Aspirin resistance and diabetes mellitus

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DOI: 10.1007/s00125-007-0898-3 · Source: PubMed

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COMMENTARY
Aspirin resistance and diabetes mellitus
R. Ajjan & R. F. Storey & P. J. Grant
Published online: 16 January 2008
#
Springer-Verlag 2007
Keywords Aspirin resistance
.
Clotting factors
.
Diabetes mellitus
.
Platelets
Abbreviations
COX-1 cyclooxygenase 1
Aspirin use in individuals with diabetes:
where is the evidence?
Despite multiple interventions t o reduce the risk of
cardiovascular disease, the majority of people with diabetes
develop macrovascular complicat ions, and mortality fol-
lowing myocardial infarction remains unacceptably high
[1]. Antiplatelet agents are used for both the primary and
secondary prevention of cardiovascular disease, although
current guidelines are not consistent in their recommenda-
tion for the use of aspirin in diabetes [2]. 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 cardiovascul ar 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 [3]. 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 [4]. 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 dim inish the effects of aspirin on platelet
function and cardiovascular riska possibility that has
led to the hotly debated concept of aspirin resi stance [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 high-
lights 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.
Diabetologia (2008) 51:385390
DOI 10.1007/s00125-007-0898-3
R. Ajjan
:
P. J. Grant (*)
Academic Unit of Molecular Vascular Medicine,
The LIGHT Laboratories, University of Leeds,
Leeds LS2 9JT, UK
e-mail: p.j.grant@leeds.ac.uk
R. F. Storey
Cardiovascular Research Unit, University of Sheffield,
School of Medicine and Biomedical Sciences,
Sheffield, UK
Cardiovascular risk reduction: aspirin and its mode
of action
The activation of platelets is a complex process involving a
number of steps (Fig. 1). The first step involves platelet
adhesion to the site of vascular injury through interaction
with the subendothelial extracellular matrix, including von
Willebrand factor and collagen. Adhesion of platelets
induces intracellular platelet signalling and activates integrins
such as glycoprotein IIb/IIIa, which also interact with the
extracellular matrix, thereby strengthening platelet adhesion.
Once platelet adhesion is initiated, platelets produce a
number of activating mediators, including thromboxane A
2
and ADP, which together with activated glycoprotein IIb/
IIIa, recruit and activate more platelets to the site of injury.
Thromboxane A
2
is produced from arachidonic acid in a
process mediated by cyclooxygenase 1 (COX-1). Throm-
boxane A
2
plays a key role in mediating platelet activation
through interaction with the thromboxane receptor, which
can also be activated by prostaglandins G
2
and H
2
.ADP,
stored in platelets in the dense granules, activates platelets
through the two protein G-coupled receptors P2Y
1
and
P2Y
12
. Another important pathway in platelet activation is
related to clotting factors. Thrombin is generated by the
exposure of tissue factor in the vessel wall and subsequent
activation of the clotting cascade. It acts as a key platelet
activator through interaction with protease-activated platelet
receptors. The antiplatelet agent aspirin inhibits COX-1,
thereby limiting thromboxane A
2
production (detailed
below), whereas the active metabolite of clopidogrel blocks
the P2Y
12
receptor, thus inhibiting platelet activation.
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 A
2
from activated platelets, such that aspirin
effectively blocks the contribution of thromboxane A
2
to
platelet aggregation and other platelet responses [9]. Throm-
boxane A
2
has a role in thrombogenesis in animal models
[10], and there is evidence of thromboxane generation within
the coronary vascular bed in patients with coronary
thrombosis [11]. Activation of phospholipase A
2
and the
liberation of arachidonic acid from membrane phospholipids
is the first step in the pathway towards thromboxane A
2
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 A
2
itself,
are linked to activation pathways that do not require
collagen, and these do not lead to thromboxane A
2
release
[14]. This explains why aspirin has little or no effect on
Exposure of vWF
and collagen
Platelet adhesion
Activation
of integrins
TXA
2
generation
(mediated by COX-1)
Release of
ADP
Interaction with
extracellular matrix
Vessel injury
Interaction with
thromboxane receptor
Strengthen platelet adhesion
Maintain platelet activation
Interaction with
P2Y
1
and P2Y
12
Exposure of tissue
factor
Activation of the
coagulation cascade
Thrombin
generation
Aspirin
Clopidogrel
Interaction with
PAR
Fig. 1 Mechanisms of platelet activation. Following vessel injury,
platelets interact with subendothelial extracellular matrix including
von Willbrand factor (vWF) and collagen, resulting in platelet
adhesion. Vessel injury also results in exposure of tissue factor and
activation of the coagulation system, culminating in the production of
thrombin. After adhesion, platelets become activated and produce
integrins and thromboxane A
2
and release stored ADP, which
collectively help to recruit and activate more platelets. Aspirin inhibits
COX-1, thereby reducing thromboxane A
2
generation, whereas the
active metabolite of clopidogrel blocks the P2Y
12
receptor. PAR,
protease-activated platelet receptor; TXA
2
, thromboxane A
2
386 Diabetologia (2008) 51:385390
numerous aspects of platelet reactivity and why antiplatelet
agents targeting other pathways may be necessary to prevent
ischaemic cardiovascular events [15].
