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06-05-2018 | Neonatal diabetes | Highlight | News

Reassuring long-term data for sulfonylurea in neonatal diabetes

medwireNews: Sulfonylurea treatment is durably effective with a low rate of side effects in patients with permanent neonatal diabetes caused by mutations in the KCNJ11 gene, a study in The Lancet Diabetes & Endocrinology shows.

Researchers from the Neonatal Diabetes International Collaborative Group followed up 81 patients who were diagnosed at a median of 8 weeks of age and transferred from insulin to sulfonylureas at a median age of 4.8 years (range 0.2 to 34.5 years), which they continued to take for a median of 10.2 years.

None of the patients discontinued treatment, and most (93%) did not require supplementary insulin to maintain glycemic control. Glycemic control was excellent overall, with the average glycated hemoglobin (HbA1c) level falling from an initial median of 8.1% to 5.9% after 1 year and remaining stable over 10 years of treatment. During this time the required sulfonylurea dose fell slightly, from a median of 0.30 to 0.23 mg/kg per day.

The six patients who required supplementary insulin were all male and had a high median HbA1c level of 8.5%, but otherwise had similar characteristics to the patients who did not need it. Andrew Hattersley (University of Exeter Medical School, UK) and co-researchers note that many patients were going through puberty, with its recognised effects on insulin sensitivity and medication adherence, adding that poor adherence was a stated issue for two of the six patients. Furthermore, the addition of insulin did not actually improve glycemic control in these six patients and they were on a “fairly modest” sulfonylurea dose (median 0.27 mg/kg per day), suggesting room for an increase.

These factors, together with the lack of insulin need in the rest of the cohort, suggest that sulfonylurea treatment was continuing to successfully block the patients’ pancreatic β-cell ATP-sensitive potassium channels and that other factors accounted for their poor glycemic control.

In patients with activating KCNJ11 and ABCC8 mutations, these channels have an increased probability of being open, which inhibits insulin secretion. Louis Philipson (University of Chicago, Illinois, USA) and co-authors of an accompanying commentary describe the treatment of these patients with sulfonylurea as “one of the best examples of precision genetic medicine in all medical practice.”

But they note the concerns caused by the poor long-term efficacy and safety profile of sulfonylurea in patients with type 2 diabetes, especially since its use in neonatal diabetes “often requires higher than approved doses and is given off-label in most countries when used in children.”

None of the patients with KCNJ11 mutations had severe hypoglycemia (causing seizure or loss of consciousness) during follow-up. The researchers point out that this compares very favorably with the rate among insulin-treated patients with type 1 diabetes, reported at 45% in one study. The patients also experienced a reduction in BMI while taking sulfonylurea, contrasting with the increase typically seen in insulin users.

Just 11 patients reported any side effects, nine of which were gastrointestinal. There was also one report of initial hepatic steatosis and one of tooth discoloration.

However, resolution of central nervous system (CNS) symptoms identified before transfer to sulfonlyureas was rare, despite improvements in features including muscle tone or weakness, concentration or attention deficit/hyperactivity disorder, gross motor skills, epilepsy, and learning difficulties. The researchers say the reason for this poor response is “not clear,” since both CNS symptoms and hyperglycemia are thought to be a direct result of the compromised function of the ATP-sensitive potassium channels.

“Further research is needed to investigate treatments to improve CNS function in patients with KCNJ11 mutations, as our data show this is a major clinical challenge for patients who have achieved excellent glycaemic control,” they conclude.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

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