Diabetic Ketoacidosis as a Debut and Immune-Mediated Complication Caused by Pembrolizumab: Case Report

Abstract

Background/Objectives: Diabetic ketoacidosis (DKA) is an acute and potentially life-threatening complication characterized by the accumulation of ketone bodies in the blood, primarily occurring in patients with type 1 diabetes and occasionally in those with type 2 diabetes under certain conditions. DKA presents with symptoms such as polyuria, polydipsia, polyphagia, and, in severe cases, mental status changes. Identifying the triggering factor is crucial to prevent complications and effectively manage this medical emergency. Methods: This report describes the case of a 58-year-old male patient with stage IIIb nodular melanoma, diagnosed in November 2022. Results: After receiving five cycles of pembrolizumab, the patient developed de novo DKA, presenting with blurred vision, asthenia, adynamia, polyuria, and polydipsia. He was admitted to the emergency department with a blood glucose level of 764 mg/dL, confirming hyperglycemia and metabolic acidosis. He was transferred to the intensive care unit for fluid resuscitation and insulin infusion. After adequate clinical evolution and meeting the criteria for DKA resolution, possible autoimmune endocrinopathies secondary to immunotherapy were considered. Due to this complication, the oncological treatment was changed. Finally, the patient was discharged with the need to continue insulin therapy and oral hypoglycemic agents, along with thyroid hormone supplementation. Conclusions: The novelty of this case lies in the presentation of DKA as an immune-mediated complication induced by pembrolizumab, highlighting the importance of closely monitoring patients receiving immune checkpoint inhibitors to detect and manage emerging autoimmune endocrinopathies. It is essential to adjust oncological treatment according to the patient’s response and promptly manage autoimmune endocrinopathies to improve clinical outcomes and the patient’s quality of life.

1. Introduction

Immunotherapy has emerged as a fundamental pillar in cancer treatment, offering hope to patients with previously considered incurable neoplasms [1]. An example is immune checkpoint inhibitors (ICIs), which target the dysfunctional immune system to induce the destruction of cancer cells by CD8-positive T cells [1,2]. Specifically, antibodies against cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA4) and antibodies against programmed cell death protein 1 (anti-PD-1) have revolutionized the treatment of many cancers, particularly in advanced melanoma. Tumor regression and long-term durable cancer control are possible in nearly 50% of patients, compared to less than 10% in historical records before immunotherapy [3].

Among them, pembrolizumab, an anti-PD-1, has shown efficacy in treating various types of cancer, including melanoma, urothelial carcinoma, and non-small cell lung cancer, among others [4]. Although pembrolizumab has achieved significant clinical benefits and is generally well-tolerated compared to conventional therapies, this biological therapy can induce immune-mediated adverse effects due to uncontrolled activation of the immune system, affecting multiple organs and systems [5]. Its complications are mainly based on its mechanism of action, which involves enhancing the immune system’s ability to recognize and attack cancer cells. Some of the main complications associated with this therapy are pneumonitis, endocrinopathies, colitis, hepatitis, nephritis, and dermatological toxicities [6].

DKA is a severe acute complication characterized mainly by hyperglycemia, ketosis, and acidosis [7,8]. Although traditionally associated with type 1 diabetes, DKA can also occur in patients with type 2 diabetes, especially in situations of physiological stress that increase insulin demands [9]. Recently, cases of DKA have been reported in patients without a previous diagnosis of diabetes, associated with the use of immunotherapeutic agents, including pembrolizumab [10]. This phenomenon suggests an immune-mediated mechanism, possibly related to the activation of autoreactive T cells against pancreatic β-cells, induced by PD-1 inhibition [11].

2. Case Report

A 58-year-old male patient, without a history of obesity, high blood pressure or diabetes, with a history of nodular melanoma in the abdominal wall, stage IIIb (pT2N2M0) and BRAF mutation, was diagnosed in November 2022. In December of the same year, a positron emission tomography (PET-CT) scan showed left inguinal lymph node involvement, leading to a radical left inguinal dissection, with histopathological results confirming metastatic melanoma.

Laboratory studies in December 2022 reported fasting glucose at 95 mg/dL and TSH at 2.79 µUI/mL, both within normal ranges. Based on these results, oncology decided to initiate pembrolizumab treatment, administering the first dose in February 2023.

However, after receiving five cycles of pembrolizumab over approximately four months, the patient presented to the emergency department in June 2023 with a clinical picture of about five days of blurred vision, asthenia, adynamia, polyuria, and polydipsia. Upon admission, he had a blood glucose level of 764 mg/dL, prompting the request for extended laboratory tests (

Table 1. Admission laboratory tests.