Another potential mode of action of aspirin is relat ed 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 cardiovas-
cular disease [16], which may be due to slower clot lysis
[17]. In vitro, clots formed from purified fibrinogen show
increased fibrin gel porosity when incubated with aspirin,
making them relatively less thrombotic [18]. In vivo,
aspirin administration to healthy volunteers favourably
alters fibrin clot structurean effect that is more pro-
nounced with lower doses of aspirin [19, 20]. Acetylation
of fibrinogen is a likely mechanism for the observ ed in
vitro and in vivo changes in clot structure after aspirin
treatment [ 21 ]. 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 1040% 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 indepe ndent of
thromboxane A
2
release. Thus, these tests do not specifi-
cally measure how effectively aspirin has inhibited its
target, COX-1. Given that baseline platelet reactivity is
increased in diabetes (see below), this wi ll give spuriously
Increased thrombosis potential and
aspirin (ASA) resistance in diabetes
Platelets Clotting factors
Basal platelet
activity
Platelet protein
glycation
Suboptimal suppression of
platelet activity
NO synthesis
Dyslipidaemia
Inflammation
? ACEI
? Statins
? Block other pathways of
platelet activation
Interaction between
glycation and acetylation
Improve diabetes control
?
Dose of ASA
? Block other pathways
of
p
latelet activation
Fibrinogen glycation
(tight clot structure)
Level and activity
of clotting factors
? Interaction between
glycation and acetylation
Insulin resistance
Hyperglycaemia
Inflammation
Dyslipidaemia
Prothrombotic
environment
? ACEI
? Statins
Improve insulin
resistance
s
a Problems
b Mechanisms
c Potential
treatment options
Fig. 2 Increased thrombotic risk and potential mechanisms of aspirin
resistance in diabetes. There is an increase in basal platelet activity in
diabetes, which may be responsible for suboptimal inhibition of
platelet function by aspirin. Furthermore, increases in the plasma level
and activity of clotting factors, associated with a prothrombotic clot
structure, have been shown in individuals with diabetes. Therefore,
reductions in plat elet re activity and the level and activity of
coagulation factors by the use of statins, angiotensin converting
enzyme inhibitors (ACEI) and modulation of insulin resistance, may
improve the clinical efficacy of aspirin. Another mechanism for
aspirin treatment failure is related to an increase in platelet and
coagulation protein glycation, which may interfere with the acetyl-
ation process. Improved glycaemic control or the use of higher doses
of aspirin may allow for more efficient acetylation of these proteins,
consequently reducing the risk of thrombosis. NO, nitric oxide
Diabetologia (2008) 51:385390 387
high figures for the prevalence of aspirin resistance. In
support of this, when platelet thromboxane A
2
release is
assessed by measurement of serum thromboxane B
2
levels,
or the surrogate marker of arachidonic acid-induced platelet
macroaggregation, it has been shown that poor platelet
response to aspirin is rare [ 2628]. 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 mechani sms
Although the concept of aspirin resistance in diabetes has
been with us for more than 20 years [29], only a limited
number of studies have investigated the potential mech-
anisms involved in this process (Fig. 2). First, 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 o f dyslipidaemia, and a disproportionate increase in
intra-platelet calcium concentration [30 ]. Second, diabetes
is characterised by an increased level and activity of
prothrombotic clotting factors, associated with a tight clot
structure and an impairment in fibrinolysis [31]. These
effects on clotting factors are largely due to insulin
resistance, dyslipidaemia and low-grade inflammation
[30]. Third, a more diabetes-specific mechanism for
increased aspirin resistance may be related to hyperglycae-
mia, particularly as no clear difference in biochemical
aspirin resistance has been shown when comparing indi-
viduals with type 1 and type 2 diabetes [25]. An interaction
between glycation and acetylation has been repeatedly
shown [3234], and increased glycation of platelet and
coagulation factor proteins may interfere with the acetyl-
ation process to contribute to aspirin resistance in the
presence of diabetes [35]. In vivo studies support this
notion, as rats with streptozotocin-induced diabetes have a
reduced platelet response to aspirin compared with non-
diabetic animals, an effect related to reduced acetylation of
platelet proteins [36]. If competition between acetylation
