Five-year follow-up of incretin-based therapy in a patient with KCNJ11-related permanent neonatal diabetes: Achieving insulin discontinuation and sulfonylurea reduction.

Permanent neonatal diabetes mellitus (PNDM) is commonly caused by pathogenic variants in KCNJ11 that impair insulin secretion through ATP-sensitive potassium (KATP) channel dysfunction. Sulfonylureas (SUs) can stimulate insulin secretion and enable insulin discontinuation, but insulin withdrawal may remain difficult even under high-dose SU, especially when therapy is initiated later in life. We describe a woman with KCNJ11-related PNDM who achieved insulin discontinuation after adding sitagliptin, followed by further improvement with semaglutide during a five-year follow-up. HbA1c remained between 6.1% and 6.5% on semaglutide 0.25 mg/week, with a 60% reduction in glibenclamide and preserved endogenous insulin secretion. A transient HbA1c rise after semaglutide interruption, followed by improvement upon resumption, confirmed its reversible effect. No episodes of severe hypoglycemia or gastrointestinal adverse events occurred. This case suggests that combining insulin secretagogues targeting both KATP-dependent (triggering: SU) and KATP-independent (amplifying: incretin-based therapy) pathways may provide additive or synergistic benefits in PNDM.