A Patient with Atezolizumab-Induced Autoimmune Diabetes Mellitus Presenting with Diabetic Ketoacidosis
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Vol. 6 No. 1 (2021) 45–50
Cardiovascular Innovations and Applications ISSN 2009-8618
DOI 10.15212/CVIA.2021.0007
CASE REPORT
A Patient with Atezolizumab-Induced
Autoimmune Diabetes Mellitus Presenting with
Diabetic Ketoacidosis
Sharen Lee1 and Gary Tse, PhD, FACC, FRCP1,2,3
1
Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, HKG, China
2
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute
of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China
3
Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, 361015, China
Received: 22 November 2020; Revised: 16 January 2021; Accepted: 1 February 2021
Abstract
Background: Atezolizumab, an immune checkpoint inhibitor, is a humanized monoclonal, anti-programmed death
ligand 1 (PD-L1) antibody used for the treatment of metastatic urothelial carcinoma that has progressed after chemo-
therapy.
Case Presentation: We describe a patient with a known history of urothelial carcinoma who presented with dia-
betic ketoacidosis 6 weeks following his second cycle of atezolizumab. His serum lactate level was slightly elevated
(2 mM) and his β-hydroxybutyrate level was elevated (3.9 mM). High anion gap metabolic acidosis secondary to dia-
betic ketoacidosis was diagnosed. Subsequent testing demonstrated hemoglobin A1c level of 9.9%, positivity for anti-
glutamic acid decarboxylase antibody (0.03 nM, reference range46 S. Lee and G. Tse, Atezolizumab-Induced Autoimmune Diabetes Mellitus
by the US Food and Drug Administration as second- Table 2 Laboratory Test Results at Presentation.
line treatment for advanced urothelial carcinoma [2].
Although immune checkpoint inhibitors are gener- Test (reference range) Value on admission
ally well tolerated compared with traditional chem- Hemoglobin (13.2–17.2 g/dL) 14.1 g/dL
otherapy, they can produce immune-related toxic Mean cell volume (83.0–98.0 fL) 93.9 fL
effects [3]. PD-L1 inhibitors are recognized to cause White blood cell count 10.4 × 109/L
thyroid problems but are now known to induce auto- ((4.0–9.7) × 109/L)
immune diabetes. In this report, we describe a patient Platelet count 380 × 109/L
((150–384) × 109/L)
with a known history of urothelial carcinoma who
Hemoglobin A1c (≤6.5%) 9.9%
presented with diabetic ketoacidosis 6 weeks follow-
Serum osmolality 316 mOsm/kg
ing his second cycle of atezolizumab. (275–295 mOsm/kg)
Serum lactate (S. Lee and G. Tse, Atezolizumab-Induced Autoimmune Diabetes Mellitus 47
His initial management included cessation of diabetes who was given the anti-PD-L1 antibody
atezolizumab treatment, intravenous sodium chlo- durvalumab and developed diabetic ketoacidosis
ride administration, and insulin pump infusion, 4 months later [26]. Here we report, to the best
after which metabolic acidosis gradually resolved. of our knowledge, the first case in an Asian male
Insulin pump was subsequently switched to patient and the fifth case published thus far showing
Protaphane at 18 units before breakfast and 8 units that atezolizumab can precipitate diabetic ketoaci-
before dinner, together with metformin at 1000 mg dosis. Our patient had a history of transitional cell
twice daily. Four weeks later his medication was carcinoma of the renal pelvis and presented with
changed to human isophane insulin plus neutral full diabetic ketoacidosis 6 weeks after his second
insulin (70%/30%; Mixtard 30 HM; 26 units/4 cycle of atezolizumab. His C-peptide level was low,
units). Linagliptin at 5 mg was added 1 month later. consistent with type 1 diabetes mellitus.
