Immune checkpoint inhibitors-induced diabetes mellitus: a growing clinical presentation requiring our attention

KEYWORDS:

• Immune checkpoints
• safety
• new-onset DM
• therapy

1.

Immune checkpoints (ICs) are small molecules playing critical roles in the maintenance of immune homeostasis and tolerance through modulation of duration and amplitude of physiological immune function [1]. Immune checkpoint inhibitors (ICIs) represent an emerging class of drugs targeting different ICs like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and causing T-cell activation and subsequent antitumor activity [2]. Since 2011, the Food and Drug Administration (FDA) in the United States (US) approved numerous ICIs for inclusion in the treatment regimens of different types of malignant diseases [3].

Nonetheless, given that ICs are vital for the preservation of immunological self-tolerance, their inhibition may trigger adverse events of autoimmune origin [4]. Indeed, endocrine complications (hypophysitis, thyroid dysfunction, diabetes mellitus (DM), primary adrenal insufficiency, and autoimmune polyendocrine syndrome type 2) are among the most common adverse effects of ICIs therapy [4], and their development may also be a predictor of response to ICIs therapy [5,6]. New-onset DM is one of the potential immune-related adverse events associated with ICIs administration. It usually resembles type 1 DM (T1DM) in its pathophysiology and clinical presentation, although some individuals may present with features of type 2 DM or with worsening hyperglycemia in case of preexistent abnormal glucose tolerance or previously diagnosed DM [7].

Although its prevalence is rare, according to the meta-analysis of 40 trials, including 24,596 patients, ICIs administration is associated with a significantly increased risk of serious hyperglycemia (odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.52–3.82), DM (OR: 3.54, 95% CI: 1.32–9.51), all-grade T1DM (OR: 6.60, 95% CI: 2.51–17.30), and serious-grade T1DM (OR: 6.50, 95% CI: 2.32–18.17), compared with placebo or other therapeutic regimens [8]. A retrospective analysis of data from the US FDA Adverse Event Reporting System between 1 January 2015 and 31 December 2019 has identified 735 cases of new-onset DM associated with ICIs administration (new-onset T1DM, fulminant T1DM, diabetic ketoacidosis [DKA], or diabetic ketosis secondary to ICIs therapy) with an estimated overall incidence of 1.27% [9]. The more recent retrospective study has analyzed data of patients treated with ICIs between 2017 and 2020, using Optum’s Clinformatics Data Mart, which captures a privately insured population from a diverse group of health plans in the US [10]. It has identified 261 cases of ICIs-induced T1DM with an estimated overall incidence of 0.86% [10].

The question, then, arises how ICIs administration induces the onset of DM. Activation of the immune system mediated by ICIs is not restricted to antitumor activity, and so it may trigger immunoreactivity against pancreatic β-cells, thus mimicking T1DM. Based on the observations from the mouse models of autoimmune diabetes, PD-1 promotes islet-specific tolerance, while its inactivation is associated with autoreactive T-cell activation [10]. Indeed, patients receiving anti-PD-1 antibodies are at significantly greater risk to develop ICIs-induced DM than those prescribed to other ICIs. This has been confirmed by the analysis of the World Health Organization database of individual case safety reports, where anti-PD-1 monotherapy accounted for 76% of all cases of ICIs-induced DM [11]. On the other hand, although CTLA-4 is a negative regulator of T-cell activation, it is not expressed in pancreatic β-cells, which provides a plausible explanation why anti-CTLA-4 treatment rarely causes ICIs-induced DM [11,12].

The time from ICIs initiation to the moment of DM diagnosis varies greatly. This period ranges from 5 days after ICIs initiation to several months after their discontinuation [10]. There is also a wide spectrum of ICIs-induced DM clinical presentations: asymptomatic hyperglycemia, classical symptoms of DM (weight loss, polyuria, polydipsia, etc.), or even DKA [13]. A typical clinical scenario includes a short time period of hyperglycemia prior to DM diagnosis, verified by almost normal or only moderately elevated glycated hemoglobin, and markedly decreased C-peptide concentration, suggesting acute pancreatic β-cell destruction [14]. Therefore, it is not surprising that DKA is frequently the first presentation of ICIs-induced DM [9,10]. Thus, as a safety precaution, screening for hyperglycemia should be conducted before the initiation of ICIs therapy and repeatedly thereafter, so that treatment could be timely discontinued in the case of severe hyperglycemia development [15].

