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Expert opinion on immunotherapy induced diabetes - 18/10/18

Doi : 10.1016/j.ando.2018.07.006 
Sarra Smati a, , Perrine Buffier b, Benjamin Bouillet b, Françoise Archambeaud c, Bruno Vergès b, Bertrand Cariou a
a Department of endocrinology, l’institut du thorax, CHU Nantes, 44000 Nantes, France 
b Service d’endocrinologie, diabétologie, maladies métaboliques, CHU Dijon, hôpital François Mitterrand, 21034 Dijon cedex, France 
c Service de médecine interne B – Endocrinologie, 87042 Limoges cedex, France 

Corresponding author.

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Abstract

Immunotherapy often incurs side-effects, mainly involving the skin, digestive tract and endocrine system. The most frequent endocrine side-effects involve the pituitary and thyroid glands. Cases of insulin-dependent diabetes, whether autoimmune or not (type 1 or 1B) have been reported with PD-1/PD-L1 inhibitors, alone or in association with anti-CTLA-4 antibodies, and were systematically associated with sudden-onset insulinopenia, frequently leading to ketoacidosis or fulminant diabetes, requiring first-line insulin therapy. This adverse effect has not so far been reported with anti-CTLA-4 monotherapy.

Recommendations

R1. In patients receiving anti-PD-1 or anti-PD-L1 treatment, blood glucose should be assayed immediately in case of onset of polyuropolydipsic syndrome, weight loss or clinical signs of ketoacidosis, with HbA1c assay in case of pathologic findings. Anti-GAD antibodies should be screened for in first line, to establish the auto-immune origin of the diabetes; if absent, anti-IA2 and anti-ZnT8 antibodies may be screened for. Blood lipase should be assayed in clinical fulminant diabetes. Pancreatic imaging is not indicated at diagnosis.
R2. As anti-PD-1/PD-L1-induced diabetes may be fulminant, with severe insulinopenia, emergency first-line multi-injection insulin therapy should be initiated, with treatment and education in a specialized center or by a mobile diabetology team. The HbA1c target is<8.0%. There are no other treatment options for immunotherapy-induced diabetes.
R3. Onset of diabetes under anti-PD-1 or anti-PD-L1 immunotherapy does not contraindicate continuation of treatment, although it may be interrupted for a few days in severe situations.
R4. Systematic fasting glucose and HbA1C assay is recommended ahead of any anti-PD-1 or anti-PD-L1 immunotherapy, to screen for pre-existing diabetes, defined by fasting glucose>1.26g/L, and/or glycemia>2g/L at any time of day in case of polyuria, and/or HbA1C6.5%.
R5. Education should be ensured for patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy, to recognize inaugural symptoms of diabetes (polyuropolydipsic syndrome, weight loss) or ketoacidosis (vomiting, digestive disorder).
R6. In patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy, fasting glucose should be assayed at each course of treatment during the first 3 months, then every 3 months or urgently in case of onset of clinical signs.
R7. In case of diabetes pre-existing anti-PD-1 or anti-PD-L1 immunotherapy, glucose self-monitoring may be proposed or reinforced if already implemented.
R8. In view of the definitive nature of the induced diabetes, treatment and monitoring should be continued after the end of immunotherapy.
R9. Glucose monitoring is not recommended in anti-CTLA-4 therapy without associated anti-PD-1/PD-L1.

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Vol 79 - N° 5

P. 545-549 - Ottobre 2018 Ritorno al numero
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