Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature

2021 ◽  
Author(s):  
V. Lo Preiato ◽  
S. Salvagni ◽  
C. Ricci ◽  
A. Ardizzoni ◽  
U. Pagotto ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Entity ◽  
Review Of The Literature

scholarly journals Diabetes mellitus secondary to treatment with immune checkpoint inhibitors

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
V. Venetsanaki ◽  
A. Boutis ◽  
A. Chrisoulidou ◽  
P. Papakotoulas
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Adverse Events ◽  
Type 1 Diabetes Mellitus ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Positive Outcome ◽  
Develop Type

Cancer immunotherapy has been one of the highlights in the advancement of cancer care. Certain immune checkpoint inhibitors bind to PD-1 on T cells and mediate an antitumour immune response. Given that immune checkpoint inhibitors are becoming part of standard care, a new class of adverse events—immune-related adverse events—has emerged.  Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in fewer than 1% of patients. We present a patient with type 1 diabetes mellitus secondary to immunotherapy, together with an overview of the associated literature. Patients who develop type 1 diabetes mellitus experience a rapid course, and diabetic ketoacidosis is commonly the presenting symptom. Insulin is currently the treatment of choice; oral antidiabetics or corticosteroids do not assist in management. Several predictive factors are under investigation, but physician awareness and prompt management are key to a positive outcome.

scholarly journals T-Lymphocyte Infiltration to Islets in the Pancreas of a Patient Who Developed Type 1 Diabetes After Administration of Immune Checkpoint Inhibitors

Diabetes Care ◽  
2019 ◽  
Vol 42 (7) ◽  
pp. e116-e118 ◽  
Author(s):  
Sho Yoneda ◽  
Akihisa Imagawa ◽  
Yoshiya Hosokawa ◽  
Megu Yamaguchi Baden ◽  
Takekazu Kimura ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Lymphocyte Infiltration

scholarly journals SAT-676 Pembrolizumab Induced Worsening Glycemic Control and DKA in Type 2 Diabetes Mellitus

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sarita Goud ◽  
Yu Yu Thar
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycemic Control ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Insulin Dependent

Abstract INTRODUCTION Pembrolizumab(Keytruda) is a humanized IgG4 anti-programmed cell death-1 (PD-1) antibody serving as an immune-checkpoint inhibitor, now approved by FDA to treat several types of cancer. Although there are few reported cases of pembrolizumab induced new onset DKA in a non diabetic patients due to its autoimmune nature, its association in worsening glycemic control and DKA in pre-existing type 2 Diabetes mellitus is not well established. CASE 79 years old female with past medical hx of DM type 2 (Hba1c 7.4 was started on metformin), COPD(on chronic steroids and trilogy machine at home), recently diagnosed with poorly differentiated adenocarcinoma of the left lung, metastasis to liver, PDL 1 positive at 99%, started on palliative chemotherapy with Keytruda, 2 weeks after the third cycle of keytruda presented to the ED for AMS. Patient noted to be very dehydrated, somnolescent and tachypnea. Labs consistent with sugars > 600, potassium 6.8, Bicarb 5, Anion gap 33, beta hydroxybutyrate 11.5 (on 7/15/19 0.6), HbA1c 9.7,(On 12/15/16 7.3, 9/25/18 6.7, 1/22/19 7.4). PH 7.31, lactate 2.4. WBC count 21.5- no infectious source identified (CXR, CT brain, UA clean). Patient was admitted for DKA and treated with IV insulin and IV fluids. After medically stable patient was discharged with Insulin regimen. Within 5 days after being discharged, patient presented to ED again with DKA with PH 7.27, Bicarb 8, anion gap 22, sugars>600, beta hydroxybuterate 13.70. Patient was Rx for DKA- after a week of hospitalization was discharged to Hospice(due to metastatic cancer) and few weeks later expired.To summarize, pt with well controlled type 2 DM on metformin presented with frequent DKA 2 weeks after treatment with third cycle of keytruda leading to worsening glycemic control in-turn making patient Insulin dependent. CONCLUSION Incidence of Type 1 DM with pembrolizumab treatment is being increasingly recognized and reported, and DKA is a common initial presentation. However we need further studies to establish the mechanism of worsening glycemic control leading to Insulin dependent and DKA in patients with pre-existing type 2 diabetes. Also, physicians should counsel patients about this potential immune related adverse effect and educate them about the symptoms of hyperglycemia and DKA. REFERENCES Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review Jeroen M K de Filette1, Joeri J Pen2, Lore Decoster3, Thomas Vissers4, Bert Bravenboer1, Bart J Van der Auwera5, Frans K Gorus5, Bart O Roep6,7, Sandrine Aspeslagh3, Bart Neyns3, Brigitte Velkeniers1 and Aan V Kharagjitsingh1,2,5,8 Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes. Anupam Kotwal1, Candace Haddox2, Matthew Block3, Yogish C Kudva1. BMJ open Diabetes and research, Vol 7, issue1.

