Decade-Long Benefit With Sulfonylureas in Rare Genetic Diabetes

Liam Davenport

March 10, 2017

MANCHESTER, UK — Children and young people with a rare form of gene-associated neonatal diabetes can be safely and effectively treated with sulfonylureas for at least 10 years, say UK researchers

The results, presented at the Diabetes UK Professional Conference 2017, indicate that almost all patients with KCNJ11 gene-mutation–related permanent neonatal diabetes remained insulin-free at 10 years.

Moreover, the patients had good glycemic control, normal growth, and no weight gains, with no serious side effects, Pamela Bowman, MD, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom, told the audience.

 "This is the first large study in an international cohort to show that sulfonylureas are safe, and they are a highly effective treatment for KCNJ11 permanent neonatal diabetes," she said.

"That contrasts markedly with the response that we see in patients with type 2 diabetes on sulfonylureas," she added.

"As clinicians, I think we can be confident in reassuring our patients with this type of diabetes that they should be on sulfonylureas and they should be able to stay on them long term."

KCNJ11 gene-mutation–related permanent neonatal diabetes is one form of what is also known as monogenic diabetes, genetic diabetes, or maturity-onset diabetes of the young (MODY) — so-called because it often goes unrecognized in younger individuals and/or people are misdiagnosed as having type 1 or type 2 diabetes. Dr Bowen's institution has a MODY calculator where physicans can input clinical characteristics of their patients to determine a diagnosis, available at Diabetes Genes.

Session cochair and pediatric endocrinologist Nicola Bridges, MD, of Chelsea and Westminster Hospital, London, United Kingdom, told Medscape Medical News afterward that, although the results show that the use of sulfonylureas in this population is a "good solution," it seems like a counterintuitive approach.

She said: "There's this obviously very small group of patients who had this form of diabetes, in which, bizarrely, you stop the insulin and you give them sulfonylureas, and their control is better, and they have a low incidence of problems.

"There's people who don't know they've got it…who've gotten diagnosed when they were young, and now 20 years later, probably they've forgotten all about [it]…and they may have MODY."

HbA1c Nicely Maintained With No Increase in Dose of Sulfonylureas

Dr Bowman began her presentation by explaining that a KCNJ11 gene mutation causes permanent neonatal diabetes because the insulin is unable to escape from the beta cells, "so it means it's locked inside," resulting in patients presenting in an insulin-deficient state.

Previous small studies have indicated that 90% of KCNJ11 permanent neonatal diabetes patients can be transferred from insulin to oral sulfonylureas, greatly improving glycemic control.

This is in stark contrast to the picture in type 2 diabetes, where approximately half of patients can no longer maintain good glycemic control after 5 to 6 years of taking the drugs.

To examine the long-term efficacy and safety of sulfonylureas in KCNJ11 permanent neonatal diabetes patients, the team, which included the Neonatal Diabetes International Collaboration, gathered data on all 55 individuals with the condition who had transitioned from insulin to sulfonylureas since 2007.

They collected information on metabolic control, sulfonylurea dose, adverse effects, hypoglycemia, complications, and growth, yielding information on a total of 49 patients (89% of those eligible) with a median follow-up of 10.2 years.

They found that 94% of the patients remained insulin-free at 10 years, while their glycemic control was "excellent."

Dr Bowman noted: "With insulin, the median HbA1c is 8.2%; at 1 year that drops to 5.9% and at 10 years it's 6.3%, so it's maintained really nicely over that long period of follow-up.

"With that, there is not an increase in the dose of sulfonylureas. If anything, there's a slight downward trend in the dose of sulfonylureas in order to maintain that excellent glycemic control."

Growth rates were also normal after 10 years of treatment with sulfonylureas, and there was no overall weight gain, as assessed by body mass index.

Dr Bowman also noted that these drugs were "really safe in these patients," with no serious side effects, no severe hypoglycemia, and no macrovascular complications, resulting in none of the patients stopping treatment due to adverse events.

Microvascular complications, primarily retinopathy, occurred in six patients, although she pointed out those patients had a median age of 22.1 years at transfer to sulfonylureas vs 4.3 years in those without any complications (= .0008), suggesting that the complications may have developed while on insulin.

She concluded: "In summary, 94% of our patients remain off insulin at 10 years. They have excellent metabolic control, without an increase in sulfonylurea dose, and no serious side effects or severe hypoglycemia.

"There's normal growth in children, no weight gain associated with improved glycemic control, and very few complications. And any complications that occur appear to be related to a long period of insulin prior to transfer to sulfonylureas."

The study was conducted by the Exeter Clinical Research Facility, with support from National Institute for Health Research and the Wellcome Trust. The authors declared no relevant financial relationships.

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Diabetes UK Professional Conference 2017. March 9, 2017; Manchester, UK. Abstract A37

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