Table 1.
Published case reports and case series of immune checkpoint inhibitors associated with diabetes mellitus.
| Authors | Patient | Cancer type | RelevantHistory | Agent | Time to onset (weeks) | Presenting features | Autoantibodies | HLA | Treatment | Discontinued ICI | Other irAEs | Outcome | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical | Glucose(mmol/liter) | C-peptide | HbA1c(%) | ||||||||||||
| Kusuki et al. (13) | 72 M | NSCLC | Colon cancer | Pembrolizumab | 16 | DKA | 27.1 | 0.39 ng/ml | 8.1 | NR | DRB1*09:01-DQB1*03:03 | NR | Yes | None | CR |
| Porntharukchareon et al. (7) | 70 M | NSCLC | None | Pembrolizumab + Ipilimumab | 14 | DKA | 44.1 | < 0.1 ng/ml | 6.5 | None | NR | Pembrolizumab (200 mg q3w), Ipilimumab (1 mg/kg q6w) | Yes | Isolated adrenocorticotropic hormone deficiency |
NR |
| Singh et al. (9) | 65 F | RCC | None | Ipilimumab + Nivolumab | 6 | DKA | 33.5 | 0.1 mg/dl | 8.5 | None | NR | Ipilimumab (55 mg × 4 cycles = 220 mg), Nivolumab (160 mg × 4 mg = 640 mg) q3w | Yes | Hypothyroidism | NR |
| Wen et al. (10) | 56 M | HCC | Chronic viral hepatitis B | Sintilimab | 24 | DKA | 22.2 | 1.12 ng/ml | 7.8 | None | A∗0201 | 200 mg q3w | Yes | None | PR |
| Yilmaz et al. (14) | 49 M | RCC | None | Nivolumab | 40 | DKA | 44.4 | 0.24 nmol/liter | 10.9 | None | NR | 3 mg/kg q2w | Yes | NR | NR |
| Falcao et al. (15) | 57 F | RCC | Type 2 DM | Nivolumab | 8 | Hyperglycemia | NR | NR | 10.5 | NR | NR | 3 mg/kg q2w | No | Autoimmune lipoatrophy, Hepatitis | PD |
| Kotwal et al. (16) | M (12) F (9) |
Lung cancer (5) Melanoma (9) Breast cancer (2) RCC (1) Multiple myeloma (1) Lymphoma (1) MCC (1) Esophageal cancer (1) Pancreatic cancer (1) |
NR | Pembrolizumab | 8.4 | DKA | 32.2 | 0.9 ng/ml | 8.6 | GAD | NR | NR | NR | Thyroiditis | NR |
| NR | Pembrolizumab | 8.8 | DKA | 53.9 | <0.1 ng/ml | 10.7 | GAD | Thyroiditis | |||||||
| NR | Pembrolizumab | 2.4 | DKA | 54 | <0.1 ng/ml | 7.8 | GAD/IA-2/IAA | Thyroiditis | |||||||
| NR | Pembrolizumab | 19.2 | Hyperglycemia | 33.3 | 0.3 ng/ml | 10.5 | GAD/IAA | NR | |||||||
| NR | Nivolumab | 22 | Hyperglycemia | 33.3 | NR | NR | NR | Thyroiditis | |||||||
| NR | Ipilimumab → Pembrolizumab |
19.6 | Hyperglycemia | 20.9 | 5.2 ng/ml | 9.7 | NR | NR | |||||||
| NR | Pembrolizumab | 31.2 | DKA | 35.8 | NR | 9.7 | None | Thyroiditis, Hypophysitis |
|||||||
| NR | Pembrolizumab | 38.8 | DKA | 25.6 | 0.7 ng/ml | 7.8 | GAD | NR | |||||||
| NR | Pembrolizumab | 94.4 | DKA | 23.8 | NR | 11.3 | NR | Dermatitis, Hypophysitis, Arthritis |
|||||||
| NR | Pembrolizumab | 12 | DKA | 23.7 | NR | 11.2 | NR | NR | |||||||
| NR | Pembrolizumab | 2.8 | DKA | 77.2 | 0.4 ng/ml | 8.8 | NR | NR | |||||||
| NR | Pembrolizumab | 32.8 | DKA | 24.9 | NR | 10.6 | None | NR | |||||||
| Type 2 DM | Nivolumab | 15.6 | Hyperglycemia | 32.2 | NR | 10 | NR | Thyroiditis | |||||||
| Type 2 DM | Nivolumab | 22.8 | Hyperglycemia | 21 | NR | 10 | NR | Dermatitis, Adrenal ansufficiency |
|||||||
| Type 2 DM | Pembrolizumab | 20 | Hyperglycemia | 13.3 | NR | 8.6 | NR | Thyroiditis | |||||||
