Glucose intolerance and insulin resistance as predictors of low platelet response to clopidogrel in patients with minor ischemic stroke or TIA

Abstract

The relation between high on-treatment platelet reactivity (HPR), and the level of glucose intolerance and insulin resistance (IR) was studied in clopidogrel-treated patients with minor ischemic stroke or TIA. The cohort consisted of 66 patients, 11 of which had known type 2 diabetes mellitus (DM). Platelet aggregation in whole blood (Multiplate™) and metabolic variables were measured 1 month after acute onset of neurological symptoms. Glucose tolerance was measured by Oral Glucose Tolerance Test (OGTT). IR was estimated by homeostasis model assessment HOMA-IR. Patients were categorized as “responders” (R) or “non-responders” (NR) to clopidogrel according to an established cut-off in platelet aggregation induced by adenosine diphosphate (ADP). In total, 14/66 (21%) patients were NR. Impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or DM was seen in 13/14 NR (93%), while for R this was the case in 25/52 (48%), p = 0.001. The percentage of NR was 33% in patients with DM and 35% in patients with IGT or IFG. In the group with normal glucose tolerance (NGT) the percentage of NR was low, 4% (1/28). Fasting plasma glucose (f-PG) was higher for NR than for R, 6.0 (5.5–6.7) mM vs. 5.3 (5.0–6.0) mM, p = 0.023. Glycated hemoglobin (HbA1c) did not differ between NR and R. NR also had higher arachidonic acid-induced platelet aggregation than R, and a tendency towards higher aggregation induced by thrombin receptor agonist peptide (TRAP), indicating that HPR reflects a global platelet hyper-reactivity. HOMA-IR was calculated for 52 of the patients above without known diabetes, 9 of which were NR (17%). NR were significantly more insulin resistant than R, with median HOMA-IR 4.5 (3.0–7.4) compared to 2.1 (1.5–3.2) for R, p = 0.001. HOMA-IR and fasting plasma insulin were the only metabolic variables with significant relationships to ADP-induced platelet aggregation. The results suggest that HPR develops in the pre-diabetic phase. A metabolic disturbance with glucose intolerance and/or high level of IR was a pre-requisite for HPR in the tested cohort. Conversely, normal glucose tolerance combined with normal or mildly elevated HOMA-IR excluded HPR. NR are likely to constitute a high-risk group among patients with ischemic cerebrovascular disease. Measurement of f-PG or HbA1c is insufficient to identify NR, while OGTT and HOMA-IR are more predictive.

• Platelet aggregation
• ischemic stroke
• TIA
• clopidogrel
• glucose tolerance
• insulin resistance

Acknowledgements

The excellent assistance of research nurses Eva Isaksson and Helena Kumpulainen is gratefully acknowledged.

Declaration of interest: This work was partly funded by the Swedish Stroke Fund, the Bert von Kantzow Foundation, and the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and Karolinska Institute, which are all gratefully acknowledged. The authors report no conflict of interests.