title: 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.
authors.affiliation: Karolinska Institute, Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine , Stockholm , Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lundström
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Laska
authors.forename: Magnus
authors.initials: M
authors.lastname: Von Arbin
authors.forename: Gun
authors.initials: G
authors.lastname: Jörneskog
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallén
mesh_terms: D000368:Aged; D001786:Blood Glucose; D001792:Blood Platelets / Q000378:metabolism*; D000077144:Clopidogrel; D005260:Female; D018149:Glucose Intolerance; D006801:Humans; D007333:Insulin Resistance; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D010979:Platelet Function Tests; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine