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Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature

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Abstract

Immune Check-Point Inhibitors (CPIs) have improved long-term patients’ outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs’ side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.

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Abbreviations

AGL-CPI:

Autoimmune generalized lipodystrophy induced by check-point inhibitors

Anti-GAD:

Anti-glutamic acid decarboxylase antibodies

Anti-IA2:

Islet antigen-2 antibodies

Anti-PD1:

Anti-programmed cell Death 1

CPI-DM:

Diabetes Mellitus induced by check-point inhibitors

CPI-FD:

Fulminant diabetes induced by check-point inhibitors

CPIs:

Check-point inhibitors

CR:

Complete response

CTLA-4:

Cytotoxic T Lymphocyte antigen 4

DKA:

Diabetic ketoacidosis.

DM:

Diabetes mellitus

FD:

Fulminant diabetes

HLA:

Human leukocyte antigen

IAA:

Insulin auto-antibodies

IrAEs:

Immune-related adverse events

MDI:

Multi-dose insulin

PD:

Progression disease

PD1:

Programmed cell Death 1

PD-L1:

Programmed cell Death 1 Ligand 1

PD-L2:

Programmed cell Death 1 Ligand 2

PR:

Partial response

PRISMA:

Preferred reporting items for systematic reviews and meta-analysis methods

SD:

Stable disease

T1DM:

Type 1 Diabetes Mellitus

T2DM:

Type 2 Diabetes Mellitus

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Acknowledgements

We would like to thank Anna Buganè for her contribution to this manuscript, and Adrian Wallwork for English revision (E4AC English for Academics).

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  1. Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy

    V. Lo Preiato, U. Pagotto & C. Pelusi

  2. Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy

    S. Salvagni & A. Ardizzoni

  3. Surgical Department, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, Sant’Orsola Hospital, Bologna, Italy

    C. Ricci

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Lo Preiato, V., Salvagni, S., Ricci, C. et al. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature. Rev Endocr Metab Disord 22, 337–349 (2021). https://doi.org/10.1007/s11154-020-09618-w

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