INTRODUCTION
Insulin autoimmune syndrome (IAS) is a rare autoimmune disease characterized by recurrent hypoglycemia resulting from raised insulin autoantibody (IAA) titers [1]. Although IAS has a low global incidence, over 85% of reported cases occur in East Asia, yet population-based prevalence remains undetermined due to a lack of epidemiological data [2]. The pathogenic mechanisms underlying IAS are multifaceted, involving complex interactions among genetic susceptibility, immunologic factors, and the use of sulfhydryl-containing drugs or exogenous insulin.
Clopidogrel, a widely used antiplatelet aggregation agent, is metabolized by cytochrome P450 enzymes to generate immunogenic compounds containing sulfhydryl groups that may precipitate hypoglycemia [3, 4]. It has been reported that most patients experience symptom resolution within three to six months after stopping the culprit drugs [5]. Despite the increasing incidence of IAS, only 13 cases of clopidogrel-induced IAS (CIAS) have been reported in the literature to date, according to PubMed and Embase searches [3-14].
To highlight the diagnostic and therapeutic challenges of CIAS, we present an elderly male who developed refractory hypoglycemia despite combined therapy, including clopidogrel withdrawal, dietary management, and alpha-glucosidase inhibitors. Eventually, glucocorticoid therapy was initiated. However, there is no standardized treatment for CIAS, and clinicians tailor treatments based on the patient’s condition.
This article aims to enhance awareness of CIAS by detailing the clinical presentation, therapeutic approach, and follow-up outcomes of a geriatric patient in our department.
CASE REPORT
In January 2024, a 77-year-old man with a BMI of 24.19 kg/m2 was admitted with recurrent hypoglycemia attacks for three months. Before admission, he experienced dizziness, palpitations, and fatigue occurring during both fasting and delayed postprandial states. His insulin release test demonstrated high insulin concentrations (Table 1), with no history of exogenous insulin use.
His medical history included hypertension and coronary atherosclerotic heart disease, for which he had been taking clopidogrel and atorvastatin for the past six months. He had moderate renal impairment but no liver disease or familial diabetes. Human growth hormone (GH), thyroid function, and cortisol rhythm were all within the normal ranges (Table 2).
Contrast-enhanced abdominal computed tomography (CT) excluded pancreatic tumors (Fig. 1), and comprehensive serological testing showed no evidence of other autoimmune disorders. During the first three days of continuous glucose monitoring (CGM) data recorded by the SIBIONICS system, blood glucose levels fluctuated between 2.2 mmol/L and 15.2 mmol/L (normal range: 3.9-7.8 mmol/L), with hypoglycemia predominantly occurring at midnight and in the late postprandial phase.
In one hypoglycemic episode, blood glucose was 2.4 mmol/L, insulin level was 995.07 mIU/L (normal range: 1.9-23.0 mIU/L), and C-peptide level was 6.97 nmol/L (normal range: 0.37-1.43 nmol/L). Critically, to further differentiate the diagnosis, an elevated IAA titer of 36.7 COI (>1.1 COI, positive) was detected, whereas no genetic variations were found through whole-exome sequencing. However, human leukocyte antigen (HLA) genotyping testing was not performed for personal reasons.
These findings confirmed the diagnosis of IAS.
Initially, treatment consisting of small, frequent meals and acarbose therapy failed to prevent hypoglycemia. Clopidogrel, containing metabolized sulfhydryl groups, was suspected as the causative agent for IAS. Consequently, the drug was ceased, and prednisolone was initiated at 30 mg/day, tapered by 5 mg per week, and maintained at 5 mg/day until discontinuation in July (Fig.
2). Upon follow-up after prednisolone withdrawal, his latest tests revealed a fasting insulin level of 8.09 mIU/L, a glycated hemoglobin (HbA1c) level of 6.2% (normal range: 0.0-6.1%), and a decrease in IAA titer from 36.7 COI to 1.35 COI in November. Until now, he has been treated with metformin to control blood glucose.
DISCUSSION
Currently, there are no recognized guidelines for the diagnosis of IAS, but the following criteria primarily informed it: first, patients frequently present with a typical Whipple’s triad; second, notwithstanding elevations in serum insulin and C-peptide levels, blood glucose levels during hypoglycemia attacks below 2.8 mmol/L; finally, the gold standard is a positive IAA test. Exclusion of all other plausible etiologies of hyperinsulinemic hypoglycemia is mandatory, encompassing insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome, and type B insulin resistance syndrome [7]. The present patient fulfilled the above criteria.
The incidence of IAS has progressively increased since its first report in 1970 [15]. So far, it is widely accepted that the production of IAA, characterized by high binding capacity and low affinity, is a central factor in IAS [1]. Mechanistically, upon binding with insulin, these antibodies rapidly form large antigen-antibody immune complexes after meals, thereby inducing postprandial hyperglycemia that accounts for the patient’s raised HbA1c level.
