Case
A 75-year-old female was admitted with severe hypoglycaemia (blood glucose 1.3mmol/L) and associated neuroglycopaenia. Relevant medical history included longstanding type 2 diabetes mellitus, end-stage renal failure secondary to diabetic nephropathy (on haemodialysis) and ischaemic cardiomyopathy.
She reported recent onset recurrent hypoglycaemia with blunted adrenergic symptoms. HbA1c was 6.7%. Risk factors for hypoglycaemia included exogenous insulin (insulin glargine 100u/mL 10 units nocte, insulin aspart 4 units pre-meal), renal impairment, reduced carbohydrate intake and perhexiline 100mg orally twice daily (commenced three months prior for angina). Retrospective review of subcutaneous insulin charts and blood glucose levels prior to perhexiline initiation did not reveal hypoglycaemia.
Exogenous insulin was ceased, and hypoglycaemia persisted for three days. This raised suspicion for possible perhexiline-associated hypoglycaemia. A perhexiline level was measured, with a result of 535ug/L (150-600), and OH-Perhexiline/Perhexiline ratio of 6.2ug/L, suggesting extensive metaboliser status. Notably, the perhexiline level measured ten days post-initiation was threefold lower (150ug/L). Plasma insulin and c-peptide were analysed on the hypoglycaemic venous sample and were mildly elevated at 14mU/L (2-23) and 2.7nmol/L (0.3-1.4) respectively, consistent with renal impairment.
Perhexiline was ceased, with improvement in appetite and resolution of hypoglycaemia two days later. FreeStyle Libre Flash Glucose Monitoring was used to monitor interstitial glucose post-discharge, with an average glucose of 9.1mmol/L. She subsequently recommenced basal insulin, with adequate glycaemic control and no ongoing hypoglycaemic burden (HbA1c 7.0%).
Discussion
Perhexiline inhibits mitochondrial carnitine palmitoyltransferase 1, shifting myocardial substrate metabolism from long-chain fatty acids towards glucose, increasing myocardial efficiency. Caution should be exerted when prescribing perhexiline to patients with diabetes on insulin or oral hypoglycaemic agents due to secondary changes in myocardial glucose utilisation and potential iatrogenic hypoglycaemia. Whilst the degree of glucose lowering does not necessarily correlate with perhexiline concentration, clinicians should remain vigilant for hypoglycaemia given perhexiline’s polymorphic and highly variable metabolism.