Immune checkpoint inhibitors may induce hyperglycemia, worsen insulin resistance for some
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A subset of patients with cancer who received an immune checkpoint inhibitor developed new hyperglycemia, suggesting the therapy may play a role in immune-related insulin resistance.
The immune system activation from immune checkpoint inhibitors is associated with immune-related adverse events, including adipose tissue inflammation, which has been associated with hyperglycemia and insulin resistance, Amanda Leiter, MD, an endocrinology fellow at Icahn School of Medicine at Mount Sinai, and colleagues wrote in an abstract presented at the virtual American Diabetes Association Scientific Sessions. Little is known about the prevalence of hyperglycemia after initiating immune checkpoint inhibitor therapy beyond autoimmune diabetes, Leiter said, and the researchers hypothesized that patients who experience hyperglycemia after immune checkpoint inhibitor therapy are more likely to have steroid exposure, preexisting diabetes and obesity; however, for a subset of patients, the cause of hyperglycemia is unexplained.
“Now that cancer therapies are improving and there are an increasing number of cancer survivors, it is important for endocrinologists and oncologists to identify and treat metabolic disease in patients with cancer,” Leiter told Healio. “The use of immune checkpoint inhibitors is increasing in patients with cancer, and we know that immune checkpoint inhibitors can cause an autoimmune beta-cell destruction that leads to insulin-deficient diabetes that resembles type 1 diabetes. In our patient population with diabetes, we noticed that many patients receiving immune checkpoint inhibitors were hyperglycemic, and there has not been anything reported on this phenomenon beyond severe presentations of autoimmune diabetes. We wanted to characterize the hyperglycemia to see what factors were associated with it.”
Hyperglycemia risk factors
Leiter and colleagues analyzed data from 411 adults with cancer who received immune checkpoint inhibitors between 2011 and 2017 at Mount Sinai, including 385 patients with at least three glucose measurements after initiating therapy. Hyperglycemia after initiating therapy was defined at a random glucose level of at least 200 mg/dL from immune checkpoint inhibitor initiation up to 6 months after cessation. Researchers recorded diabetes diagnosis and steroid exposure as documented in the medical record and compared patients with and without hyperglycemia after initiating immune checkpoint inhibitor therapy.
Within the cohort, 105 patients (27.3%) experienced hyperglycemia after initiating immune checkpoint inhibitor therapy.
Compared with patients who did not develop hyperglycemia after immune checkpoint inhibitor therapy, those who experienced hyperglycemia were more likely to be men (71% vs. 59%; P = .04), have preexisting diabetes (54% vs. 10%; P < .01) and have obesity (31% vs. 18%; P < .01). Among the 105 patients who experienced hyperglycemia, 59 (56%) had hyperglycemia before initiating immune checkpoint inhibitor therapy, nine (8.6%) had no available glucose data before starting therapy, and 37 (35.2%) had new-onset hyperglycemia after immune checkpoint inhibitor therapy.
Of the 37 patients with new-onset hyperglycemia after therapy, 25 (67.6%) had steroid-related hyperglycemia and none had antibody-confirmed autoimmune diabetes, Leiter said. Of the remaining 12 patients, three experienced a worsening of preexisting diabetes.
Nine patients experienced hyperglycemia after immune checkpoint inhibitor therapy and had no precipitant to explain the condition, the researchers wrote.
“We thought this was hypothesis generating, that potentially in some patients, immune checkpoint inhibitors could lead to some hyperglycemia,” Leiter said. “That is not the same as insulin-dependent type 1 diabetes, but perhaps the hyperglycemia may be related to insulitis or potentially adipose tissue inflammation, as has recently been described in case reports.”
Monitor blood glucose
The timing of hyperglycemia after immune checkpoint inhibitor initiation ranged from 4 to 107 weeks (median, 12.3 weeks), according to Leiter. Hyperglycemia resolved without intervention for five patients, she said.
“As more than one-quarter of patients on immune checkpoint inhibitor therapy had hyperglycemia, monitoring for hyperglycemia is very important, particularly in patients with risk factors like diabetes and steroid use,” Leiter said. “This is important because we know hyperglycemia can lead to worse cancer morbidity and mortality.”
As Healio previously reported, recently approved immune checkpoint inhibitor therapies are now increasingly used for a variety of cancers and other conditions, yet clinicians are only beginning to confront a range of endocrinopathies triggered by such treatments, including thyroid disease, pituitary disorders and insulin-dependent diabetes.
In a plenary presentation at the 2019 American Association of Clinical Endocrinologists annual meeting, Kevan Herold, MD, PhD, professor of immunobiology and medicine at Yale University, noted that case reports are beginning to reveal that some patients treated with checkpoint inhibitors, typically anti-PD-1 or anti-PD-L1 therapies, develop new-onset autoimmune diabetes or a “dramatic increase” in insulin requirements for patients with type 2 diabetes. In these cases, which frequently present as diabetic ketoacidosis, observed patients have rapidly progressed to having undetectable levels of C-peptide, and it does not appear that steroids will prevent the complete loss of beta-cell function, he said.
Recovery, Herold said, is rare. Emerging data suggest that the number of people affected by new-onset or worsening diabetes due to checkpoint inhibitor therapy is likely much larger than previously thought. Researchers, in turn, are working to determine predictors of insulin-dependent diabetes to better manage outcomes.
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Leiter A, et al. Characterization of immune checkpoint inhibitor-mediated hyperglycemia: Beyond insulin-dependent diabetes. Presented at: American Diabetes Association Scientific Sessions; June 12-16, 2020 (virtual meeting).
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