| Type 2 DM | Pembrolizumab | 15.2 | Hyperglycemia | 20.4 | NR | 11.3 | NR | Ocular | |||||||
| Type 2 DM | Pembrolizumab | 5.6 | Hyperglycemia | 11.6 | NR | 9 | NR | NR | |||||||
| Type 2 DM | Pembrolizumab | 27.6 | Hyperglycemia | 13.8 | NR | 8.1 | NR | Thyroiditis, Hypophysitis |
|||||||
| Type 2 DM | Ipilimumab → Pembrolizumab |
49.2 | Hyperglycemia | 16.9 | NR | 11.8 | NR | Hepatitis | |||||||
| Type 2 DM | Nivolumab | 7.2 | Hyperglycemia | 10 | NR | 9.5 | NR | Thyroiditis | |||||||
| Type 2 DM | Pembrolizumab | 6.8 | Hyperglycemia | 55.5 | NR | 12 | NR | NR | |||||||
| Hakami et al. (17) | 52 M | Melanoma | None | Pembrolizumab | 23 | DKA | 38.6 | <0.01µg/liter | 8.3 | None | NR | 2 mg/kg q3w | No | Hypothyroidism | NR |
| Mengíbar et al. (18) | 55 M | Urothelial cancer | Asymptomatic subclinical hyperthyroidism |
Durvalumab | 3 | DKA | 23.2 | 0.02 ng/ml | 8.4 | GAD/IA-2 | NR | 10 mg/kg | Yes | Primary autoimmune hypothyroidism | NR |
| Okahata et al. (19) | 52 M | Breast cancer | None | Nivolumab | 8 | F1DM | 22.3 | 0.3 ng/mL | 7.8 | None | DRB1* 14:05, 14:06 DQB1* 03:01, 03:03 |
0.36 mg/kg q2w | NR | None | NR |
| Sakaguchi et al. (20) | 68 F | Melanoma | Graves disease | Nivolumab | 81 | DKA | 17.4 | 0.2 nmol/liter | 8.2 | None | DRB1*09:01 | 3 mg/kg q3w | NR | Thyrotoxicosis | NR |
| Shibayama et al. (21) | 81 F | MCC | None | Avelumab | 20 | F1DM | 26.8 | 1.07 ng/ml | 7.5 | GAD/IA-2 | DRB1*09:01:02, DRB1*14:54:01, DQA1*01:04, DQA1*03:02, DQB1*05:02:01, DQB1*03:03:02 | 523 mg q2w | Yes | None | NR |
| Marchand et al. (22) | 55 M | Pleomorphic carcinoma | None | Nivolumab | 9 cycles | DKA | NR | Undetectable | 8.2 | None | None | NR | NR | Hypophysitis, Pancreas atrophy |
NR |
| Gauci et al. (6) | 73 M | Melanoma | None | Nivolumab | 6 | DKA | 27.78 | Undetectable | 7.2 | GAD/ZnT8/IA-2 | NR | NR | Yes | NR | NR |
| 84 F | Melanoma | None | Pembrolizumab | 6 | DKA | 26.71 | NR | 8.6 | GAD/ZnT8/IA-2 | NR | NR | Yes | NR | NR | |
| 34 M | Melanoma | None | ipilimumab + Nivolumab | 11 | DKA | 21.44 | NR | 5.4 | None | NR | NR | No | NR | NR | |
| Li et al. (23) | 67 M | NSCLC | None | Pembrolizumab | < 7 | DKA | 26.98 | 0.51 ng/ml | 8 | None | NR | 2 mg/kg q3w | Yes | NR | NR |
| Dehghani et al. (24) | 63 M | Melanoma | None | Nivolumab | 72 | Hyperglycemia | 11 | 0.41 nmol/liter | 9.3 | None | NR | NR | Yes | Pancreatitis, Pancreatic atrophy |
PD |
| Matsuura et al. (25) | 78 M | NSCLC | Type 2 DM | Nivolumab | 5 | Asymptomatic | 527 | <0.1 ng/ml | 6.1 | GAD | None | 3 mg/kg q2w | Yes | NR | NR |
| Zaied et al. (26) | 70 M | RCC | None | Nivolumab | 6 | DKA | 48.8 | 0.4 ng/ml | 8.4 | None | NR | 3 mg/kg q2w | Yes | None | Death |
| Shiba et al. (27) | 80 F | Melanoma | None | Ipilimumab | 4 | F1DM | 35.5 | <0.01 ng/ml | 7.7 | IAA | DR4 | 3 mg/kg | NR | None | NR |
| Takahashi et al. (28) | 74 F | Melanoma | None | Nivolumab | 17 | F1DM | 31.7 | Urinary C-peptide <0.6 μg/day | 8.0 | None | NR | 2 mg/kg q3w | Yes | None | NR |
