in 62%, the most common being immune mediated thyroid disease. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months; 67% presented with diabetic ketoacidosis and 83% with low or undetectable C-peptide. Autoantibodies were elevated in 5/7 (71%) at the time of new-onset diabetes. Diabetes did not resolve during a median follow-up of 1 year.

Conclusions PD-1 inhibitors can lead to insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes, with a frequency of 1.8 %. The underlying mechanism appears similar to spontaneous type 1 diabetes but there is a faster progression to severe insulin deficiency. Better characterization of ICI-induced diabetes will improve patient care and enhance our understanding of immune-mediated diabetes.

  • immune pathogenesis type 1 diabetes
  • islet autoimmunity
  • cancer
  • insulin deficiency
  • adult diabetes

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  • Presented at The initial abstract of this manuscript was presented at Endocrine Society’s 100th Annual Meeting and Expo, Chicago, Illinois, in March 2018, and published in Endocrine Reviews 2018;39(2).

  • Contributors AK researched the data, analyzed the data and wrote the manuscript; CH researched the data and wrote the manuscript, MB reviewed/edited the manuscript, YCK developed the research question, supervised all aspects of the project as principal investigator and reviewed/edited the manuscript.

  • Funding This work was supported by the Landow gift through the Center for Immunology and Immune Therapies, Mayo Foundation. This publication was made possible by CTSA Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH).

  • Disclaimer Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Mayo Clinic Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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