The precise pathogenesis of ICIs-induced DM is still not fully elucidated, and so timely identification of patients at increased risk for its development is vital, but remains elusive [13]. The presence of pancreatic islet-cell autoantibodies (primarily glutamic acid decarboxylase [GAD] autoantibodies), or susceptible human leukocyte antigen genotypes (e.g. DR4-DQ4) could be indicative of a greater risk. However, this is far from certain, granted that only around half of patients with ICIs-induced DM are positive for at least one pancreatic islet-cell autoantibody [15].

A special population of patients embarking on ICIs consists of patients with preexisting hyperglycemia. Indeed, ICIs treatment might lead to a progressive worsening of their glycemic control caused by rapid progression to severe insulin deficiency, which most often leave these patients dependent on life-long insulin therapy. Thus, special caution during ICIs therapy administration is essential in this group of patients.

Taking all these facts into account, oncologists need to screen for hyperglycemia prior to ICIs initiation and closely follow glycemia regularly afterward. Additionally, they should inform and educate patients and other enrolled healthcare professionals (primary care physicians, emergency medicine specialists, nurses, clinical pharmacists, etc.) about the irreversible nature and usual necessity of insulin treatment of ICIs-induced DM. Involved healthcare professionals should also be acquainted with a need of referral of these patients to oncology specialists for further treatment and assessment of suitability for ICIs therapy continuation. Finally, oncologists should work closely with diabetologists in cases of ICIs-induced DM development or worsening of preexisting hyperglycemia, which sometimes requires discontinuation of ICIs therapy (Table 1).

Table 1. Immune checkpoint inhibitors-induced diabetes mellitus: patient’s education and oncologist’s approach.

Patient education	Oncologist`s approach
Inform about the potential risk of developing immune checkpoint inhibitors-induced diabetes mellitus	Perform blood glucose and glycated hemoglobin testing prior to immune checkpoint inhibitors initiation
Explain the nature of this potential adverse effect and the high likelihood it will require life-long insulin therapy	Repeat blood glucose and glycated hemoglobin measurements regularly after immune checkpoint inhibitors initiation
Educate about the classical symptoms and signs of hyperglycemia and diabetic ketoacidosis	Consult diabetologist in cases of diabetes mellitus development or worsening of preexisting hyperglycemia
Draw attention to the possibility of deterioration of glycemic control in patients with preexisting hyperglycemia	Discontinue, at least temporarily, immune checkpoint inhibitors therapy regime in cases of severe hyperglycemia development
Emphasize the importance of regular self-monitoring of blood glucose in patients with preexisting hyperglycemia	Educate healthcare professionals about nature, treatment, and further care of immune checkpoint inhibitors-induced diabetes mellitus

In conclusion, DM is an uncommon adverse effect of ICIs therapy. It usually mimics T1DM and most often requires life-long insulin therapy. Therefore, treatment of patients receiving such therapy should, ideally, be multidisciplinary and include both oncologist and diabetologist.

Declaration of interests

DS Popovic declares associations with: Abbott, Alkaloid, AstraZeneca, Boehringer-Ingelheim, Berlin-Chemie, Eli Lilly, Galenika, Krka, Merck, Novo Nordisk, PharmaSwiss, Sanofi-Aventis, Servier, Viatris, and Worwag Pharma. T Koufakis has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, and Novo Nordisk, for advisory boards from Novo Nordisk, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk. B Kovacevic is currently a Key Account Specialist at MSD Serbia. M Rizzo is former Director, Clinical Medical & Regulatory Department, Novo Nordisk Europe East and South; he has given lectures, received honoraria and research support, and participated in conferences, advisory boards, and clinical trials sponsored by many pharmaceutical companies including Amgen, Astra Zeneca, Boehringer Ingelheim, Kowa, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Novartis, Roche Diagnostics, Sanofi, and Servier. N Papanas has been an advisory board member of TrigoCare International, Abbott, AstraZeneca, Elpen, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, and Takeda; has participated in sponsored studies by Eli Lilly, MSD, Novo Nordisk, Novartis, and Sanofi-Aventis; received honoraria as a speaker for AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Elpen, Galenica, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda, and Vianex; and attended conferences sponsored by TrigoCare International, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

DSP searched literature and wrote the first draft; TK searched literature, interpreted and edited the manuscript; BK searched literature, interpreted and edited the manuscript; MR searched literature, interpreted and edited the manuscript; NP conceived and finalized the manuscript

Additional information

Funding

This paper was not funded.