His HbA1c level declined to 8.1% 1 year later. Of the previous 33 cases, 31 patients under-
went autoantibody testing, of whom 18 showed
positive results. Our patient was positive for anti-
Discussion glutamic acid decarboxylase antibody, albeit only
at a low level of 0.03 nM (reference range48 S. Lee and G. Tse, Atezolizumab-Induced Autoimmune Diabetes Mellitus
leads to the development of tolerance. By contrast, This is supported by experimental observations
when either protein is inhibited, autoreactive T cells that PD-L1-driven tolerance reverses diabetes in
are relieved from inhibition and can induce cell nonobese diabetic (NOD) mice, a model for auto-
death of the islet cells, leading to the development immune type 1 diabetes [36]. There thus appears to
of autoimmune diabetes. Significantly, the available be a balance of risk of cancer on the one hand and
evidence suggests that even after discontinuation risk of diabetes on the other. Indeed, epidemiology
of immunotherapy, insulin therapy was required, studies clearly demonstrate the high rates of can-
which would indicate that the diabetes is irrevers- cer and type 2 diabetes in developing areas where
ible [24]. In our case, the patient required long-term autoimmune type 1 diabetes is rare.
insulin therapy with adjunct hypoglycemic agents,
which led to a decline of HbA1c level from 9.9%
to 8.1% 1 year later. These findings are in keeping Conclusion
with the notion of irreversible pancreatic damage.
PD-L1 inhibitors, like PD-1 inhibitors, can induce
The use of experimental animal models has pro-
type 1 diabetes, and patients can present with dia-
vided some insights into possible mechanistic path-
betic ketoacidosis. Blood glucose levels should be
ways. Thus, Pdcd1−/− mice, which are deficient in
regularly monitored in patients who are prescribed
PD-1, demonstrate an accelerated onset and fre-
these medications.
quency of type 1 diabetes [32]. These findings are
consistent with the notion that PD-1/PD-L1 interac-
tions are important for the regulation of autoreactive Consent for Publication
T-lymphocyte responses by mediating peripheral
tolerance [33], which suppresses diabetes. Indeed, Written informed consent was obtained from the
clinical studies have reported the association patient for publication of this case.
between PD-L1 gene haplotype [34], its polymor-
phisms, and low serum PD-L1 levels [35] and type
1 diabetes. Together these findings demonstrate the Conflicts of Interest
importance of PD-1/PD-L1 pathways in pancreatic
None declared.
cell function and that treatment modalities targeting
these proteins can exert adverse effects on glucose
control, thereby precipitating or inducing diabetes. Author Contributions
Thus, activating the PD-1 pathway may help to
induce immune tolerance and prevent type 1 dia- Both authors drafted and critically revised the man-
betes but increase the risk of cancer or metastasis. uscript and approved the final version.
References
1. Rosenberg JE, Hoffman-Censits J, for the treatment of patients with 4. Pedoeem A, Azoulay-Alfaguter
Powles T, van der Heijden MS, Balar progressive advanced urothelial I, Strazza M, Silverman GJ, Mor
AV, Necchi A, et al. Atezolizumab in carcinoma after platinum-con- A. Programmed death-1 pathway
patients with locally advanced and taining chemotherapy. Oncologist in cancer and autoimmunity. Clin
metastatic urothelial carcinoma who 2017;22:743–9. Immunol 2014;153:145–52.
have progressed following treat- 3. Zhou J, Tse G, Wang X, Lakhani I, 5. Atkins MB, Clark JI, Quinn DI.
ment with platinum-based chemo- Lee S, Yang L, et al. Adverse car- Immune checkpoint inhibitors in
therapy: a single-arm, multicentre, diovascular complications follow- advanced renal cell carcinoma:
phase 2 trial. Lancet 2016;387: ing prescription of programmed cell experience to date and future
1909–20. death 1 (PD-1) and programmed cell directions. Ann Oncol 2017;28:
2. Ning YM, Suzman D, Maher VE, death ligand 1 (PD-L1) inhibitors. 1484–94.
Zhang L, Tang S, Ricks T, et al. FDA medRxiv 2020. https://doi.org/10.1 6. Godwin JL, Jaggi S, Sirisena I,
approval summary: atezolizumab 101/2020.12.21.20248648. Sharda P, Rao AD, Mehra R, et al.S. Lee and G. Tse, Atezolizumab-Induced Autoimmune Diabetes Mellitus 49
Nivolumab-induced autoimmune presentation, management and out- inhibitor-induced type 1 diabe-
diabetes mellitus presenting as come. Cancer Immunol Immunother tes. Cancer Immunol Immunother
diabetic ketoacidosis in a patient 2016;65:765–7. 2017;66:25–32.
