REVIEW PAPER doi: 10.1111/j.1559-4572.2008.00037.x

Utility of Aspirin Therapy in Patients With the CardiometabolicSyndrome and Diabetes

The cardiometabolic syndrome(CMS), which includes a hyper-

coagulable state among several hemo-dynamic and metabolic abnormalities,leads to substantial increases in cardio-vascular disease (CVD) morbidity andmortality. The diagnosis of the syn-drome can be made when an individualhas 3 of 5 components: increased waistcircumference, increased triglycerides,low high-density lipoprotein choles-terol, increased blood pressure, andincreased glucose. According toNational Health and Nutrition Exami-nation Survey (NHANES) III datausing Adult Treatment Panel (ATP) IIIguidelines, between 21% and 24% ofadults in the United States meet criteriafor CMS. Affected individuals haveapproximately a 3-fold higher preva-lence of coronary heart disease,myocardial infarction, and stroke.Hyperglycemia or dysglycemia (glucoselevels above normal but not necessarilyhigh enough for a patient to be classi-fied as diabetic) are also associated witha continuum of CVD risk.1 CMS isalso linked to type 2 diabetes mellitus(T2DM), and by one estimate 92% ofpatients with T2DM have CMS.Although all of the mechanisms leadingto increased CVD risk in CMS havenot been fully elucidated, increasedplatelet aggregation/adhesion, endothe-lial dysfunction, and hypercoagulabilityare likely important contributors. Inthis review, we will iterate the patho-physiologic underpinnings of thesemetabolic and cardiovascular abnor-malities and the potential role of aspi-rin in reducing CVD in patients withCMS and T2DM.

PlateletsIncreased platelet aggregation and adhe-sion have an established role in acutearterial thrombosis, and agents directlytargeting the prevention of plateletaggregation/adhesion have therapeutic

benefits in the treatment of acute coro-nary syndrome2 and stroke.3 The pro-cess of thrombus formation is complexand involves a number of mediators. Inresponse to vascular injury, plateletsinteract with collagen and von Wille-brand factor (vWF) in the subendothe-lial matrix via their respective receptors,glycoprotein (GP) VI and GPIb/V/IX.4

This interaction leads to structuralchanges in platelets with subsequentrelease of ADP and thromboxane A2(TxA2) and formation of thrombin onthe surface of the platelets, leading tothe recruitment of more platelets andcausing further activation and amplify-ing the injury response. Integrin GPIIb/IIIa of untreated platelets interact withadhesive proteins, particularly fibrino-gen and vWF, resulting in plateletaggregation.4 Thrombus formation then

ultimately results from the interplay ofthrombin, fibrin, and the platelet.

In addition to their role in thrombusformation, platelets also play a signifi-cant role in atherosclerotic diseasethrough the release a number of inflam-matory mediators. In animal models ofatherosclerotic vascular disease, acti-vated platelets promote monocyterecruitment to the involved vessels, withresultant disease progression via thedelivery of chemokines on the surface ofinflammatory and endothelial cells.5

Platelet dysfunction in CMS has notbeen studied directly; however, there isa substantial amount of informationabout platelet function in patients withT2DM, obesity, and/or insulin resis-tance, all of which have a very close asso-ciation with CMS. Platelet-dependentthrombosis is increased with increasing

Paralleling the rise in obesity, the cardiometabolic syndrome is a rapidly growing health

problem in the United States. There is a 3-fold increase in the prevalence of coronary

heart disease, myocardial infarction, and stroke due to the coagulation, hemodynamic,

and metabolic abnormalities seen in these individuals. The use of aspirin for secondary

prevention and, to a lesser degree, primary prevention of cardiovascular events is a

well-established standard of care. However, in patients with diabetes or the cardiomet-

abolic syndrome, the role of aspirin in prevention of cardiovascular events remains con-

troversial. In this review, the authors examine the clinical trial data on the use of aspirin

in diabetes and the cardiometabolic syndrome for cardiovascular protection. They also

explore, in addition to aspirin’s effects on platelet aggregation, some of the mecha-

nisms by which aspirin may favorably alter the course of atherosclerosis, effects on

endothelial function, and glycemia. J Cardiometab Syndr. 2009;4:96–101. �2009

Wiley Periodicals, Inc.

