Endocrine Abstracts

Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion, leading to severe and persistent hypoglycemia especially in the newborn period. Mutations in the ABCC8 and KCNJ11 genes (which encode the SUR1 and the KIR subunit of KATP channels, respectively) are the commonest genetic cause of CHI. These mutations impair KATP channel function, leading to persistent depolarization of pancreatic beta cells and excessive insulin release. Patients with ABCC8 or KCNJ11mutations present with severe, medically refractory hypoglycemia, necessitating aggressive interventions such as partial or near-total pancreatectomy. The first line drug therapy for CHI is diazoxide, however most patients with ABCC8/KCNJ11 mutations do not respond. Other treatment options include octreotide (both short and long acting), nifedipine and sirolimus but even with these therapies most patients will continue to have episodes of hypoglycemia. Alpelisib, a selective phosphatidylinositol3-kinase (PI3K) inhibitor plays a crucial role in regulating cell growth, insulin signalling, and glucose metabolism. Originally approved for treating PIK3CA-mutated, hormone receptor-positive advanced breast cancer and overgrowth syndromes, alpelisib has also shown efficacy in managing non-islet-cell tumor hypoglycemia.The major side effect of alpelisib in patients with PIK3CA-mutated, hormone receptor-positive advanced breast cancer is hyperglycemia (with diabetic ketoacidosis reported in a few patients). Given the hyperglycemic effect of alpelisib we describe our observations in three patients with severe genetic forms of CHI where we re-purposed Alpelisib therapy for treating the hypoglycemia. Treatment was initiated at 12.5mg orally daily, with gradual dose adjustments based on clinical responses. Outcome measures included blood glucose variability, frequency of hypoglycemic episodes, need for supplemental feeding, and treatment safety. Alpelisib significantly improved glycemic control, reducing the frequency of hypoglycemic episodes in all three patients. This allowed for the tapering of other medications and in two patients discontinuation of all other medications (diazoxide and octreotide) and facilitated a transition to bolus gastrostomy-tube/oral feeding. No significant adverse effects were reported, growth and weight of all the patients remained normal. These observations suggest that alpelisib may be used for treating patients with CHI who are refracotry to all other forms of medical therapy. Randomized controlled trials are needed to assess its long-term safety and efficacy for CHI.