ESPE Abstracts (2018) 89 FC10.5

A 5-Year Single-Centre Experience on the Safety and Efficacy of Sirolimus Therapy used for the Treatment of Congenital Hyperinsulinaemic Hypoglycaemia

Maria Güemesa,b, Antonia Dastamania, Michael Ashworthc, Kate Morgana, Sian Ellardd, Sarah Flanagand, Mehul Dattania,b & Pratik Shaha,b


aEndocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; bSection of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London Great Ormond Street Hospital Institute of Child Health, London, UK; cHistopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; dMolecular Genetics Department, University of Exeter Medical School, Exeter, UK


Background: Case reports have documented variable glycaemic response to the mTOR inhibitor Sirolimus in severe diazoxide+/−octreotide unresponsive forms of congenital hyperinsulinaemic hypoglycaemia (CHI). A high incidence of adverse effects has been reported in patients receiving this medication.

Objective(s): To describe the efficacy and safety of Sirolimus use over a 5-year period in the largest cohort of CHI patients treated to date.

Methods: Retrospective data were collected on CHI patients treated with Sirolimus in a single centre between 2013 and 2018. Our data were then compared with those reported in 15 previously published case reports of Sirolimus treatment in CHI (PubMed search). Complete response to Sirolimus was defined as glycaemic stabilisation exclusively on this drug, partial response as CHI being managed on a combination of Sirolimus plus concomitant medication for CHI, and unresponsiveness as non-existent glycaemic amelioration despite combination of Sirolimus with other CHI medications.

Results: Twenty-two CHI patients (14 female) were included. A partial response to Sirolimus was observed in 20/22 (90.9%) cases. One patient (4.5%) showed a complete response, and one patient (4.5%) was unresponsive. Compound heterozygous ABCC8 mutations were present in 52.4% (11/21) of the partially/fully responsive patients. Complications during Sirolimus treatment occurred in 86.4% (19/22) of treated patients; infections were the most prevalent (17/22; 77.3%), of which 64.7% (11/17) were caused by bacteraemia. Three patients (13.6%) developed persistent diarrhoea, while hyperglycaemia occurred in 9.1% (2/22). Sirolimus was discontinued in 17/22 (77.3%) patients, 13 (76.4%) of whom had infections, 2 (11.7%) had hyperglycaemia, and 2 (11.7%) responded well to alternative Lanreotide treatment. When compared with existing literature on the use of mTOR inhibitors in CHI, our study shows a higher number of cases that are partially/fully responsive to Sirolimus, whilst complication rates are comparable to previously published data.

Conclusions: Frequent and potentially serious complications render Sirolimus as an agent that is only suitable for trial in selected cases of severe CHI that are unresponsive to other medications. We suggest that its use for short periods, until glycaemic stabilisation is achieved using other therapies such as Lanreotide, could be contemplated as it may avoid pancreatectomy. The potential benefit of Sirolimus in cases of CHI associated with certain genetic mutations needs to be explored further.

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