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Severe relapsing sulphonylurea-induced hypoglycaemia: a diagnostic and therapeutic challenge
Q1: Describe the factors that increase the risks of sulphonylurea hypoglycaemia
Predisposing factors for severe sulphonylurea-induced hypoglycaemia include advanced age, use of long acting agents such as glibenclamide and chlorpropamide, caloric restriction, sustained physical exercise, acute systemic illnesses, alcohol, and renal, hepatic, and cardiovascular disease.1,2 In the elderly even shorter acting agents such as gliclazide can cause hypoglycaemia, especially if renal or hepatic dysfunction is present. About 60%–70% of a dose of gliclazide is excreted in the urine, with the rate of excretion being slowed when creatinine clearance decreases below 20 ml/min. The British National Formulary recommends gliclazide dose reduction in renal failure.3 Polypharmacy can increase the risk either by direct pharmacokinetic interaction (for example, inhibition of sulphonylurea metabolism by drugs such as fluconazole) or by effects on appetite, food intake, and absorption.4 Metformin may augment hypoglycaemia if co-prescribed with sulphonylurea or other insulin secretagogues. Prescription errors in non-diabetic subjects and deliberate overdose may occur.5 Finally, glibenclamide has been found in unorthodox medications. A combination of factors probably produced hypoglycaemia in our patient notably reduced food intake during the surgical admission, good recent glycaemic control as judged by her glycated haemoglobin and a degree of renal impairment
Q2: What was the reason for this patient’s prolonged hypoglycaemia?
Sulphonylureas bind to receptors on islet β-cells leading to insulin release. Fasting hypoglycaemia results if hyperinsulinaemia suppresses endogenous (predominantly hepatic) glucose production. Intravenous hypertonic glucose (20–50 ml 50% glucose via a large vein) will rapidly correct hypoglycaemia but then acts as a potent secretagogue to the sulphonylurea-sensitised β-cells. Insulin secretion is stimulated and hypoglycaemia recurs. For this reason, it is unwise to discharge patients with sulphonylurea-induced hypoglycaemia after a satisfactory response to a glucose bolus; intravenous glucose may be required for several days. The blood glucose concentration should be maintained around 5–7 mmol/l as this is sufficient to prevent neuroglycopenia, while avoiding maximal insulin secretion. By monitoring the serum potassium concentration the risk of hypokalaemia (from insulin and glucose) is reduced. Glucagon should be avoided as it stimulates insulin secretion.
Severe sulphonylurea-induced hypoglycaemia is a medical emergency.
The clinical presentation may be atypical requiring a high index of suspicion.
Relapse after a satisfactory response to intravenous glucose is well recognised.
Octreotide can reduce the relapse rate by inhibiting insulin secretion.
Treatment with glucose and octreotide may be required for several days.
Diazoxide may be used to reduce insulin secretion but should be used cautiously particularly in the elderly.
Q3: What pharmacological agents are available to treat hypoglycaemia in this situation?
Suppression of insulin secretion is a logical adjunct to intravenous glucose therapy in sulphonylurea-induced hypoglycaemia. Diazoxide inhibits insulin release,6 but hypotension and reflex tachycardia may preclude its use in elderly patients with coronary heart disease.7 The long acting somatostatin analogue octreotide has a potent inhibitory effect on insulin. Controlled studies in healthy volunteers have confirmed that octreotide effectively suppresses glucose-stimulated insulin secretion by sulphonylurea-sensitised β-cells.8 Several reports have also confirmed a clinical (but unlicensed) role for octreotide in patients with severe refractory sulphonylurea-induced hypoglycaemia.9–13 It should be administered subcutaneously in an initial dose of 50 μg three times a day and may be required for several days, especially for long acting or sustained release sulphonylurea preparations. Adverse effects include dose related transient abdominal pain and steatorrhoea.8