with metastatic lung cancer. J 16. Gaudy C, Clevy C, Monestier S, 24. Gauci M-L, Boudou P, Baroudjian
Immunother Cancer 2017;5:40. Dubois N, Preau Y, Mallet S, et al. B, Vidal-Trecan T, Da Meda L,
7. Aleksova J, Lau PKH, Soldatos Anti-PD1 pembrolizumab can induce Madelaine-Chambrin I, et al.
G, McArthur G. Glucocorticoids exceptional fulminant type 1 diabe- Occurrence of type 1 and type 2
did not reverse type 1 diabetes tes. Diabetes Care 2015;38:e182–3. diabetes in patients treated with immu-
mellitus secondary to pembroli- 17. Miyoshi Y, Ogawa O, Oyama Y. notherapy (anti-PD-1 and/or anti-
zumab in a patient with meta- Nivolumab, an anti-programmed CTLA-4) for metastatic melanoma: a
static melanoma. BMJ Case Rep cell death-1 antibody, induces ful- retrospective study. Cancer Immunol
2016;2016:bcr2016217454. minant type 1 diabetes. Tohoku J Immunother 2018;67:1197–208.
8. Hofmann L, Forschner A, Loquai C, Exp Med 2016;239:155–8. 25. Kapke J, Shaheen Z, Kilari D,
Goldinger SM, Zimmer L, Ugurel 18. Hickmott L, De La Pena H, Turner Knudson P, Wong S. Immune
S, et al. Cutaneous, gastrointestinal, H, Ahmed F, Protheroe A, Grossman checkpoint inhibitor-associated
hepatic, endocrine, and renal side- A, et al. Anti-PD-L1 atezolizumab- type 1 diabetes mellitus: case series,
effects of anti-PD-1 therapy. Eur J induced autoimmune diabetes: a review of the literature, and opti-
Cancer 2016;60:190–209. case report and review of the litera- mal management. Case Rep Oncol
9. Okamoto M, Okamoto M, Gotoh ture. Target Oncol 2017;12:235–41. 2017;10:897–909.
K, Masaki T, Ozeki Y, Ando H, 19. Gauci ML, Laly P, Vidal-Trecan T, 26. Way J, Drakaki A, Drexler A,
et al. Fulminant type 1 diabetes Baroudjian B, Gottlieb J, Madjlessi- Freeby M. Anti-PD-L1 therapy
mellitus with anti-programmed cell Ezra N, et al. Autoimmune diabetes and the onset of diabetes mel-
death-1 therapy. J Diabetes Investig induced by PD-1 inhibitor-retro- litus with positive pancreatic
2016;7:915–8. spective analysis and pathogenesis: autoantibodies. BMJ Case Rep
10. Teramoto Y, Nakamura Y, Asami Y, a case report and literature review. 2017;2017:bcr2017220415.
Imamura T, Takahira S, Nemoto M, Cancer Immunol Immunother 27. Kotwal A, Haddox C, Block M,
et al. Case of type 1 diabetes asso- 2017;66:1399–410. Kudva YC. Immune checkpoint
ciated with less-dose nivolumab 20. Lowe JR, Perry DJ, Salama AK, inhibitors: an emerging cause of insu-
therapy in a melanoma patient. J Mathews CE, Moss LG, Hanks BA. lin-dependent diabetes. BMJ Open
Dermatol 2017;44:605–6. Genetic risk analysis of a patient Diabetes Res Care 2019;7:e000591.
11. Munakata W, Ohashi K, Yamauchi with fulminant autoimmune type 1 28. Youssef N, Noureldein M, Daoud
N, Tobinai K. Fulminant type I diabetes mellitus secondary to com- G, Eid AA. Immune checkpoint
diabetes mellitus associated with bination ipilimumab and nivolumab inhibitors and diabetes: mechanisms
nivolumab in a patient with relapsed immunotherapy. J Immunother and predictors. Diabetes Metab
classical Hodgkin lymphoma. Int J Cancer 2016;4:89. 2020;30:101193.
