Low-dose diazoxide therapy in hyperinsulinaemic hypoglycaemia

Dear Editor,

Hyperinsulinaemic hypoglycaemia (HH) is a rare condition with elevated and unregulated levels of insulin, resulting in low blood glucose concentrations. It is the most common cause of persistent hypoglycaemia in infants and children, causing a high risk of developing brain injuries such as epilepsy, cerebral palsy, or neurological impairment.¹ Diazoxide remains the first-line medication used to treat HH.¹ It binds to the SUR1 subunit of KATP channels to inhibit β-cell depolarisation and thus insulin secretion. However, it is important to note that fluid retention, hypertrichosis, and feeding problems are common side effects of diazoxide. Rare severe consequences can also occur like pulmonary hypertension and congestive heart failure. Apart from a single study reporting the use of low-dose diazoxide in small for gestational age (SGA) infants, diazoxide has been reported to be used in doses of 5−20 mg/kg/day.²

Chandran et al. highlighted the efficacy and safety of using ≤5 mg/kg/day of diazoxide in 27 SGA babies.² Twenty-six (97%) of these passed a fasting study before discharge from the hospital, establishing normal glucose control on low-dose diazoxide. Furthermore, diazoxide was discontinued at a median age of 63 days, and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study. Their study benefits from a robust trial protocol with a modest sample size considering that HH is a rare disease and that Singapore has a small population.

Similarly, we conducted a retrospective analysis evaluating the effectiveness and outcomes of using low-dose diazoxide (≤5 mg/kg/day) that have successfully managed HH. We have identified 34 patients with biochemically confirmed HH that were treated with low-dose diazoxide at two tertiary children hospitals in London from April 2020 to March 2023. Patient characteristics (birth weight and gestational age) and treatment details were collected from electronic patient records. For the comparative analysis, the patients were stratified into two groups based on their birth weight: SGA and non-SGA (appropriate for gestational age–AGA and large for gestational age–LGA). SGA was defined as birth weight <10th centile. The patients were also differentiated by their gestational age: preterm (<37 weeks) and term (≥37 weeks). Patient outcomes that were assessed included: (1) median age of starting and stopping treatment; (2) median dosage of diazoxide on discharge from hospital; and (3) follow-up outcomes: side effects from diazoxide, adjustment of diazoxide dose, and neurodevelopmental outcomes.

Of the 34 infants, 15 were SGA and 19 were non-SGA. The patient characteristics and details of diazoxide treatment are summarised in Table 1. All babies had their total fluid volume adjusted to approximately 130 mL/kg/day when initiating diazoxide. All infants underwent an age appropriate controlled fast successfully before discharge from the hospital, showing normal glucose control whilst on diazoxide.

We did not gain ethical approval specifically to start diazoxide as is standard of care, however, every patient was reviewed by the hospital pharmacist who agreed to the use of low-dose diazoxide. Furthermore, a general consensus exists on the use of a lower dose of diazoxide which is used in many centres and is reported in the United Kingdom consensus guidelines (due to be published soon). This would be the first published report on the efficacy and outcomes from the use of low dose diazoxide in these cohort of patients.

During follow-up, there were 6 (17.6%) babies who had documented episodes of hypoglycaemia (i.e., ≤3.5 mmol/L); one each had three and two episodes of hypoglycaemia respectively, and the remaining four babies had one episode. The lowest documented blood glucose reading was 3.3 mmol/L. Three babies in the SGA group (two preterm) and three babies in the non-SGA group. All patients required only once increment of diazoxide <1 mg/kg/day in view of these observations, with the total daily dosage still remaining ≤5 mg/kg/day given the infant's weight gain. It is worth noting that there were no reports of symptomatic hypoglycaemia. Five (14.7%) infants were identified to have minimal fluid retention during follow-up which resolved on increasing the dose of diuretics. Two infants had a genetic confirmation of HNF4A mutation, done in view of the strong family history of diabetes. No significant neurodevelopmental concerns have been identified on follow-up so far.

HH may be transient or persistent, lasting from a few days to being life-long.¹ The patient cohort that responded to low dose diazoxide in our study had mostly transient HH, with the median age of stopping diazoxide being 4 months. These observations are encouraging to note as some babies may only need to be on medications for a few months, lowering the risk of the side effects from diazoxide.

Our study is the first report to show the effectiveness of low-dose diazoxide in stabilising blood glucose across all groups (SGA, non-SGA, preterm, and term). In addition, we report two cases of congenital HH caused by a mutation of HNF4A. The HNF4A gene encodes for the transcription factor hepatocyte nuclear 4a which controls the expression of genes involved in insulin secretion.³ The sibling of one of these patients has been reported previously and was known to have HH that was very sensitive to diazoxide treatment, requiring lower doses⁴ and developed hyperglycaemia on traditional doses of diazoxide. It may be that this particular mutation in HNF4A (p.Ser419Ter; c.1256C>G) leads to exceptional sensitivity to diazoxide or that mutations in HNF4A in general require smaller doses of diazoxide. Notably, HNF4A is associated with maturity-onset diabetes of the young (MODY). These children will need to be continuously monitored for signs of diabetes so that early treatment can be commenced.

To conclude, low-dose diazoxide can be an effective treatment for babies with HH, independent of birth weight, and may avoid prolonged stay in the hospital. Certain genetic forms of HH may also be suitable for treatment with low dose diazoxide. Hence, lower doses of diazoxide should be considered in infants with HH before using traditionally published doses (>5 mg/kg/day) with close and frequent blood glucose monitoring. Although generally well-tolerated, fluid retention can develop in a minority of patients, confirming a need for regular follow-ups and vigilance even at lower doses. The use of low-dose diazoxide would benefit from a larger cohort and multicentre study.