Aspirin resistance and diabetes mellitus
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- Ajjan, R., Storey, R.F. & Grant, P.J. Diabetologia (2008) 51: 385. doi:10.1007/s00125-007-0898-3
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KeywordsAspirin resistanceClotting factorsDiabetes mellitusPlatelets
Aspirin use in individuals with diabetes: where is the evidence?
Despite multiple interventions to reduce the risk of cardiovascular disease, the majority of people with diabetes develop macrovascular complications, and mortality following myocardial infarction remains unacceptably high . Antiplatelet agents are used for both the primary and secondary prevention of cardiovascular disease, although current guidelines are not consistent in their recommendation for the use of aspirin in diabetes . In fact, there is little direct evidence supporting its efficacy in this group of patients. Instead, there is convincing data in the literature to suggest inadequate cardiovascular protection by aspirin in diabetes. In a meta-analysis of 287 randomised trials, antiplatelet treatment (aspirin in most studies) reduced the risk of ischaemic events by 22%, but the risk reduction in the subgroup with diabetes was only 7%, which was not statistically significant . This outcome was mirrored in the Primary Prevention Project trial, which reported that cardiovascular risk reduction with aspirin was marginal and non-significant in the presence of diabetes . Despite this, there are no published studies specifically designed to evaluate the clinical efficacy of aspirin in individuals with diabetes, a surprising omission in the era of ‘evidence-based’ medicine.
These findings from clinical trials raise the question as to why there should be a reduction in the clinical efficacy of aspirin in patients with diabetes compared with a non-diabetic population. Diabetes is intrinsically associated with particular biochemical abnormalities that may have the capacity to diminish the effects of aspirin on platelet function and cardiovascular risk—a possibility that has led to the hotly debated concept of aspirin resistance [5, 6]. Unfortunately, aspirin resistance suffers from a lack of a standardised definition, although now generally thought of as either (1) reflecting clinical aspirin resistance (or perhaps, more accurately, treatment failure), characterised by the occurrence of a thrombotic episode despite treatment with aspirin; or (2) biochemical aspirin resistance where platelet responses persist despite platelet exposure to aspirin. Controversy remains as to the cause of biochemical aspirin resistance, its relevance to clinical outcomes, and the place of aspirin treatment in the management of cardiovascular risk in diabetes patients. All of this highlights the urgent need to understand the mechanisms that underpin the interactions between diabetes and aspirin, to establish the role of aspirin in particular, and antiplatelet therapy in general, in the amelioration of cardiovascular events in individuals with diabetes.
Cardiovascular risk reduction: aspirin and its mode of action
Aspirin acts on platelets by irreversibly acetylating a serine residue in COX-1 in a reaction that is rapid and irreversible, so the effects endure for the life of the platelet (~10 days) [7, 8]. This inhibits the formation and release of the platelet agonist thromboxane A2 from activated platelets, such that aspirin effectively blocks the contribution of thromboxane A2 to platelet aggregation and other platelet responses . Thromboxane A2 has a role in thrombogenesis in animal models , and there is evidence of thromboxane generation within the coronary vascular bed in patients with coronary thrombosis . Activation of phospholipase A2 and the liberation of arachidonic acid from membrane phospholipids is the first step in the pathway towards thromboxane A2 release, and the activation of platelets by collagen switches on this pathway [12, 13]. However, many other platelet agonists, such as ADP, serotonin and thromboxane A2 itself, are linked to activation pathways that do not require collagen, and these do not lead to thromboxane A2 release . This explains why aspirin has little or no effect on numerous aspects of platelet reactivity and why antiplatelet agents targeting other pathways may be necessary to prevent ischaemic cardiovascular events .
Another potential mode of action of aspirin is related to its effect on clotting factors and fibrin clot structure. Previous work has shown that fibrin clots composed of thin fibres, with small pores and a compact structure are associated with increased risk of thrombosis and cardiovascular disease , which may be due to slower clot lysis . In vitro, clots formed from purified fibrinogen show increased fibrin gel porosity when incubated with aspirin, making them relatively less thrombotic . In vivo, aspirin administration to healthy volunteers favourably alters fibrin clot structure—an effect that is more pronounced with lower doses of aspirin [19, 20]. Acetylation of fibrinogen is a likely mechanism for the observed in vitro and in vivo changes in clot structure after aspirin treatment . Other mechanisms include modulation of thrombin generation and inhibition of coagulation factor XIII activation [22, 23].
Assessment of biochemical aspirin resistance
Importantly, recent work suggests that around 10–40% of people with diabetes display biochemical aspirin resistance [24, 25]. However, 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. Given that baseline platelet reactivity is increased in diabetes (see below), this will give spuriously high figures for the prevalence of aspirin resistance. In support of this, when platelet thromboxane A2 release is assessed by measurement of serum thromboxane B2 levels, or the surrogate marker of arachidonic acid-induced platelet macroaggregation, it has been shown that poor platelet response to aspirin is rare [26–28]. Thus, many studies have reported relatively high rates of resistance because they have used methods that assess components of platelet reactivity that are independent of thromboxane formation and which are not expected to be inhibited by aspirin.
Aspirin resistance/treatment failure in individuals with diabetes: potential mechanisms
Accumulating clinical and laboratory evidence suggest a reduced efficacy of aspirin in patients with diabetes. The exact mechanisms that underline the poor response to aspirin treatment in patients with diabetes are not entirely clear, but hyperglycaemia appears to be one factor involved. High blood glucose results in glycation of platelet proteins, making them less accessible to acetylation, potentially predisposing to treatment failure. Similar mechanisms may operate on clotting factors, which have been shown to undergo both glycation and acetylation. This interaction between acetylation and glycation may explain the greater effectiveness of clopidogrel in preventing vascular events in diabetes compared with low-dose aspirin . Hypothetically, two simple approaches may help in increasing the efficacy of antithrombotic therapy in diabetes, including the administration of higher doses of aspirin or the use of other antiplatelet agents such as clopidogrel. The combination of aspirin and clopidogrel is also a possibility, particularly in those who show a partial response to either drug. Unfortunately, none of the above strategies can be recommended at present because of the lack of evidence supporting a clinical benefit of such an approach. It should be stressed that aspirin administration is associated with a significant risk of gastrointestinal haemorrhage, which seems to be dose dependent  and can be fatal. Therefore, aspirin-treated diabetes patients may be exposed to a considerable risk that may outweigh the small benefits of such treatment.
There is an urgent need for further clinical and basic research to clarify the prevalence of biochemical aspirin resistance in individuals with diabetes, to understand the relationship with clinical treatment failure and to elucidate the mechanisms involved. Establishing reliable indicators of efficacy will help to provide more effective and less hazardous treatment strategies in these individuals.
R. Ajjan is funded by a Department of Health Clinician Scientist Award.
Duality of interest
R. Ajjan has received consultancy fees/honoraria/educational grants from AstraZeneca, Sanofi-Aventis, GlaxoSmithKline, Daiichi Sankyo, Takeda, NovoNordisk, Merck Sharp & Dohme and Pfizer. R. F. Storey has received grants/consultancy fees/honoraria from: AstraZeneca, Eli-Lilly, Daiichi Sankyo, The Medicines Company. P. J. Grant has received consultancy fees/honoraria/educational grants from GlaxoSmithKline, Eli-Lilly, Merck Sharp & Dohme and Takeda.