| Sakurai et al. (29) | 68 F | RCC | None | Nivolumab | 14 | Hyperglycemia | 26.3 | 0.24 ng/ml | 6.9 | None | DRB1*09:01, DQB1*03:03 |
3 mg/kg q2w | No | Subclinical Hypothyroidism, Adrenal insufficiency |
NR |
| Capitao et al. (30) | 74 F | Lung cancer | Arterial hypertension, Hypercholesterolaemia |
Nivolumab | 5 | DKA | 58.9 | <0.01 ng/ml | 8.7 | GAD | DRB1*04 | 3 mg/kg q2w | No | Dehydration, Acute kidney injury |
PR |
| Kumagai et al. (31) | 73 M | NSCLC | None | Nivolumab | 25 | Hyperglycemia | >1111.1 | 0.49 ng/ml | 13.4 | None | DRB1*09:03-DQB1*03:03 DRB1*01:01-DQB1*05:01 |
3 mg/kg q2w | NR | Pneumonitis, Vitiligo |
NR |
| Changizzadeh et al. (4) | 42 M | Melanoma | None | Nivolumab + Ipilimumab. | 12 | DKA | 40.4 | NR | 6.5 | None | NR | Ipilimumab (3 mg/kg), Nivolumab (1 mg/kg) q3w |
NR | Immune-mediated colitis | NR |
| Godwin et al. (32) | 34 F | NSCLC | None | Nivolumab | 4 | DKA | 739 | <0.1 ng/ml | 7.1 | GAD/IA-2/IAA | A30:01,30:02 (A30) D09:CTZ,09:CTZ (DR9) |
3 mg/kg q2w | Yes | NR | CR |
| Hickmott et al. (1) | 57 M | Urothelial cancer | None | Atezolizumab | 15 | DKA | 24 | 0.65 ng/ml | 7.5 | None | DRB1*04, DQB1*03 |
NR | No | No | Death |
| Munakata et al. (8) | 72 M | Hodgkin lymphoma | None | Nivolumab | 12 | F1DM | 20.8 | Urinary C-peptide 5.0 μg/day | 7.3 | None | B*4002 | 3 mg/kg q2w | Yes | Pancreatitis | PD |
| Chae et al. (33) | 76 M | NSCLC | NR | Pembrolizumab | 3 | Asymptomatic | 34.2 | 0.81 ng/ml | 6.3 | GAD/IA-2 | NR | NR | No | NR | NR |
| Kapke et al. (34) | 83 M | HNSCC | Hypothyroidism | Nivolumab | 12 | DKA | 23.7 | 0.32 ng/ml | 7.4 | GAD | DRB1*08, DRB1*11, DQB1*03, DQB1*04, DQA1*04, and DQA1*05 |
240 mg q2w | Yes | Diffuse colitis | NR |
| 63 M | Urothelial Carcinoma | Hypothyroidism | Atezolizumab | 24 | DKA | 44.5 | 0.02 ng/ml | 7.8 | GAD | DRB1*03, DRB1*04, DQB1*02, DQB1*03, DQA1*03, and DQA1*05 |
200 mg q3w | NR | Cardiac tamponade, Distal tracheal narrowing |
Death | |
| Teramoto et al. (35) | 63 F | Melanoma | None | Nivolumab | 30 | DKA | 36.7 | <0.1 ng/ml | 8.9 | None | NR | 2 mg/kg q3w | Yes | NR | PD |
| Ishikawa et al. (36) | 54 F | Melanoma | None | Nivolumab | 40 | Hyperglycemia | 32.2 | 1 ng/ml | 7 | None | HLA-B*15:01,*40:06, DRB1*04:05,*04:06, DQB1 *03:02, and *04:01 | 2 mg/kg q3w | No | NR | SD |
| Usui et al. (37) | 31 M | NSCLC | None | Nivolumab | <2 | DKA | 40.8 | <0.03 ng/ml | 6.4 | GAD | DRB1*04:05-DQB1*04:01 | NR | NR | NR | NR |
| 62 F | NSCLC | None | Nivolumab | 10 | Hyperglycemia | 13.7 | Urinary C-peptide 2.6 µg/day | 6.5 | None | DRB1*09:01-DQB1*03:03 | NR | NR | NR | NR | |
| Mizab et al. (38) | 58 M | Melanoma | None | Pembrolizumab | 12 | F1DM | 33.4 | 0.007 nmol/l | 7.4 | None | NR | 2 mg/kg q3w | NR | NR | NR |
| Leonardi et al. (39) | 66 M | NSCLC | None | Pembrolizumab | 20 | DKA | 35.3 | 0.3 ng/ml | 7.6 | GAD | NR | 2 mg/kg q3w | No | NR | NR |
| Hofmann et al. (40) | 58 F | Melanoma | None | Pembrolizumab | 3 | Hyperglycemia | NR | Low | NR | GAD/IA2 | NR | NR | Yes | NR | SD |