Hematol 2017;105:383–6. 21. Usui Y, Udagawa H, Matsumoto 29. Luo X, Herold KC, Miller SD.
12. Hughes J, Vudattu N, Sznol M, S, Imai K, Ohashi K, Ishibashi M, Immunotherapy of type 1 diabetes:
Gettinger S, Kluger H, Lupsa B, et al. et al. Association of serum anti- where are we and where should
Precipitation of autoimmune diabe- GAD antibody and HLA haplotypes we be going? Immunity 2010;32:
tes with anti-PD-1 immunotherapy. with type 1 diabetes mellitus trig- 488–99.
Diabetes Care 2015;38:e55–7. gered by nivolumab in patients with 30. Fife BT, Pauken KE. The role of the
13. Mellati M, Eaton KD, Brooks- non-small cell lung cancer. J Thorac PD-1 pathway in autoimmunity and
Worrell BM, Hagopian WA, Martins Oncol 2017;12:e41–3. peripheral tolerance. Ann N Y Acad
R, Palmer JP, et al. Anti-PD-1 and 22. Ishikawa K, Shono-Saito T, Yamate Sci 2011;1217:45–59.
anti-PDL-1 monoclonal antibodies T, Kai Y, Sakai T, Shimizu F, et al. 31. Schuster C, Brosi H, Stifter K,
causing type 1 diabetes. Diabetes A case of fulminant type 1 diabetes Boehm BO, Schirmbeck R. A miss-
Care 2015;38:e137–8. mellitus, with a precipitous decrease ing PD-L1/PD-1 coinhibition regu-
14. Martin-Liberal J, Furness AJ, Joshi in pancreatic volume, induced by lates diabetes induction by prepro-
K, Peggs KS, Quezada SA, Larkin J. nivolumab for malignant mela- insulin-specific CD8 T-cells in an
Anti-programmed cell death-1 ther- noma: analysis of HLA and CTLA-4 epitope-specific manner. PLoS One
apy and insulin-dependent diabe- polymorphisms. Eur J Dermatol 2013;8:e71746.
tes: a case report. Cancer Immunol 2017;27:184–5. 32. Wang J, Yoshida T, Nakaki F, Hiai H,
Immunother 2015;64:765–7. 23. Chae YK, Chiec L, Mohindra N, Okazaki T, Honjo T. Establishment
15. Hansen E, Sahasrabudhe D, Gentzler R, Patel J, Giles F. A of NOD-Pdcd1-/- mice as an effi-
Sievert L. A case report of insulin- case of pembrolizumab-induced cient animal model of type I dia-
dependent diabetes as immune- type-1 diabetes mellitus and dis- betes. Proc Natl Acad Sci U S A
related toxicity of pembrolizumab: cussion of immune checkpoint 2005;102:11823–8.50 S. Lee and G. Tse, Atezolizumab-Induced Autoimmune Diabetes Mellitus
33. Keir ME, Liang SC, Guleria I, the development of type 1 diabetes 1 diabetes in Chile. Diabetes Metab
Latchman YE, Qipo A, Albacker mellitus in Japanese children. Hum Res Rev 2014;30:761–6.
LA, et al. Tissue expression of Genet 2007;121:223–32. 36. Li R, Lee J, Kim M-s, Liu V, Moulik
PD-L1 mediates peripheral T cell tol- 35. Pizarro C, Garcia-Diaz DF, Codner M, Li H, et al. PD-L1–driven toler-
erance. J Exp Med 2006;203:883–95. E, Salas-Perez F, Carrasco E, ance protects neurogenin3-induced
34. Ni R, Ihara K, Miyako K, Kuromaru Perez-Bravo F. PD-L1 gene poly- islet neogenesis to reverse estab-
R, Inuo M, Kohno H, et al. PD-1 morphisms and low serum level of lished type 1 diabetes in NOD mice.
gene haplotype is associated with PD-L1 protein are associated to type Diabetes 2015;64:529–40.You can also read