Laboratory Test	Result	Reference Range
Complete Blood Count (CBC)	WBC 15.69 × 103/µL	4–10 × 103/µL
	ANC 13.34 × 103/µL	1.8–7 × 103/µL
	Hb 17.4 g/dL	13–16 g/dL
	Hct 58.2%	40–48%
	Platelets 441 × 103/µL	150–450 × 103/µL
Creatinine	1.82 mg/dL	0.7–1.3 mg/dL
Blood Urea Nitrogen	39 mg/dL	9–23 mg/dL
Sodium	132 mEq/L	135–145 mEq/L
Potassium	5.51 mEq/L	3.5–4.5 mEq/L
Lactic Acid	0.94 mmol/L	<2 mmol/L
Glucose	764 mg/dL	70–130 mg/dL

WBC: white blood cells, ANC: absolute neutrophil count, Hb: hemoglobin, Hct: hematocrit.

), which confirmed hyperglycemia and elevated nitrogen levels. In response, intravenous fluid resuscitation was initiated with 2000 mL of 0.9% saline solution over one hour, followed by 250 cc per hour. Further studies to classify the type of hyperglycemic crisis revealed arterial blood gas results of pH 7.250, HCO₃ 11.8 mmol/L, PCO₂ 27.6 mmHg, PO₂ 90.2 mmHg, and SO₂ 96.0%, indicating metabolic acidosis, ketone bodies at 5.8 mmol/L (positive) and HbA1C at 8.76% (elevated). Given these findings, internal medicine evaluated the patient, diagnosing de novo diabetes mellitus associated with diabetic ketoacidosis and acute kidney injury KDIGO II. Consequently, he was transferred to the intensive care unit to continue fluid resuscitation and initiation of crystalline insulin infusion at 0.1 U/kg/h.

The follow-up laboratory tests reported a complete blood count (CBC) with WBC at 10.23 × 10³/µL, ANC at 6.55 × 10³/µL, Hb at 12.9 g/dL, Hct at 39.2%, platelets at 257 × 10³/µL, creatinine at 0.94 mg/dL, BUN at 21.8 mg/dL, ketone bodies at 2.3 mmol/L, arterial blood gasses with pH at 7.399, HCO₃ at 19.4 mmol/L, PCO₂ at 32.1 mmHg, PO₂ at 89.2 mmHg, SO₂ at 97% and potassium at 3.71 mEq/L. A chest X-ray (Figure 1) was also requested, which was described as normal given the favorable clinical response, insulin infusion was reduced to 0.5 U/kg/h, and intravenous potassium supplementation was initiated. After achieving blood glucose levels below 250 mg/dL, intravenous dextrose fluids were added, with subsequent monitoring of ketone bodies, which decreased to 0.3 mmol/L.

Approximately 48 h after admission and following the described medical management, the patient showed clinical improvement, meeting the criteria for DKA resolution. Consequently, the insulin infusion was discontinued, and a transition to basal–bolus insulin therapy at a dose of 0.5 IU/kg/day was implemented.

An endocrinology consultation was requested, given the clinical presentation and history, to rule out autoimmune endocrinopathies. Hormonal studies were ordered, including TSH at 7.41 µUI/mL, free T4 at 0.70 ng/dL, baseline cortisol at 9.79 µg/dL, total testosterone at 356.38 ng/dL, FSH at 12.2 mUI/mL, LH at 9.44 mUI/mL, PTH at 19.60 nmol/L, and IGF-1 at 65.20 ng/mL. Based on these results, a diagnosis of de novo diabetes mellitus with diabetic ketoacidosis secondary to pembrolizumab use was considered, as well as de novo hypothyroidism, possibly related to thyroiditis also attributed to prior anti-PD-1 therapy. Levothyroxine supplementation at a dose of 50 µg per day was initiated.

After the patient tolerated oral intake and showed improved metabolic control, endocrinology recommended outpatient management with basal insulin glargine and preprandial correction with insulin glulisine, in addition to metformin/linagliptin and continued oral levothyroxine supplementation.

Clinical oncology, in light of the endocrinological complications, decided to discontinue pembrolizumab. Given the BRAF mutation in the tumor, adjuvant therapy with trametinib and dabrafenib was indicated.