and glycation of proteins affects the efficacy of aspirin in
diabetes, it will be important to evaluate whether improving
glycaemic control enhances the efficacy of aspirin and
whether, in the presence of poor control, increased doses of
aspirin are required [37, 38]. In support of this, a study
comparing individuals with and without diabetes found no
difference in biochemical aspirin resistance when higher
doses of aspirin (325 mg/day) were used [39]. However, the
use of 650 mg/day of aspirin in the Early Treatment
Diabetic Retinopathy Study (ETDRS) was associated with
a non-significant reduction in vascular events in partic-
ipants with diabetes, casting doubts about the efficacy of
higher doses of aspirin [40]. Patients in this study were not
taking agents that may improve the antithrombotic effects
of aspirin, such as angiotensin receptor inhibitors or statins
[41], and the general applicability of these results to current
practice is uncertain.
Conclusions
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 mech-
anisms 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 preven ting
vascular events in diabetes compared with low-dose aspirin
[42]. Hypothetically, two simple approaches may help in
increasing the efficacy of antithrombotic therapy in dia-
betes, 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 [43
] and can be fatal.
Therefore, aspirin-treat ed diabetes p atients 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 individua ls.
Acknowledgement R. Ajjan is funded by a Department of Health
Clinician Scientist Award.
Duality of interest R. Ajjan has received consultancy fees/hono-
raria/educational grants from AstraZeneca, Sanofi-Aventis, Glaxo-
SmithKline, Daiichi Sankyo, Takeda, NovoNordisk, Merck Sharp &
Dohme and Pfizer. R. F. Storey has received grants/consultancy fees/
388 Diabetologia (2008) 51:385390
honoraria from: AstraZeneca, Eli-Lilly, Daiichi Sankyo, The Medi-
cines Company. P. J. Grant has received consultancy fees/honoraria/
educational grants from GlaxoSmithKline, Eli-Lilly, Merck Sharp &
Dohme and Takeda.
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390 Diabetologia (2008) 51:385390
    • "Aspirin non-responsiveness in diabetic patient was first hypothesised in 1986 by DiMinno et al., who showed that there was a high rate of platelet turnover in diabetic patients, relating to more young platelets entering the blood stream. [13,14] Later, some studies found high proportion of non-responders to aspirin in obese insulin-resistant diabetic patients, compared with control (insulin-sensitive). [15,16] Some studies concluded that aspirin therapy decreases the risk of ischaemic events by 22%, but the reduction in the diabetic patients was only 7%. [17] In the 2005 study conducted by Fateh-Moghadam et al., about 21.5% of patients with type II diabetes under chronic aspirin therapy were resistant and about 16.9% were partially resistant to aspirin using the PFA-100 system. Moreover, inappropriate dosing of aspirin and the presence of alternative pathways independent of arachidonic acid that may activate platelets or block COX-1 against acetylation by certain non-steroidal anti-inflammatory drugs or due to the genetic changes in the COX-1 protein [18] leads to non-responsiveness in diabetes. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Aspirin is widely used as either a primary or secondary preventive measure in of cardiovascular events however, platelets from diabetic patients are less responsive to aspirin and are unable to protect themselves from thrombotic events. Objective and Method: 180 diabetic patients were enrolled for measuring their platelet aggregation. The aim was to evaluate the prevalence of aspirin non-responsiveness among Saudi type II diabetic patients. Serum glucose level and other clinical data were collected to find out the possible determinant of reduced platelet sensitivity to aspirin. Results: The prevalence of aspirin non-responsiveness was 9.44%. A significant correlation between aspirin test and each of fasting blood sugar, HbA1c, cholesterol and platelet count was observed. In contrast, there was no correlation among aspirin non-response, body mass index, age or hypertension. Conclusion: The relationship between the levels of glucose in the blood and aspirin resistance relates the importance of controlling blood glucose in diabetic patients to guarantee better aspirin action. Regular examining of type II diabetic patients to determine the sensitivity of platelet to the antiplatelet therapy is necessary to protect them from the risks of cardiovascular complications.
