Pembrolizumab-Induced Type 1 Diabetes in a 95-Year-Old Veteran With Metastatic Melanoma

Assessing the need for inpatient evaluation includes obtaining urine ketones and acid-base status as screening for DKA.¹⁷ Antibodies and C-peptide can be sent to support diagnosis of new onset T1DM, although the initiation of therapy should not be delayed for these results.¹⁷ As noted before, many of these patients also are antibody negative.^13-16 Low C-peptide levels should prompt a high suspicion for CPI-induced T1DM, and initiation of insulin therapy should be strongly considered.¹⁷ In a case series of 27 patients, 85% exhibited a rapid loss of β-cell function, evidenced by the acute progression to hyperglycemia and low or undetectable levels of C-peptide at diagnosis.⁹ Likewise, our patient had a low C-peptide level and negative anti-GAD antibody titer but was treated before these results were available. Inpatient admission for close glycemic monitoring may be reasonable; several cases reported prompt diagnosis and avoidance of DKA in this setting.¹⁷

In contrast to other irAEs, there is no available evidence that high-dose corticosteroids alter the course of pembrolizumab-induced T2DM.¹⁸ Depending on the degree of hyperglycemia, endocrinology consultation and insulin treatment are appropriate where the diagnosis of T1DM is suspected even without evidence of DKA.¹⁷ For patients with T2DM, there may be a positive synergistic effect of metformin in combination with CPIs in tumor control.¹⁹ Our patient’s C-peptide improved with insulin treatment, consistent with correction of glucose toxicity and a honeymoon period in his course. However, in patients reported with pembrolizumab-induced T1DM, insulin requirement for treatment generally persists despite cessation of pembrolizumab therapy.^13-16

Conclusions

Pembrolizumab-induced T1DM is a rare, but potentially life-threatening irAE. The acute risk of DKA requires early recognition and prompt treatment of patients taking CPIs. More than 90% of primary care physicians (PCPs) fulfill general medical care roles for patients with cancer; therefore, they play an essential role in evaluating symptoms during therapy.²⁰ Further studies evaluating the role of PCPs and outcomes when PCPs are involved in oncologic care should be conducted.

With increased index of suspicion, this clinical scenario presents an opportunity for PCPs that may help reduce irAE-associated morbidity and mortality of patients on CPIs, like pembrolizumab. Figure 2 illustrates an example addendum that can be used to alert and tag a PCP of a mutual patient after initiation of CPI therapy. Determining the optimal interface between PCPs, oncologists, and endocrinologists in delivering and coordinating high-quality cancer care in the setting of immunotherapy is an important area for ongoing quality improvement.

Acknowledgment

The authors thank all the staff and health care professionals at VA Greater Los Angeles Healthcare System who were involved in the care of this patient.