Aim
To describe a case of rapid-onset clopidogrel-induced Insulin Autoimmune Syndrome (IAS; Hirata syndrome) presenting with recurrent hypoglycaemia which highlights associated conditions and diagnostic challenges related to insulin autoantibody (IAA) interference.

Methods
An 86-year-old man presented with recurrent symptomatic hypoglycaemia two months after commencing clopidogrel following a transient ischaemic attack.  During hypoglycaemia (plasma glucose 2.8 mmol/L), serum insulin (>1000 mU/L) and C-peptide (4.9 nmol/L) were markedly elevated, confirming Whipple’s triad. Pancreatic imaging including CT and 68Ga-DOTATATE PET/CT were performed. IAA levels were measured, and polyethylene glycol (PEG) precipitation studies were performed to assess assay interference. Autoimmune panels, serum protein electrophoresis and sulfonylurea testing conducted for secondary screening.

Results
IAA titres were markedly elevated (1769 U/mL; reference 0–0.5), consistent with IAS. PEG precipitation demonstrated significant depletion of insulin/C-peptide immunoreactivity, supporting antibody interference. Pancreatic imaging was negative. Low-level IgG lambda paraprotein consistent with monoclonal gammopathy of undetermined significance (MGUS) was detected. Clopidogrel was ceased and aspirin reinstated. Weaning prednisolone (maximum dose 30 mg daily) resulted in resolution of hypoglycaemia. IAA titres declined progressively (311 U/mL at 3 weeks; 39 U/mL at 7 weeks; near-normal by 9 months). The patient remained hypoglycaemia-free over four years, with complete IAA normalisation by 14 months.

Conclusion
Clopidogrel can precipitate rapid-onset IAS, likely via a sulfhydryl-containing metabolite and there may be an increased predisposition to hypoglyceamia due to MGUS. Markedly elevated insulin levels during hypoglycaemia should prompt consideration of IAS to reduce unnecessary pancreatic investigations. Interpretation of insulin/C-peptide assays must consider IAA interference. This report demonstrates that clopidogrel-induced IAS may develop rapidly. Early recognition, withdrawal of the offending agent, and short-term immunosuppression can achieve sustained remission. It reinforces the importance of recognising rare, idiosyncratic adverse drug reactions associated with IAS.