Michael Gardner, MD; John Palmer, MD; Camila Manrique, MD; Guido Lastra, MD;

David W. Gardner, MD; James R. Sowers, MD

From the Diabetes and Cardiovascular Center, University of Missouri School of

Medicine and Truman VA Hospital, Columbia, MO

Address for correspondence:

Michael Gardner, MD, Diabetes and Cardiovascular Center, University of Missouri

School of Medicine and Truman VA Hospital, Columbia, MO, 65212

E-mail: gardnermj@health.missouri.edu

Manuscript received September 25, 2007; revised July 11, 2008;

accepted July 11, 2008

aspirin therapy in patients with CMS JCMS spring 200996

levels of fasting glucose, even within arange of glucose that would generally beconsidered normal.1,6 Also, centralobesity in nondiabetic women with nor-mal lipid values is associated withincreased platelet activation, which isreversible with weight loss.7 In thisregard, increased in vitro leptin levels,consistent with levels found in obeseindividuals, have been found to act syn-ergistically with ADP to activate plate-lets.8 Also, persons with T2DM havebeen found to have increased sensitivityof platelet purinergic receptors to ADP.This leads to an increased number ofcirculating platelet microaggregates,which can serve as a nidus for thrombusformation. The reversibility of thesemicroaggregates was inversely asso-ciated with levels of hemoglobin A1c.

9

Hypertriglyceridemia, one of the defin-ing features of CMS, also increasesplatelet aggregation, likely via very-low-density lipoprotein cholesterolstimulation of CD36 ligand causingincreased production of TxA2.10 Tri-glycerides also are the source of freefatty acids utilized in the production ofTxA2, which is a crucial player in plate-let aggregation. Tight metabolic controlin T2DM has been shown to result in asignificant reduction of in TxA2 biosyn-thesis. There is also increased plateletsurface expression of GPIb and GPIIb/IIIa in persons with T2DM and inap-propriate basal platelet activation, asevidenced by increased levels of intracel-lular Ca++ and platelet activation mark-ers such as P-selectin, CD40L, andCD63.11 Furthermore, platelets fromobese insulin-resistant individuals haveimpaired response to the antiaggregat-ing effects of nitric oxide and prostacy-clin due to diminished production ofthese compounds as well as reducedactivity of the second messengers cGMPand cAMP.12 They are also resistant tothe normal antiaggregating effects ofinsulin10,13 and the normal inhibition,by insulin, of platelet deposition oncollagen.13 Collectively, these datasuggest that both insulin resistanceand hyperglycemia contribute to theenhanced platelet aggregation and adhe-sion seen in patients with obesity andT2DM.

Role of the Endothelium inPlatelet Aggregation andAdhesionUnder normal physiologic conditions, ahealthy endothelium inhibits plateletadhesion and exerts other antiathero-sclerotic actions on the vasculature. Ithas important roles in regulation of vas-cular tone, thrombolysis, and inflam-mation. In addition, there is a balanceof proaggregatory influences from acti-vated platelets and antiaggregatoryinfluences of the endothelium primarilyfrom the release of nitric oxide andprostacyclin.14 In T2DM, obesity, andsome other metabolically abnormalstates, there is a decrease in the release ofboth substances in part due to effectsmediated by increased free fattyacids.10,14 In addition, there is evidencethat increased levels of leptin, as foundin obese individuals, down-regulatesthrombomodulin, which is an impor-tant endothelial anticoagulant enzyme.8

Thus, endothelial dysfunction in associ-ation with metabolic disorders is associ-ated with decreased defenses againstplatelet adhesion.

Hypercoagulability in T2DMand CMSIn addition to platelet dysfunction,multiple other coagulation pathways areabnormal in individuals with CMS.There is impaired fibrinolysis, in partdue to elevated plasminogen activatorinhibitor 1 (PAI-1) levels.10,15 IncreasedPAI-1 levels are associated with throm-botic disorders, including myocardialinfarction, and are an important predic-tor of the development of T2DM.15

Several components of CMS contributeto this elevation of PAI-1: One is insulinresistance and resulting hyperinsulin-emia, possibly independent of hypergly-cemia, as there is an insulin promotersite on the PAI-1 gene.15 Another factorpromoting increases in PAI-1 are theelevations in triglycerides and very-low-density lipoprotein cholesterol, whichalso promote PAI-1 synthesis.10 Fur-thermore, PAI-1 is also produced byplatelets in excessive amounts by vis-ceral adipocytes.16 Hypercoagulationmay also be promoted by other adipo-kines produced by visceral fat, such as

tumor necrosis factor a (TNF-a),adiponectin, interleukin-6, and others,in association with CMS.16 There isalso increased activation of factor VII aswell as increased levels of fibrinogenand vWF in obesity, CMS, and T2DM.

