Treat Neonatal Diabetes Early With Sulfonylureas

Becky McCall

October 14, 2015

Sulfonylureas improve neurological development in children with neonatal diabetes owing to potassium-channel mutations, supporting prompt diagnosis and early treatment with such agents, shows the first study of its kind.

The paper was published online in Diabetes Care October 5 by Jacques Beltrand, MD, PhD, from the Necker University Hospital for Sick Children, Paris, and colleagues and is the follow-up of two previous studies (Lancet Diabetes Endocrinol. 2013;1:199–207; N Engl J Med. 2006;355:467–477).

Senior author Michel Polak, MD, PhD, from the same institution, told Medscape Medical News that "glibenclamide [known as glyburide in the US] allows the definitive discontinuation of insulin and noticeably improves hypotonia, gesture conception, and realization and hyperactivity.

"It also leads to an improvement in motor skills and sociability and favors quality of life and school integration," he added.

The work is the first to show that one of the sulfonylurea class, used for decades to treat type 2 diabetes in adults, also has a direct effect on children's brains. And there is a "better result when the drug is started before 4 years of age, indicating starting therapy with glibenclamide early in life," highlighted Dr Polak.

In the 2006 NEJM paper, the researchers showed the importance of stopping insulin therapy in patients with neonatal diabetes.

Sulfonylureas Bind Potassium Channels in the Brain

Neonatal diabetes is a rare condition that develops during the first months of life, with an estimated incidence of one in 90,000 newborns, and around 40% of such patients are thought to have mutations in genes that produce proteins involved in functioning of the ATP-sensitive potassium channels (KATP).

Around 20% of patients with these mutations have mild to severe neurological abnormalities and developmental delay, but, when tested properly, most of those children do have some mild neuropsychological dysfunction, including dyspraxia, noted Dr Polak,

Sulfonylureas interact with the potassium channel via the ATP mechanism and result in an increased supply of insulin.

Also previously, the researchers have shown that receptors of SUR1 (a protein component of the potassium channel), which bind glibenclamide, were widely present in the brain.

"It was logical to test in a formal way — not only single case study — that the drug could cross the blood-brain barrier and improve cognition in these children," explained Dr Polak, who added that neurodevelopmental parameters are known to be unresponsive to insulin.

"We and others have shown that sulfonylureas are effective when used instead of subcutaneous insulin in children and adults with Kir6.2- or SUR1-activating mutations. Sulfonylurea therapy provided excellent metabolic control without the hypoglycemic episodes commonly seen with insulin," write the authors.

And, Dr Polak pointed out, "Instead of injecting insulin, sulfonylurea therapy means giving a medication by mouth, which is a major improvement for the children and families."

Switch From Insulin to Sulfonylureas

The researchers carried out the current prospective single-center cohort study in 18 patients with neonatal diabetes owing to potassium-channel mutations who were aged 5 months to 18 years and were switched from insulin to sulfonylurea therapy. Eight of the 18 were under 4 years of age.

At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common.

Before the switch and at 6, 12, and 18 months afterward, the children underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing.

"A major strength of our study is the use of a standardized normative neurodevelopmental test battery validated in normal French children and performed by a single examiner. This…allowed us to obtained accurate information about sulfonylurea effects on developmental parameters," write the authors.

They switched the treatment rapidly in hospital inpatients; glibenclamide, given off label, was started at a dose of 0.1 mg per kg twice daily and was increased daily by 0.2 mg per kg per day until insulin independence was achieved.

For young children unable to take tablet medication, oral glibenclamide (glyburide) was produced off label, by crushing the tablets and diluting those as much as possible in water. .

Glibenclamide was given at a median dose of 0.37 mg/kg/day (range, 0–1.4) at month 18.

The effect of glibenclamide seems "to target specific brain regions, as the greatest improvements were for cerebellar functions…and thalamic functions," the researchers explain.

Upon assessment after 12 months of sulfonylurea therapy, motor abnormalities were noticeably improved, including intelligence scores, hypotonia (in 12 of 15 patients), visual-attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in five of eight older patients).

"In the younger patients, hypotonia and attention deficits were greatly improved or corrected, contributing to improved motor skills," the authors note.

"In children over 4 years, tone, laterality, and visual functions showed the greatest improvements, contributing to measurable improvements in gesture conception and realization."

Glibenclamide also improved HbA1c levels (median change, -1.55% from HbA1c of 7.75% to 6.4%; P < .0001), and no patients experienced hypoglycemia.

Switch Early to Gain Maximum Benefit

However, the researchers found no improvement in either intelligence score or language impairments within the study period.

"It was a short-term study with only 1 year of follow-up and also in a way a late treatment," explained Dr Polak. "We should rush to treat these children as newborns or at least in the first months of life."

As the drug is used in neonatal diabetes patients without an official marketing authorization, the pediatric endocrinologists at Necker University Hospital for Sick Children are now developing a new galenic form of glibenclamide suitable for infants and children that will allow for easier administration and a more precise dosage, he noted.

Dr Polak and Dr Beltrand have declared no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

Diabetes Care. Published online October 5, 2015. Abstract


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