Situation JJ is a neonate born with diabetes due to a suspected KCNJ11 mutation which was later confirmed by genetic testing. The KCNJ11 mutation results in the patient being unable to produce insulin due to an inability to close a potassium dependent ATP channel required for the process. Prior to the administration of an intravenous (IV) insulin infusion JJ’s blood glucose levels reached 17 mmol/L. A plan for long term management of this patient’s condition was required before discharge.

Background Untreated or uncontrolled neonatal diabetes can result in severe complications such as reduced renal function or intra-ventricular haemorrhage therefore prompt and continued management of blood glucose levels is essential.

Outcome Options for JJ’s long term management were considered by the paediatric diabetes multi-disciplinary team (MDT) following the suggestion of use of a sulphonylurea. Prior experience of its use had been found to be the most effective therapy in patients with KCNJ11 mutations.¹ Continuation of IV therapy was unsuitable because of poor IV access and challenging monitoring requirements. Subcutaneous therapy was dismissed due to variability and unpredictability of pharmacokinetics and pain on injection in a neonate. Expert advice was sought from Exeter University specialists who recommended the use of glibenclamide specifically. A literature search described its use in a 3 month old at a dose of 0.1 mg/kg/day.¹ A reference discussed 3 extemporaneous formulations and demonstrated chemical stability² but with rapid settling and poor dose uniformity. It was decided that an extemporaneous product was also unsuitable due to potential for variation of formulation between primary and secondary care. As glibenclamide is insoluble in water a suspension was required to ensure uniformity of distribution of the drug and therefore reliable dosing. An acceptable product manufactured by a specials company as a suspension was identified and product information requested to determine potential suitability for use in neonates with regards to excipients.

JJ was discharged at 2 weeks of age with frequent planned review by the MDT. His blood glucose levels were stable, although there were some instances of hypoglycaemia post-dose and hyperglycaemia pre-dose therefore the dose was eventually reduced to 0.04 mg/kg/day and split into 3 divided doses to prevent this. He remains well, is showing normal growth and development with stable blood glucose results since the dose amendment.

Lessons learnt Sulphonylureas close the potassium dependent channel independently of ATP that patients with KCNJ11 mutations cannot. This results in the ability of these patients to produce insulin endogenously whereas previously they would have required full insulin supplementation. Prompt and clear MDT communication and the use of glibenclamide in a neonate enabled discharge due to improved blood glucose levels within 48 hours of initiation.

References

1. Pearson ER, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutation. New England Journal of Medicine 2006;355(5):467–77.

2. Di Folco U, et al. Stability of three different galenic liquid formulations compounded from tablet containing glibenclamide. Journal of Nutritional Therapeutics 2012;1:152–160.