Abnormalities of visceral fat and itsmetabolic function may provide a com-mon precursor insulin resistance, lipidabnormalities, and abnormalities incoagulation/fibrinolysis. Visceral fatproduces proinflammatory cytokinessuch as interleukin-6 and TNF-a,which in turn elevate fibrinogen levels.These cytokines are responsible forsome of the endothelial dysfunctionthat causes an increase in vWF. FactorVII, a key element in stimulating the tis-sue factor–induced extrinsic clottingcascade, is abnormally activated in per-sons with CMS. There is also someexperimental evidence to support thenotion that the coagulopathy is drivenby hyperglycemia rather than hyperin-sulinemia.15 Nevertheless, most studieshave found a relation of either hyperin-sulinism or hypertriglyceridemia tospecific abnormalities in coagulation.10

Aspirin Therapy in CMS andDiabetesEarly descriptions of a medical role forsalicylic acid occurred over 100 yearsago when it was discovered to have anti-inflammatory properties. Salicylic acidgave way to acetylsalicylic acid (aspirin)and was used widely for the treatment ofrheumatism. Through subsequent years,the uses of and indications for aspirinhave evolved, and the basis of therapeu-tic indications has been predicated on itsvasodilatory, anti-inflammatory, andantithrombotic effects. Today, aspirinremains the most commonly used medi-cation for the treatment of pyrexia, pain,and inflammation; however, its role inthe prevention and treatment of acutecoronary syndrome14 as well as ischemicstroke prevention is the focus of ourreview.

Mechanism of Action ofAspirinThe primary action of aspirin lies inthe interruption of the synthesisof prostaglandins.2,14 The production

aspirin therapy in patients with CMS JCMS spring 2009 97

of prostaglandins occurs through theoxidation of arachidonic acid, which isderived from membrane phospholipids.Following oxidation, arachidonic acid isfurther transformed by prostaglandin Hsynthase, which is more commonlyreferred to as cyclooxygenase (COX).COX in turn is responsible for the pro-duction of thromboxanes and prostacy-clin, which work in opposition to eachother, acting as vascular mediators andmaintaining vasodynamic function andplatelet activity.

COX has 2 separate isoforms, COX-1 and COX-2. COX-1 is a constitutiveisoform found in most tissues, whereasthe COX-2 isoform is cytokine-inducedand found in states of inflammation.Also of therapeutic importance, COX-2, unlike COX-1, is absent in thestomach. Aspirin inhibits both COXisoforms by the irreversible acetylationof serine 530, which impedes the accessof arachidonic acid to the active site.14

The process is similar with COX-2;however, the inhibition on COX-1 is170-fold greater secondary to differ-ences in substrate channels. As a resultof COX-1 inhibition, aspirin has a keyantiplatelet effect. This occurs throughits inhibition of TxA2, which is a potentplatelet agonist and platelet aggregator.Since endothelial cells have syntheticcapacity for COX, there is little effecton the production of prostacyclin.Because its binding of COX-1 is irre-versible and platelets lack synthetic

capacity, aspirin permanently elimi-nates the aggregatory properties ofaffected platelets (Figure 1).14

Another effect of aspirin is todecrease thrombin generation. Of inter-est, this effect is reduced with increasinglevels of cholesterol.17 Although itseffect on fibrinolysis is unclear, it altersfibrinogen acylation in normal individ-uals, making resulting fibrin gels moreporous and less well developed.17,18

Aspirin and Glucose MetabolismInsulin resistance is the primary patho-physiologic derangement in the devel-opment of the abnormal glucosehomeostasis seen in patients with CMS.The mechanism by which aspirin influ-ences glucose metabolism is unclear,but several hypotheses have been pro-moted. Aspirin was first demonstratedto have an impact on glycemic controlas far back as 1877, when Ebstein notedthat high-dose aspirin therapy resultedin considerable reduction in glucosuriain diabetic patients.19 In addition,patients who were receiving high dosesof aspirin for the treatment of rheuma-tologic disorders were also noted tohave improved glucosuria as well asimproved blood glucose levels.14

