Permanent neonatal diabetes mellitus (PNDM) is a genetic disorder, characterized by a decrease in endogenous insulin secretion. Therefore, exogenous insulin supplementation plays a central role in controlling glycemia. Although adding a sulfonylurea can help to discontinue insulin, discontinuation is sometimes difficult when the sulfonylurea is administered at older ages. A 24-year-old woman with longstanding PNDM who had poor glycemic control using insulin (47 U/day) and high-dose glibenclamide (0.6 mg/kg/day), had successfully discontinued insulin after initiating the dipeptidyl peptidase-4 inhibitor sitagliptin (50 mg/day). Additionally, hemoglobin A1c levels decreased by 4.8%. Double dosing of sitagliptin and subsequent switching to the glucagon-like peptide-1 receptor agonist semaglutide (0.25 mg/week followed by 0.5 mg/week) further decreased hemoglobin A1c values, with graded improvements in endogenous insulin secretion. There were no episodes of hypoglycemia during which glibenclamide was titrated down from 0.6 to 0.4 mg/kg/day. Intra- and inter-day glucose variability as assessed by continuous glucose monitoring was also improved. In patients with PNDM, administration and dose escalation of incretin-based drugs, in addition to a high-dose sulfonylurea, could be a useful treatment strategy. This strategy may be helpful for discontinuing insulin, downtitrating sulfonylureas, and subsequent achievement of better glycemic control regarding long-term stability and short-term variability.