Be vigilant for diabetes triggered by immune checkpoint inhibitors

Sudden and irreversible diabetes triggered by immune checkpoint inhibitors will become more common as immunotherapy becomes the standard of care in cancer therapy, endocrinologists say.

Fulminant islet autoimmunity that presents as diabetic ketoacidosis (DKA) has been considered a rare complication of anti-PD1 cancer therapies with an incidence of 0.4%. However, the ‘real world’ incidence may be higher as the treatments come into wider use, according to clinicians from the Royal Melbourne Hospital.

Writing in Diabetic Medicine, they report nine cases of life-threatening immune-mediated type 1 diabetes seen at two Melbourne centres between 2015 and 2017, which occurred within weeks of patients starting treatment with immune checkpoint inhibitors.

They say the cases of drug-induced diabetes are examples of rapid onset islet autoimmunity triggered by checkpoint inhibitors because of their mode of action to ‘release the brakes’ on the immune system to combat tumour cells.

Checkpoint inhibitors such as ipilimumab, pembrolizumab and nivolumab act on CTLA-4, PD-1, and PD-L1 pathways to activate T cell immune responses and this is linked to a range of immune related adverse effects, they note.

And while some of the immune-related adverse effects can be reversed with immunosuppression, the effects on endocrine beta cells are irreversible, according to Dr Anna Galligan and collagues of the Department of Diabetes and Endocrinology, Royal Melbourne Hospital. In their case series the patients presented within one-12 weeks of starting the first dose of checkpoint inhibitor treatment, with fulminant DKA and symptomatic hyperglycaemia that required hospital admission. HbA1c tended to be low at onset, in keeping with rapid islet destruction, allowing less time for glycoslylation of haemoglobin.

“Individuals exhibited marked glycaemic variability, with frequent episodes of hypoglycaemia despite regular insulin adjustment. This rapid onset and fulminant course implies an accelerated islet autoimmunity in contrast to the more protracted kinetics of spontaneous Type 1 diabetes in children and young adults.”

Six of the patients who had HLA typing showed high risk alleles, supporting the premise that checkpoint inhibitors may trigger an islet cell autoimmune response in some people with a specific genetic background, they said.

The report authors said they are now conducting a prospective study to investigate predictive risk factors, including pre-treatment islet antibodies and HLA status.

“The clinical utility of HLA-typing and baseline islet antibody testing to stratify risk and manage potential immune-related adverse effects remains to be prospectively evaluated,” they suggested.

In the meantime, as checkpoint inhibitors become standard of care in many tumour types they urged clinicians to anticipate an increased incidence of iatrogenic Type 1 diabetes.

“People receiving anti-PD1 therapy should receive education on recognising symptoms of hyperglycaemia to aid early presentation, “ they advised.

“Endocrinologists and oncologists need to be increasingly vigilant to ensure early recognition and prompt treatment for this life-threatening form of diabetes.“

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