In response, islet β-cells increase insulin secretion, while substantial amounts of free insulin are released into the blood due to dissociation of insulin-antibody complexes during the late postprandial phase, ultimately causing hypoglycemia. Since the association and dissociation of insulin from immune complexes are independent of blood glucose levels, the patient described here exhibited recurrent hypoglycemia and hyperglycemia. Moreover, hypoglycemic episodes occurred between 2 a.m. and 5 a.m., suggesting that insulin antibodies are sensitive to circadian variations in the internal environment.
Epidemiologically, a recent review documented 795 IAS cases worldwide, with the highest prevalence in Japan and China, respectively [2]. This geographic distribution correlates with the strong association between IAS and HLA-DR4, particularly DRB1*0406, an allele highly prevalent in Japan [16]. Although the absence of HLA genotyping in this case did not affect the diagnostic confirmation of IAS, it may have limited the complete immunogenetic characterization.
Additionally, several sulfhydryl-containing drugs can cause IAS, possibly because of the sulfhydryl group’s ability to disrupt insulin disulfide bonds, among which clopidogrel represents a causative agent [3]. Of particular clinical relevance, a case review indicated that the average age at CIAS onset was 74.8 ± 8.6 years, with symptom onset ranging from one week to nearly two years following clopidogrel treatment [4]. Notably, the features observed in our patient align closely with the findings mentioned above (Table 3).
The treatment schemes for CIAS patients included the withdrawal of causative drugs, dietary modifications, glucocorticoids [5-10], plasmapheresis [8], rituximab [17], and other interventions. While existing literature suggests that glucocorticoids do not significantly affect recovery time in CIAS, ticagrelor may be an alternative, although it is not routinely recommended [4]. Considering the patient's advanced age and preexisting cardiovascular/renal comorbidities, a moderate-dose glucocorticoid regimen (0.5 mg/kg/day prednisone equivalent) was initiated, consistent with published CIAS cases demonstrating effective autoimmune antibody suppression and a favorable safety profile [7, 9].
The glucocorticoid tapering protocol was individualized based on glycemic stabilization, reduction in both serum insulin levels and IAA titers from peak values, and absence of hypoglycemic episodes. This approach effectively balanced immunosuppression against risks of disease recurrence and steroid-related complications (notably gastrointestinal bleeding, adrenocortical insufficiency, and osteoporosis). Given the patient’s high bleeding risk (age > 65 years, hypertension, and renal dysfunction) and limited evidence for alternative antiplatelet agents in IAS, no replacement therapy was administered after clopidogrel discontinuation.
Glycemic management is a considerable challenge for IAS patients treated with glucocorticoids, as these agents can disrupt glucose metabolism. In this context, real-time CGM provides substantial benefits for monitoring and optimizing glucose control. Prior to prednisolone initiation, CGM detected alternating phenomena of hypoglycemia during fasting and delayed postprandial states, along with hyperglycemia in the early postprandial phase, accompanied by elevated glycemic variability (coefficient of variation, CV=37.27%, above the recommended 36% threshold) (Fig.
3A). Guided by CGM data, we implemented a personalized nutrition intervention consisting of reduced meal portions during daytime and complex carbohydrate intake before bedtime, with dietary adjustments initiated when the time in range (TIR, glucose level: 3.9-7.8 mmol/L) fell below 70% or the time below range (TBR, glucose level <3.9 mmol/L) exceeded 3%. After prednisolone discontinuation, a 10-day CGM report showed improved TIR (89.6%), reduced TBR (0.8%), and lower CV (19.94%) (Fig.
3B), suggesting a near absence of hypoglycemic attacks. Especially the observed decline in CV, which correlates with lower cardiovascular risk independent of HbA1c levels, underscores CGM’s unique capacity to simultaneously assess acute hypoglycemia risk through TBR monitoring, making it an essential tool for glycemic management in patients with significant glucose fluctuations [18]. In summary, CGM can develop individualized therapies based on real-time glucose data and promptly identify hypoglycemia, thereby reducing cardiovascular risks.
CONCLUSION
In conclusion, our case report highlights the importance of recognizing IAS as a rare adverse effect associated with clopidogrel therapy. Particularly in geriatric patients exhibiting recurrent hypoglycemia, the differentiation of IAS from other etiologies poses a diagnostic challenge. The observed decline in serum insulin levels and IAA titers, coupled with the absence of further hypoglycemic episodes during follow-up, supports the efficacy of glucocorticoid therapy in alleviating IAS symptoms.
For clinicians, prompt recognition of CIAS, along with immediate drug discontinuation, individualized consideration of glucocorticoids, and intensive glucose monitoring, is critical to accelerate clinical remission. Future multicenter studies are needed to establish optimal treatment protocols and explore safe antiplatelet alternatives to reduce the risk in IAS patients.