| 78 F | Melanoma | Type 2 DM | Ipilimumab + Nivolumab | 3 | DKA | NR | Low | NR | GAD | NR | NR | NR | Vomiting, diarrhea | SD | |
| 70 F | Melanoma | None | Nivolumab | 6 | Hyperglycemia | NR | <16 pmol/l | NR | None | NR | NR | No | NR | CR | |
| Okamoto et al. (41) | 55 F | Melanoma | None | Nivolumab | 48 | F1DM | 32 | 1.0 ng/ml | 7.0 | None | DRB1*04, DQB1*04 |
2 mg/kg q3w | Yes | Pancreas atrophy | NR |
| Miyoshi et al. (42) | 66 F | Melanoma | None | Nivolumab | 16 | F1DM | 29 | 0.23 ng/ml | 7.3 | None | DQB1*03 | 2 mg/kg q3w | No | None | NR |
| Hansen et al. (43) | 58 M | Melanoma | NR | Pembrolizumab | 51 | F1DM | 22.2 | NR | 9.7 | GAD | NR | 2 mg/kg q3w | No | Hypothyroidism, Fatigue, Hair depigmentation, Gastroesophageal reflux | SD |
| Aleksova et al. (44) | 60 M | Melanoma | None | Ipilimumab → Pembrolizumab |
5 | DKA | 27 | 57 pmol/liter | 7.1 | None | NR | Ipilimumab (3 mg/kg, 4 cycles), Pembrolizumab (2 mg/kg, 5 weeks) |
Yes | None | NR |
| Humayun et al. (45) | 55 M | Melanoma | None | Ipilimumab | 9 cycles | F1DM | 42 | NR | 10.7 | None | NR | NR | Yes | Hypopituitarism | NR |
| Martin-Liberal et al. (46) |
54 F | Melanoma | Asthma | Ipilimumab → Pembrolizumab |
9 | DKA | NR | NR | NR | GAD | DRB1*04, DQB1*0302 |
Ipilimumab (3 mg/kg, 4 cycles), Pembrolizumab (2 mg/kg, 3 cycles) |
No | NR | PR |
| Hughes et al. (47) | 55 F | Melanoma | Autoimmune thyroid disease |
Nivolumab | 20 | DKA | 30 | <0.1 ng/ml | 6.9 | NR | A2.1+, DR4+ | NR | NR | NR | NR |
| 83 F | NSCLC | None | Nivolumab | 4 | DKA | 29 | <.0.1 ng/ml | 7.7 | GAD | A2.1+, DR4+ | NR | NR | NR | NR | |
| 63 M | RCC | Hypertension | Nivolumab | 16 | Hyperglycemia | 19 | 1.3 ng/ml | 8.2 | GAD/ICA/IAA | A2.1+, DR4+ | NR | NR | NR | NR | |
| 58 M | SCLC | Type 2 diabetes | Nivolumab | 1 | DKA | 42 | <0.1 ng/ml | 9.7 | GAD | A2.1+ | NR | NR | NR | NR | |
| 64 F | Melanoma | Autoimmune thyroid disease, Psoriasis |
Pembrolizumab | < 4 | DKA | 39 | 0.5 ng/ml | 7.4 | NR | DR4+ | NR | NR | NR | NR | |
| Mellati et al. (48) | 70 M | Lung cancer | NR | PDL-1 inhibitor (not named) | 15 | DKA | 23 | 0.3 ng/ml | 9.8 | None | NR | NR | NR | NR | Death |
| 66 F | SCC Jaw | NR | PDL-1 inhibitor (not named) | 7 | DKA | 42 | <0.1 ng/ml | 9.4 | GAD | DR3-DQ2, DR4-DR8 |
NR | NR | NR | NR | |
| Gaudy et al. (49) | 44 F | Melanoma | Autoimmune thyroid disease |
Pembrolizumab | 5 | DKA | 50 | Undetectable | 6.85 | None | NR | NR | Yes | Acute renal failure | NR |
SCC Jaw, Sarcomatoid squamous cell carcinoma of the Jaw; NSCLC, Non-small cell lung cancer; SCLC, Small-cell lung cancer; RCC, Renal cell carcinoma; MCC, Merkel cell carcinoma; HNSCC, Head and neck squamous cell carcinoma; HCC, Hepatocellular carcinoma; Type 2 DM, Type 2 diabetes mellitus; NR, Not reported; DKA, Diabetic ketoacidosis; GAD, Glutamic acid decarboxylase; IA-2, Islet-associated antigen-2; IAA, Insulin autoantibodies; ICA, Islet cell antibody; ZnT8, Zinc transporter 8; F1DM, Fulminant type 1 diabetes; q2w, every two weeks; q3w, every three weeks.