Sulfonylurea for improving neurological features in neonatal diabetes: A systematic review and meta‐analyses

Abstract

Objective: In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP-channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo-motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8-related neonatal-onset diabetes mellitus.Research Design and Methods: We conducted a systematic review and metaanalyses of the literature (PROSPERO, CRD42021254782), including individualpatient data, according to PRISMA, using RevMan software. We also graded the level of evidence.Results: We selected 34 of 776 publications. The evaluation of global neurological function before and after sulfonylurea (glibenclamide) treatment in 114 patients yielded a risk difference (RD) of 58% (95%CI, 43%-74%; I 2 = 54%) overall and 73% (95%CI, 32%-113%; I 2 = 0%) in the subgroup younger than 4 years; the level of evidence was moderate and high, respectively. EEG studies of epilepsy showed a RD of 56% (95%CI, 23%-89%; I 2 = 34%) in patients with KCNJ11 mutations, with a high quality of evidence. For hypotonia and motor function, the RDs were 90% (95%CI, 69%-111%; I 2 = 0%) and 73% (95%CI, 35%-111%; I 2 = 0%), respectively, with a high level of evidence.Conclusions: Glibenclamide significantly improved neurological abnormalities in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations. Hypotonia was the symptom that responded best. Earlier treatment initiation was associated with greater benefits.

Early treatment of neonatal diabetes with oral glibenclamide in an extremely preterm infant

“…Neonatal hyperglycemia is observed in more than one out of four very low birthweight infants [10][11][12] and generally treated with insulin, even though the actual benefits of insulin treatment remain highly debated. 13,14 The benefits of sulfonylureas on neurodevelopmental outcome 3,5 and the unknown actual prevalence of potassium channel mutations in infants developing transient hyperglycemia suggest the need for further investigations aimed to explore the frequency of the mutations in neonatal hyperglycemia as well as the use of glibenclamide as first-line treatment for neonatal hyperglycemia.…”

“…Such an effect, besides the largely demonstrated metabolic benefits, 2,3 seems to be inversely correlated with the age-of-treatment onset, with earlier treatment showing more pronounced improvement in visual and motor neurodevelopmental domains. 4,5 Several barriers still prevent an early beginning of treatment in newborns with suspected neonatal diabetes, including the delay of genetic testing and the absence of neonatal-adapted formulation able to easily titrate neonatal dose and to be adjusted to specific neonatal administration as the need for mixing with maternal or formula milk.…”

“…The use of sulphonylureas for the treatment of neonatal diabetes secondary to mutations in potassium‐channel subunits has been proven to produce marked improvements in neuropsychomotor development, 1 including the domains of attention, motor coordination, and language. Such an effect, besides the largely demonstrated metabolic benefits, 2,3 seems to be inversely correlated with the age‐of‐treatment onset, with earlier treatment showing more pronounced improvement in visual and motor neurodevelopmental domains 4,5 …”

Systematic Review of Treatment of Beta-Cell Monogenic Diabetes

“…Systematic review will allow a comprehensive assessment of the strength of the evidence for the specific recommendations for precision medicine approaches. To our knowledge there is only one area of beta-cell monogenic diabetes where robust systematic reviews have been used-this is in the glycemic treatment of KATP-ND with high dose SU 5 and the partial response of neurological features in KATP-ND to high dose SU therapy 6 .…”

Corrigendum

“…In the article de Gouveia Buff Passone et al, 1 the authors would like to acknowledge that this work was financed in part by a grant from the Agence Nationale de la Recherche (ANR) called Neurogli.…”