Aspirin is an essential antiplatelet therapy for primary and secondary prevention of cardiovascular (CV) disease. However, it appears less protective in diabetic patients than in the general population due to a higher level of aspirin resistance observed in these patients 1 who already are at an increased risk of CV events.
Apart of its antithrombotic effects, many studies demonstrated additional anti-inflammatory properties of aspirin. However a recent study in diabetic patients did not approve with this concept: Hovens et al 2 measured 2 inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6) in type 2 diabetic patients without cardiovascular disease. He randomised 40 diabetic patients into 3 groups: Placebo, aspirin 100 mg, and aspirin 300 mg. After a follow-up of 6 weeks, the use of aspirin didn’t cause a statistically significant decrease in markers between placebo group and the one taking 100 mg. In addition, there were also no significant differences in effects on CRP and IL-6 between 100 and 300 mg aspirin.
The mechanisms underlying the resistance are not fully understood. It seems that there is an increase in platelet reactivity in patients with diabetes through decreased endothelial nitric oxide production, increased platelet turnover, altered platelet structure as a result of dyslipidaemia, and a disproportionate increase in intra-platelet calcium concentration 3. Additionally, diabetes is characterised by an increased level and activity of prothrombotic clotting factors, associated with a tight clot structure and impairment in fibrinolysis. These effects on clotting factors are largely due to insulin resistance, dyslipidaemia and low-grade inflammation. Third, as no clear difference in biochemical aspirin resistance has been shown when comparing individuals with type 1 and type 2 diabetes, a more diabetes-specific mechanism for increased aspirin resistance may be related to hyperglycaemia.
Importantly, recent work suggests that around 10–40% of people with diabetes display biochemical aspirin resistance 4. This has been based on platelet function tests that assess aspects of platelet reactivity independent of thromboxane A2 release. Thus, these tests do not specifically measure how effectively aspirin has inhibited its target, COX-1. Other studies have reported relatively high rates of resistance because they have used methods that assess components of platelet reactivity that are not expected to be inhibited by aspirin.
The ASPECT study run by DiChiara et al reported that diabetic patients exhibit a global high platelet reactivity phenotype that may be partially overcome by higher aspirin doses 5. Indeed, the group examined the effect of aspirin (81, 162, and 325 mg/day for 4 weeks each) on platelet aspirin responsiveness in 120 stable outpatients (30 diabetic patients and 90 nondiabetic patients) with coronary artery disease. Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients; they also exhibited higher platelet function measured. Higher aspirin doses significantly inhibited platelet function and decreased aspirin resistance in diabetic patients (P < 0.05). In addition, increased aspirin dosing resulted in similar rates of resistance and platelet function levels between groups.
Recently Van der Grabben et al reported that prolonged fasting induces profound peripheral insulin resistance in healthy lean individuals 6. In contrast to type 2 diabetes mellitus, high-dose salicylate does not affect fasting-induced peripheral IR although it did increase TNF receptors I and II.
Does giving aspirin and clopidogrel together decrease the resistance? We couldn’t answer although it seems to be a synergetic effect between both of them. Serebruany et al 7 run a study whose objective is to compare the antiplatelet profiles of clopidogrel + aspirin in combination versus aspirin alone in 70 patients with type 2 diabetes mellitus using several biochemical markers. They found out that combined treatment for 1 month provides significantly greater inhibition of platelet activity than aspirin alone. Nevertheless, diabetic patients exhibit high residual activity of some platelet biomarkers, including unaffected protease-activated receptor expression despite double antiplatelet regimen.