    Full-text · Article · Jan 2016
    • "This has been associated with a four-fold increased risk of recurrent cardiovascular events [7]. The causes of reduced antiplatelet effect of aspirin are multifactorial and likely comprise clinical, biological, pharmacological, and genetic elements [6,8]. As shown by our group, a reduced antiplatelet effect of aspirin may be related to metabolic disorders including type 2 diabetes (T2D) [9] and an accelerated platelet turnover causing increased numbers of large, immature highly reactive platelets in the circulation101112. "
    [Show abstract] [Hide abstract] ABSTRACT: Hyperglycaemia may attenuate the antiplatelet effect of aspirin and thereby increase the risk of cardiovascular events. We investigated the influence of increased haemoglobin A1c (HbA1c) levels on platelet aggregation and turnover in a large cohort of patients with coronary artery disease (CAD) with type 2 diabetes, prediabetes or no diabetes.In this observational study, we included 865 stable CAD patients on 75 mg aspirin as mono-therapy of whom 242 patients had type 2 diabetes and were receiving antidiabetic drugs. Among 623 patients without diabetes, we classified 303 patients with prediabetes (HbA1c ≥5.7-6.4% [39-47 mmol/mol]) naive to antidiabetic drugs. Platelet aggregation was evaluated by the Multiplate Analyzer using arachidonic acid and collagen and by the VerifyNow Aspirin. Platelet turnover was evaluated by immature platelets using flow cytometry and platelet activation by soluble P-selectin.CAD patients with type 2 diabetes had higher platelet aggregation (all p-values
    Full-text · Article · Jul 2015
    • "Several instances of aspirin resistance in diabetic populations (Angiolillo & Suryadevara, 2009; Tasdemir, Toptas, Demir, Esen, & Atmaca, 2014) and inefficacy in reducing oxidative stress and vascular inflammation (Raghavan, Laight, & Cummings, 2014 ) have also been demonstrated. The potential mechanisms of resistance include increased platelet activity due to decreased endothelial nitric oxide production, increased activity and levels of prothrombotic clotting factors, and hyperglycaemia (Ajjan, Storey, & Grant, 2008). The reduction in arachidonic acid-stimulated platelet aggregation by targeting the COX-1 pathway of activation and inhibition of P2Y12/ P2Y1 ADP receptors under oxidative stress suggests that QGPJ may confer natural anti-thrombotic effects and prevention of recurrent ischaemic events in diabetic and obese individuals resistant/non-responsive to COX-1 inhibitors or other antiplatelet drugs. "
    [Show abstract] [Hide abstract] ABSTRACT: Increased oxidant production in humans induces a number of thrombotic consequences; including platelet hyperactivity/aggregability, which could be countered through specifically developed functional foods. We sought to determine the antithrombotic properties of anthocyanin-rich Queen Garnet plum juice (QGPJ) supplementation with and without exercise-induced oxidative stress. Thirteen healthy participants were investigated in a randomised, double-blind, placebo-controlled, cross-over trial. Participants consumed 200 mL/day of QGPJ and placebo juice for 28-days, with treatments separated by a two-week wash-out period. Blood samples were collected at baseline and after 1 h of exercise (70% peak-O2 uptake) both before and after oral supplementation and evaluated for platelet function and haemostatic activity. QGPJ supplementation inhibited adenosine diphosphate-induced platelet aggregation both without and under exercise-induced oxidative stress by 10.7% (P < 0.01) and 12.7% (P < 0.001) respectively; arachidonic acid-induced aggregation under oxidative stress by 28.8% (P < 0.05); reduced platelet activation-dependant P-selectin expression by 32.9% (P < 0.01) and 38.7% (P < 0.001) both without and under oxidative stress respectively; and exhibited favourable effects on coagulation parameters both with and without oxidative stress. The anti-thrombotic activity exhibited by anthocyanin-rich QGPJ suggests a potential for cardiovascular disease risk reduction and may be considered as complementary anti-platelet nutritional therapy in pro-thrombotic population.
    Full-text · Article · Mar 2015
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