Immune Checkpoint inhibitors: Diabetes mellitus type 1 and oncological immunotherapy

Oncological treatment with PD1 or PD-L1 inhibitors can trigger type 1 diabetes. This undesirable effect usually occurs early, often accompanied by acute ketoacidosis. Current data on the issue were presented.

Many advantages - but also side effects

Treatment of oncological diseases with PD1 or PD-L1 inhibitors can trigger type 1 diabetes mellitus. This undesirable effect usually occurs early and is often accompanied by pronounced ketoacidosis. Current data on the incidence and management of this side effect were presented by Jeroen M.K. de Filette (University Hospital Brussels, Belgium), at the virtual Annual Meeting of the European Association for the Study of Diabetes in September 2020.

Immune Checkpoint inhibitors have led to a breakthrough in the treatment of many cancers in recent years. They include CTLA4 antibodies such as ipilimumab or tremelimumab, anti-PD1 antibodies such as nivolumab, pembrolizumab, or cemiplimab, and PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab.

The immune checkpoint inhibitors were initially used in malignant melanoma and lung cancer. Now they are standard for a wide range of different cancers - and the list is growing.

The substances do not act directly on the tumor, but they increase the activity of the body's own immune system to eliminate the tumor. Because of this mechanism of action, they are also associated with a different spectrum of side effects than the classic chemotherapeutic agents. Characteristic are the "immune-related adverse events" (irAEs), which can affect all organ systems.

Different irAEs with CTLA4 and PD1/PD-L1 inhibitors

A meta-analysis of 101 studies involving 19,922 patients showed that pituitary gland inflammation occurred in 5.6% of cases when treated with ipilimumab, which was more frequent than with nivolumab (0.5%) and pembrolizumab (1.1%). Among PD-1/PD-L1 inhibitors, thyroid dysfunction was more common, especially hypothyroidism (nivolumab 8.0%, pembrolizumab 8.5%).

Combined immunotherapy was also associated with a high incidence of hypothyroidism (10.2-16.4%), hyperthyroidism (9.4-10.4%), hypophysitis (8.8-10.5%), and primary adrenal cortex insufficiency (5.2-7.6%). Diabetes mellitus and adrenocortical insufficiency were less common with monotherapy.

Diabetes mellitus with immunotherapy

In a systematic review, de Filette and colleagues investigated the frequency of diabetes mellitus when treated with checkpoint inhibitors. By searching the literature, they identified 90 cases, the majority of which had been treated with a PD1 or PD-L1 inhibitor in monotherapy (79%) or in combination with a CTLA-4 inhibitor (15%). On average, diabetes occurred after 4.5 cycles, and after 2.7 cycles with combination therapy. However, very early cases were also observed.

Ketoacidosis was present in 71% of patients, and elevated lipase levels were seen in 52%. 24% of the patients also had thyroid gland disorders. Predisposing HLA alleles were detected in 65%, mostly DR4.

The therapy is primarily based on the administration of insulin to control blood sugar levels together with other supportive measures such as hydration and electrolyte correction. de Filette warned against high-dose glucocorticoids. There were indications that this would reduce the effect on the carcinoma.

The Belgian Society of Medical Oncology (BSMO) has developed an online tool with guidelines for the treatment of immuno-associated side effects of Immune Checkpoint inhibitors. It is available here.

Sources:
1. De Filette J. Autoimmune diabetes due to checkpoint inhibitors. Virtual EASD Annual Meeting 2020 S29.
2. De Filette J, et al A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors. Horm Metab Res. 2019;51:145-156. 
3. De Filette J, et al Immune Checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019;181:363-374.

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