Diabetic ketoacidosis in patients exposed to antipsychotics: a systematic literature review and analysis of Danish adverse drug event reports

Rationale: Patients exposed to second-generation antipsychotics (SGAs) have approximately 10 times increased risk of diabetic ketoacidosis (DKA) compared with the general population. However, as DKA is a rare complication of type 2 diabetes mellitus, and susceptible patients exposed to antipsychotics may rapidly develop DKA independently of treatment duration and weight gain, this is rather suggestive of type 1 diabetes mellitus (T1DM) or latent autoimmune diabetes in adults.

Objectives: We performed a systematic review of current studies regarding antipsychotic-associated DKA with type 1 etiology and analyzed Danish adverse drug event (ADE) reports (previously unpublished cases).

Methods: PubMed, Embase, and the Cochrane Library were searched for all relevant studies, and the Danish Medicines Agency retrieved ADE reports using the Danish ADE database (up to date as of June 28, 2016). Diagnosis of antipsychotic-associated DKA with type 1 etiology was either considered confirmed or possible depending on authors' conclusions in the studies and/or clinical aspects. In addition, clinico-demographic risk factors were extracted.

Results: A total of 655 records and 11 ADE reports were identified, and after screening for eligibility, we included 21 case reports/series and two ADE reports (n = 24). No relevant clinical studies were included. Although fatal cases were identified, these were excluded because of diagnostic uncertainties (n = 15). DKA occurred in 15 males (62.5 %) and nine females (37.5 %), with a mean age ± standard deviation of 34.8 ± 12.4 years. Median time to DKA was 5 months (interquartile range: 1.4-11 months). Associated antipsychotics were olanzapine (n = 9, 36 %), aripiprazole (n = 6, 24 %), risperidone (n = 6, 24 %), clozapine (n = 3, 12 %), and quetiapine (n = 1, 4 %). Nine patients (37.5 %) were confirmedly diagnosed with T1DM following DKA resolution, whereas 15 patients (62.5 %) had possible T1DM. In 22 patients (91.7 %), ongoing insulin treatment was required for glycemic control.

Conclusions: Increased awareness of the potential risk of antipsychotic-associated DKA and subsequent T1DM diagnosis, with insulin requirements for glycemic control, is warranted. The underlying mechanisms are poorly understood but most probably multifactorial. Certainly, further studies are warranted. Clinicians must utilize appropriate monitoring in susceptible patients and consider the possibility of continuing antipsychotic treatment with appropriate diabetic care.