Efficacy and Safety of Sirolimus (mTOR Inhibitor) in Two Patients with Diazoxide-Unresponsive Hyperinsulinemic Hypoglycemia

Although sirolimus is a novel treatment option for congenital hyperinsulinism (CHI), which often requires surgery, its immune suppressive and toxic side effects may limit its usage. We present the efficacy and safety of sirolimus in two patients with diazoxide-unresponsive CHI.
Case 1: A male presented at the first postnatal day with hypoglycemic convulsions and a diagnosis of CHI was confirmed. Genetic analysis identified two homozygous mutations, p.L270M and p.E288K in the KCNJ11 gene. Despite maximum doses of diazoxide, octreotide, and glucagon, the requirement of 18 mg/kg/min glucose infusion suggested medically unresponsive CHI. At postnatal day 15, sirolimus was commenced at a dose of 0.5 mg/m2/day which was gradually increased and glucose infusion was tapered accordingly. Blood sirolimus level of 27.9 ng/mL (N: 5-15 ng/mL) was attained at a dose of 2 mg/m2/day and normoglycemia was achieved with no need for treatment. The patient however developed renal and hepatic failure which recovered spontaneously following withdrawal of sirolimus. When sirolimus level dropped to therapeutic range, hypoglycemia episodes recurred. He also had three episodes of blood culture-confirmed sepsis. He was referred to another center for surgery.
Case 2: A 5-year-old male was admitted with a history of CHI diagnosed at postnatal day 45 having previous partial (80%) pancreatectomy. Following the identification of homozygous p.R1494W mutation in the ABCC8 gene, diazoxide was stopped and sirolimus was commenced. Dose was gradually increased to 1.0 mg/m2/day and the patient showed a good glycemic response. Octreotide dose was reduced from 20 µg/kg/day to 6.6 µg/kg/day with no hypoglycemia episode and excellent fasting tolerance up to 10 hours. Except for mild elevation of liver enzymes, no side effects were observed. In conclusion, we present two distinct experiences on the efficacy and safety of sirolimus. These findings suggest a comprehensive need for identifying the optimal doses and therapeutic blood level in addition to careful monitoring for side effects.