856 Preliminary review of Diabetes Mellitus incidence in patients treated with immune checkpoint inhibitors (ICI) therapy – Roswell Park Comprehensive Cancer Center (RPCCC) experience

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A909-A909
Author(s):  
Zhen Zhang ◽  
Grazyna Riebandt ◽  
Rajeev Sharma ◽  
Lamya Hamad ◽  
Jordan Scott ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Diagnosed Diabetes ◽  
Newly Diagnosed Diabetes ◽  
New Onset

BackgroundImmune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment and has become a standard of care. There are now numerous FDA approved indications for ICIs and an increasing number of patients receiving these treatments, which has led to an increase in the risk of immune-related adverse events (irAEs) including endocrinopathies. Diabetes mellitus is a rare irAE of ICI therapy with an approximate incidence of 1-2%. There is paucity of data in literature about incidence, characteristics and possible predictive factors of ICI-induced diabetes mellitus. Due to limited data on ICI-induced diabetes, we conducted a retrospective review of patients who received ICI therapy at RPCCC and developed diabetes mellitus. The goal of this study is to report incidence and characteristics of new onset and worsening of diabetes in patients treated with ICI therapy.MethodsWe conducted a retrospective chart review of patients who received ICIs treatment from January 1st, 2010 to May 15th, 2020. We identified patients with newly diagnosed diabetes and worsening of preexisting diabetes. Newly diagnosed diabetes was defined as fasting blood glucose ≥ 126 or hemoglobin A1c (HbA1c) ≥ 6.5, random blood glucose ≥ 200 mg/dL with symptoms or 2-hour blood glucose ≥ 200 mg/dL on oral glucose tolerance test. Worsening of preexisting diabetes, defined as more than 0.5% increase in absolute HbA1c value in preceding 3-6 months or need for insulin in stable patients with diabetes on oral hypoglycemic agents. Subjects with pre-existing type 1 diabetes mellitus or on systemic corticosteroids for more than 1-week duration prior to diagnosis of diabetes mellitus were excluded.ResultsAmong 2,382 reviewed patients who received one or multiple ICIs, 15 patients developed new onset of diabetes and 12 patients experienced worsening of pre-existing Type 2 diabetes. In these 27 patients, 8 presented with diabetic ketoacidosis. Median time to new onset diabetes or worsening diabetes from ICI treatment initiation was 19 weeks, ranging from 2 to 320 weeks. Positive autoantibodies were found in 3 patients, among who 2 patients with positive Glutamic Acid Decarboxylase (GAD65) antibodies and one patient with positive insulin autoantibodies (IAA).ConclusionsThe incidence of new onset diabetes and worsening diabetes in patients treated with ICI therapy was 1.1%.Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center‘s Ethics Board, IRB ID STUDY00001278/BDR 129520.Consent exemptReferencesAzoury SC, Straughan DM, Shukla V. Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety. Curr Cancer Drug Targets 2015;15(6):452-462.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group. J Immunother Cancer 2017;5(1):95.Akturk HK, Kahramangil D, Sarwal A, Hoffecker L, Murad MH, Michels AW. Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis. Diabet Med 2019;36(9):1075-1081.

scholarly journals Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Fumi Kikuchi ◽  
Takanobu Saheki ◽  
Hitomi Imachi ◽  
Toshihiro Kobayashi ◽  
Kensaku Fukunaga ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Type 1 Diabetes ◽  
Side Effects ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Cancer Patients

Abstract Background Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). Case presentation A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. Conclusions Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.

scholarly journals Endocrine toxicity of cancer immunotherapy: clinical challenges

2021 ◽  
Author(s):  
Bliss Anderson ◽  
Daniel L Morganstein
Keyword(s):  
Type 1 Diabetes ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Thyroid Disease ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Endocrine Dysfunction ◽  
Life Threatening ◽  
The Common

Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab

2020 ◽  
pp. 107815522092154
Author(s):  
Nikhila Kethireddy ◽  
Steffi Thomas ◽  
Poorva Bindal ◽  
Prateek Shukla ◽  
Upendra Hegde
Keyword(s):  
Type 1 Diabetes ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Polymyalgia Rheumatica ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Close Monitoring ◽  
Programmed Death ◽  
Programmed Death 1