Three months later, the patient was readmitted to the emergency department with approximately 10 days of adynamia and general malaise, accompanied by progressive lower limb edema, culminating in anasarca. Initial blood glucose was 150 mg/dL (within normal limits), but laboratory studies showed elevated nitrogen levels, leading to a diagnosis of acute kidney injury KDIGO stage 3. Nephrology assessed the patient, suspecting possible kinase inhibitor-induced nephropathy (trametinib + dabrafenib), and recommended discontinuation of the drugs, resulting in clinical improvement and renal function recovery. For diabetes management, continued insulin therapy was advised, and metformin/linagliptin was switched to empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, due to its positive renal effects.

In November 2023, oncology decided to conclude the adjuvant therapy. Follow-up labs showed uncontrolled hypothyroidism, with TSH at 49.7 µUI/mL and free T4 at 0.58 ng/dL, necessitating an increase in the levothyroxine dose at 100 mcg per day.

The patient is currently relapse-free, with adequate metabolic control and completes 20 months of overall survival.

3. Discussion

Drugs known as immune checkpoint inhibitors (ICIs), including anti-CTLA-4, anti-PD-1, and their ligand (PD-L1), have transformed the therapeutic approach to cancer [12,13]. These ICI therapies have increased the survival rate in a wide range of malignant tumors, including those that previously did not respond to treatments, such as melanoma and lung cancer [14]. According to the NCCN Guidelines, the adjuvant therapy for high-risk melanoma (IIB-IIID stages) has become a standard of care [15]. All randomized controlled trials of immune checkpoint inhibitor therapies and targeted therapies in the adjuvant setting have shown improvements for recurrence-free survival [16,17,18,19,20]. Almost one-third of patients receiving the placebo experienced distant metastases as the first site of relapse mainly in the lung, liver, and brain. The relative risk reduction in relapse with target therapy (trametinib and dabrafenib) or anti pd1 inhibitors such as pembrolizumab and nivolumab compared with the placebo is approximately 40%, and the absolute reduction in the risk of relapse varies between 15 and 20% [21].

With the results of the Keynote 054 and Keynote 716 trials (pembrolizumab), Checkmate 238 and Checkmate 76 k trials (nivolumab), and the COMBI-AD trial (trametinib- dabrafenib), the use of adjuvant therapy in patients with high-risk melanoma with ECOG 0-1 is supported [16,17,18,19,20]. Pembrolizumab monotherapy and nivolumab monotherapy are indicated in patients with Braf-mutated and non-mutated melanoma IIB-IIID stage while dabrafenib and trametinib are indicated only in patients with Braf-mutated melanoma III stage [15].

ICIs work via removing immune system inhibitions, allowing immune cells to identify and eliminate cancer cells. However, T-cell activation by ICIs can lead to various side effects, including autoimmune conditions [22]. It has been reported that between 4% and 30% of patients treated with ICIs experience autoimmune endocrinopathies, with thyroid problems being the most frequent [23].

When comparing this study with other case reports on pembrolizumab-induced DKA, such as those by Salangsang et al., 2023 [24], Maia et al., 2024 [25], and Sankar et al., 2021 [26], several key similarities and differences emerge. Regarding similarities, DKA is identified as a rare but serious adverse effect of ICIs like pembrolizumab. As in the case presented by Salangsang et al., 2023 [24], the patient in this study developed DKA without a prior history of diabetes, supporting the hypothesis that ICI treatment can trigger de novo type 1 diabetes mellitus. Both cases highlight common symptoms such as severe hyperglycemia and metabolic acidosis, which are characteristic of DKA.

Despite these clinical similarities, there were notable differences in severity and management. In this case, the patient responded well to treatment, which included insulin infusion and electrolyte supplementation, followed by a transition to subcutaneous insulin therapy. However, unlike the case described by Sankar et al., 2021 [26], which involved a milder presentation of pembrolizumab-induced DKA compared to classic type 1 DKA, the patient in this report had a more severe clinical picture with significantly higher glucose levels (764 mg/dL), necessitating intensive care.

A distinctive aspect of this study is the co-occurrence of DKA with hypothyroidism, likely secondary to autoimmune thyroiditis induced by pembrolizumab. This multiple endocrine involvement was less common in other studies, such as Maia et al., 2024 [25], which described DKA without concurrent hypothyroidism. The combination of multiple endocrinopathies in patients treated with ICIs, though rare, underscores the importance of thorough monitoring, as highlighted by Sankar et al., 2021 [26].

