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Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons
David Carmody1, Charles D Bell, Jessica L Hwang
1Departments of Medicine and Pediatrics (D.C., C.D.B., J.L.H., J.T.D., R.N.N., L.H.P., S.A.W.G., Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois 60637; Department of Pediatric Endocrinology (D.I.S.), Albany Medical Center Hospital, Albany, New York 12208; Department of Endocrinology and Diabetes (D.L.F.), Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, Louisiana 70112; Academic Endocrinology and Edward Hospital (C.A.Z.), Naperville, Illinois 60540; Department of Pediatrics (A.O.D.), Division of Pediatric Endocrinology, MetroHealth Medical Center, Cleveland, Ohio 44109; and Nunnelee Pediatric Specialty Clinic (K.K.), Betty H. Cameron Women's and Children's Hospital, New Hanover Regional Medical Center, Wilmington, North Carolina 28401.
Insights
Initiating sulfonylurea therapy before genetic testing in neonatal diabetes is safe and effective. Early treatment can improve glycemic control and neurodevelopmental outcomes in infants with monogenic diabetes.
Area of Science:
- Pediatric Endocrinology
- Genetics
- Metabolic Disorders
Background:
- Neonatal diabetes mellitus (NDM) predominantly has a monogenic cause.
- Mutations in KCNJ11 and ABCC8 are the most frequent genetic culprits in NDM.
- Early intervention with sulfonylurea (SU) therapy shows promise for improving outcomes in specific NDM genetic subtypes.
Purpose of the Study:
- To evaluate the safety and efficacy of initiating sulfonylurea therapy empirically before definitive genetic testing results are available in neonatal diabetes patients.
- To assess the risks and benefits associated with early SU treatment in this population.
Main Methods:
- An observational retrospective study was conducted using data from the University of Chicago Monogenic Diabetes Registry.
- Included were subjects diagnosed with diabetes before six months of age.
- The study analyzed response to SU (insulin discontinuation) and adverse events in patients receiving empirical treatment.
Main Results:
- Of 154 neonates with diabetes, 118 (77%) received a genetic diagnosis, with 73 (47%) harboring KCNJ11 or ABCC8 mutations.
- The median time to genetic diagnosis was 10.4 weeks.
- Nine patients received empirical SU treatment within 28 days of diagnosis; eight had confirmed genetic causes, and all discontinued insulin within 14 days of SU initiation.
Conclusions:
- Empirical sulfonylurea therapy appears safe and effective for neonatal diabetes patients awaiting genetic test results.
- Early SU treatment may positively impact glycemic control and neurodevelopmental outcomes.
- While empirical SU trials can be considered due to potential benefits and testing delays, genetic diagnosis remains crucial for long-term management and prognosis.
Context:
Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes.
Objective:
Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available.
Design, Setting, And Patients:
Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry.
Main Outcome Measures:
Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically.
Results:
A total of 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range, 1.6 to 58.2 wk). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases.
Conclusions:
Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.
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