Introduction Immune agents including anti-programmed death receptor-1 and anti-cytotoxic T-lymphocyte antigen-4 have been associated with numerous immune-related complications. Pembrolizumab, a programmed death-1 inhibitor, has been associated with a number of immune-related adverse events such as pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and type 1 diabetes. Case report We present a rare case of an elderly male on pembrolizumab who suffered from four autoimmune toxicities including type 1 diabetes, pneumonitis, hypothyroidism, and polymyalgia rheumatica likely catalyzed by age-related immune activation. Management and outcome: Immunotherapy was indefinitely stopped, and patient was started on steroids for the immune-related adverse events with complete resolution of polymyalgia rheumatica. Thyroid dysfunction resolved once he started thyroid replacement therapy. His diabetes is well controlled with insulin and is followed by endocrinology. He continues on prednisone for immune-mediated pneumonitis with a good response with regular monitoring via computed tomography scans and pulmonary consultation. Discussion Few cases wherein multiple toxicities are seen within one patient are reported. Aging appears to be a risk factor for immune-related adverse events. Aging is associated with an increased incidence of autoimmunity as programmed death-1 ligand expression represents an important mechanism that tissues use to protect from self-reactive effector T cells. Programmed death-1 blockade breaks this protective mechanism and enhances autoimmune diseases. Therefore, close monitoring and extreme vigilance is warranted while using immune checkpoint inhibitors including pembrolizumab as multiple toxicities can occur within a short span of infusion, especially in elderly individuals. Prompt discontinuation and the use of a multidisciplinary team are prudent to prevent further morbidity and mortality.

scholarly journals SAT-674 Anti PD1 Induced Type 1 Diabetes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Belen Naranjo ◽  
David S Rosenthal ◽  
Salini Chellappan Kumar ◽  
Amal Shariff
Keyword(s):  
Systematic Review ◽  
Type 1 Diabetes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
C Peptide

Abstract Introduction: Pembrolizumab t is used to treat various cancers. It is associated with immune related adverse events (IRAEs) that can be life threatening [1,4]. We describe a patient who presented autoimmune Diabetes after the use of Pembrolizumab. Case: 64 y/o African American female PMHX of lung non-small cell lung cancer diagnosed in 2017 Clinical stage IV with gluteal metastasis, and dementia. Pt was referred by Oncology. The patient had a family history of Type 1 DM. and complained of dizziness, and unintentional weight loss (30 pounds) over a year. She had received 2 cycles of Pembrolizumab. The last cycle given 5 weeks before presentation to Endocrinology.Physical examination revealed cachectic female (weight 35 kg, height 147cm), dry mouth, BP 135/82, Plasma glucose 383mg%, A1c 7, negative Islet cell antibodies, positive anti-GAD, undetectableserum C-peptide. Cortisol 27, Acth 21 at 8 am and TSH 2.3. Discussion: In a systematic literature review, the early pattern of Diabetes onset with the use of checkpoint inhibitors was evaluated and on average after 4.5 treatment cycles [4].The incidence of immune checkpoint inhibitor-induced Type 1 Diabetes is estimated at 1% [3].This appeared to be earlier for the combination of anti-cytotoxic T-Lymphocyte associated antigen 4 monoclonal antibody and PD-1 therapy. The onset of β cell inflammation is often fulminant, suggested by the relatively low glycated hemoglobin levels, while C-peptide levels are usually low or undetectable at diagnosis and mostly positive GAD antibodies [5]. This side effect is predominantly found in patients exposed to blockade of the PD-1/PD-Ligand pathway. The IRAEs are primarily managed by immunosuppression with corticosteroids and discontinuation of immunotherapy except in autoimmune Diabetes which is irreversible. Physicians should be aware of and patients educated about the important multiorgan side effects since a growing number of patients are treated with checkpoint blockade.Azoury SC, Straughan DM, Shukla V. Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety. Curr Cancer Drug Targets 2015;15: 452-462Weber JS, Postow M, Lao CD, et al. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016;21:1230-40Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H,Weiss SA et al Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 2018;67(8):1471-1480de Filette JMK, Pen JJ, Decoster L, et al. Immune checkpoint inhibitors and Type 1 Diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019;181(3):363–374.Akturk HK, Kahramangil D, Sarwal A, Hoffecker L, Murad MH, Michels AW. Immune checkpoint inhibitor-induced Type 1 Diabetes: a systematic review and meta-analysis. Diabet Med. 2019;36(9):1075–1081.

Sign in / Sign up

Export Citation Format

Share Document