Although the incidence of pembrolizumab-induced DKA is low (0.1% in clinical trials, as reported by Salangsang et al. [24] and Maia et al. [25]), its occurrence can be life-threatening if not promptly diagnosed and treated. In this case, rapid intervention and appropriate management prevented further complications, reinforcing the importance of continuous glucose monitoring in patients receiving ICIs, a recommendation supported by other authors, including Chae et al., 2016 [27].

As Maia et al., 2024 [25], and Salangsang et al., 2023 [24], emphasize, these case reports play a crucial role in raising awareness among clinicians about the need for routine thyroid function and blood glucose testing before and during ICI therapy. Early identification of immune-related adverse events and timely intervention are essential for improving patient outcomes.

Currently, immunotherapy with ICIs is the standard treatment for numerous types of cancer [28]. Approximately 10% of patients receiving this treatment develop thyroiditis, with a higher risk in those with pre-existing thyroid autoimmunity [28,29]. The incidence of thyroiditis is higher with anti-PD-1 treatments or combined therapies involving these drugs, compared to monotherapy with anti-PD-L1 and anti-CTLA-4 treatments [30]. These toxicities, known as immune-related adverse events (irAEs), occur more frequently with the combined inhibition of anti-CTLA-4 and anti-PD-1 checkpoints, presenting a variety of symptoms and potentially affecting any organ system (most commonly the skin, colon, endocrine system, and liver), sometimes mimicking classical autoimmune diseases [31].

An example of this is ICI-induced type 1 diabetes mellitus (ICI-T1DM), a rare but potentially fatal complication that occurs in 0.6% to 1.4% of patients receiving ICIs [32]. ICI-T1DM is characterized by rapid cell destruction, which can occur as early as five days after starting ICIs or up to several months after discontinuation [1,33]. Between 40% and 76% of patients diagnosed with ICI-T1DM experience DKA, a condition that frequently requires intensive care unit management [34]. Additionally, almost all these patients will require continuous insulin treatment indefinitely [35,36]. In addition, pembrolizumab-induced DKA was reported in only 0.1% of patients participating in the clinical trials [37]. Among the risk factors for immune-mediated adverse events associated with the use of pembrolizumab, the following have been identified: body mass index >25 kg/m², a diagnosis of melanoma, receiving at least four cycles of treatment, having a cumulative dose greater than or equal to 600 mg, and a lymphocyte/neutrophil ratio less than three [38]. Other risk factors described for adverse events in patients receiving immunotherapy include: age > 60 years, ECOG ≥ 2, and LDH levels > 245 [39].

A meta-analysis by Irfan Vardarli et al., 2024 [40], on the risk and incidence of irAEs of any grade in patients with solid malignancies treated with ICIs found a relative risk of hypothyroidism of 7.81 (95% CI, 5.68–10.74, p < 0.0001) and insulin-dependent diabetes mellitus of 1.52 (95% CI, 1.07–2.18, p = 0.02). These findings underscore the importance of timely monitoring and identifying the risk of possible irAEs, especially in patients receiving anti-PD-1 therapy.

Finally, this case report focused on describing a patient with melanoma treated with pembrolizumab who subsequently developed DKA as an immune-mediated adverse event. Through this case review, we aim to raise awareness about this complication, which, although rare, can be potentially lethal. It emphasizes the importance of early identification of symptoms related to irAEs and prompt management of autoimmune endocrinopathies. This report also highlighted the need for a multidisciplinary approach in managing cancer patients, particularly those receiving biological therapies. The collaboration among oncologists, endocrinologists, and the primary care team is crucial to effectively identify and treat immune-related adverse events, ensuring patient safety and well-being during oncological treatment.

4. Conclusions

This case report highlights the importance of a multidisciplinary approach in managing immune-related DKA, particularly in patients undergoing ICI therapy. DKA, a severe and potentially life-threatening condition, demands prompt recognition and intervention. In the case of pembrolizumab-induced DKA, the absence of a prior diabetes diagnosis underscores the need for continuous glucose monitoring during ICI treatment, as immune activation can lead to rapid beta-cell destruction. Effective management involves normalizing metabolic disturbances and closely monitoring for triggers such as stress or acute illness.

The coexistence of DKA and hypothyroidism due to pembrolizumab-induced thyroiditis illustrates the complexity of managing multiple irAEs. These events, affecting various organ systems, require balancing the benefits of immunotherapy against its risks, particularly in high-risk patients. Early identification and management of irAEs like DKA and thyroiditis are critical to minimizing morbidity, necessitating a coordinated approach from oncologists, endocrinologists, and primary care providers to ensure patient safety and improve outcomes during cancer treatment