Clopidogrel-Induced Insulin Autoimmune Syndrome: A Newly Recognized Cause of Hypoglycemia in a Patient Without Diabetes

Abstract

Insulin autoimmune syndrome (IAS), defined as hyperinsulinemic hypoglycemia with high titers of anti-insulin antibodies, is frequently reported in Japanese patients but rarely observed in whites. We report in this study on a 79-year-old white male without diabetes who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia. The patient presented with recurrent symptomatic hypoglycemia. During one episode, serum glucose was 45 mg/dL, whereas insulin and C-peptide levels were 40,000 mIU/mL and 40 ng/mL, respectively. Additional studies revealed no intake of insulin or its secretagogues, whereas anti-insulin antibody titer was high (59.3 nmol/L). Although total insulin levels were consistently high, free insulin concentrations (polyethylene glycol precipitation) were appropriate for ambient glycemia. The patient was found to have HLA-DRB1*0404, a feature often reported in Japanese patients with IAS. Three weeks prior to symptom onset, he was started on clopidogrel, a drug that does not have a sulfhydryl group, but its active metabolite does. Clopidogrel was switched to a nonsulfhydryl antiplatelet agent, and glucocorticoid therapy was initiated. Shortly thereafter, the frequency of hypoglycemic episodes decreased, and glucocorticoids were tapered over the ensuing 3 months. No hypoglycemic episodes were noted during 6 months of observation after discontinuing glucocorticoids, whereas the total insulin and anti-insulin antibody levels normalized. The data indicate that IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.

Keywords: clopidogrel; drug-induced hypoglycemia; hypoglycemia; insulin autoimmune syndrome.

Figure 1.

(a) Levels of total insulin (dashed line) and free insulin (solid line) plotted against the corresponding serum glucose levels on x-axis prior to treatment. The graph shows that although the total serum insulin levels were consistently high, free insulin levels when determined by PEG precipitation were appropriate for ambient glycemia during the initial treatment phase. (b) Levels of total insulin (dashed line) and free insulin (solid line) plotted against the corresponding serum glucose levels on x-axis during the 3 months of observation after discontinuing glucocorticoids. The graph shows that the total serum insulin levels have greatly decreased (note different scale), although the levels were still higher than free insulin levels. The latest levels are quite comparable with glucose of 84 mg/dL.

Figure 2.

Chemical structure of clopidogrel is shown not to have a sulfhydryl group. A thiol derivative of the drug is shown after activation by the P450 enzyme system. The active metabolite does contain a sulfhydryl group (arrow).

Figure 3.

Levels of serum total insulin (y-axis) plotted against the time in months (x-axis) during the course of treatment. The initial drop in total insulin levels during the first month was due to methylprednisolone and prednisone given as a treatment of COPD exacerbation. One month after symptom onset, clopidogrel was discontinued, and he was started on dexamethasone (DEX). The graph shows that the total insulin levels decreased to normal levels by the end of 4 months. Inset figure is the magnification of the graph during the last 3 months of treatment and shows a drastic decrease of total insulin levels. CHO, carbohydrate; IV, intravenous.

Figure 4.

Levels of serum anti-insulin antibodies (y-axis) plotted against the time in months (x-axis) during the course of treatment. The initial drop in anti-insulin antibodies levels during the first month was due to methylprednisolone and prednisone given as a treatment of COPD exacerbation. One month after symptom onset, clopidogrel was discontinued, and he was started on dexamethasone (DEX). The graph shows that the anti-insulin antibodies decreased to normal levels by the end of 4 months. Inset figure is the magnification of the graph during the last 3 months of treatment and shows a drastic decrease of the anti-insulin antibodies titers. CHO, carbohydrate; IV, intravenous.