One mechanism of action of aspirininvolves the modulation of TNF-a.TNF-a levels have been demonstratedto be elevated in individuals with insu-lin resistance and obesity.20,21 Fattyacid activation of a serine kinase cascade

results in increased levels of TNF-a,20,21 which has deleterious effects on anumber of steps in the insulin signalingpathway, including disruption of insu-lin metabolic signaling.21 TNF-a hasbeen shown to cause serine phosphory-lation of insulin receptor substrate 1(IRS-1), which prevents downstreammetabolic signaling (Figure 2).21,22

One study showed that aspirin inhib-ited 4 of the 6 serine kinases that havebeen shown to cause IRS-1 phosphory-lation, suggesting that aspirin mayenhance insulin sensitivity by protectingIRS-1 from serine phosphorylation,thus allowing optimal tyrosine phos-phorylation and downstream signalingthrough the PI3-kinase and proteinkinase B (Akt) pathway.23

Additional studies have focused onthe actions of aspirin on nuclear factorjB. Aspirin and salicylate have beenshown to inhibit the activity of nuclearfactor jB and its upstream activatorIjB-kinaseb (IKKß). In this model, sub-cutaneous administration of either high-dose aspirin or sodium salicylate resultedin marked improvement in hyperglyce-mia, insulin sensitivity, and dyslipide-mia in insulin-resistant obese rodents.24

The authors of this study furtherdemonstrated the importance of IKKßby showing that IKKß knockout modelswere protected against insulin resistancedevelopment and thus demonstratingthat the beneficial effect was not second-ary to the inhibition of COX.24

The effects of aspirin on glucosehomeostasis in patients with insulinresistance seen in CMS are less clear.One study evaluated the use of high-dose aspirin and its role in glucosemetabolism in patients with T2DM.25

In this study, 9 patients with T2DMwere treated with approximately 7 g ofaspirin daily and followed for 2 weeks.Significant improvement in fastingplasma glucose (�25%), reduction intotal cholesterol (�15%), reduction inC-reactive protein (�15%), and reduc-tion in triglycerides (�50%) werefound at the end of this trial.25 Whilethis study showed significant benefit,albeit in a small trial with suprathera-peutic dosing, other trials haveproduced inconsistent results.

Figure 1. Mechanism of action of aspirin. Through the irreversible inhibition of cyclooxygen-ase, aspirin blocks the production of prostaglandins, prostacyclins, and thromboxane A2. The netresult is antiaggregatory, as platelets lack the synthetic capacity to regenerate their cyclooxygenase-1.

aspirin therapy in patients with CMS JCMS spring 200998

Aspirin and CVD RiskAspirin as a CVD preventative agentwas first examined in secondary preven-tion trials. The major studies in this areahave been aggregated in the meta-analysis by the Antithrombotic Trialists’Collaborative,26 which showed a signifi-cant preventive effect of antiplatelettherapy on serious cardiovascular eventoutcomes, myocardial infarction, andstroke in patients that had preexistingevidence of vascular disease either dueto history of a prior event or interven-tion. Also included in this meta-analysiswere a small number of studies that ana-lyzed patients without prior acuteevents or interventions who were atincreased risk for CVD due to the pres-ence of comorbid diseases such asT2DM, carotid artery disease, or end-stage renal disease requiring dialysis.When examined as a separate subpopu-lation, this group of high-risk individu-als had nearly identical statisticallysignificant degrees of protection as thesubpopulation with a history of vascularevents.

In the last 20 years, there have been6 major trials to assess the efficacy ofaspirin in the primary prevention ofCVD.27–32 They have had mixed resultswith respect to achieving their primaryend points of reduction of CVD events(myocardial infarction or compositeend point of stroke, myocardial infarc-tion, and CVD death). The Hyperten-sion Outcome Trial (HOT)29 showed arelative risk (RR) (aspirin vs placebo) ofthe composite cardiovascular diseaseend point of 0.85 (95% confidenceinterval [CI], 0.73–0.99),29 the Throm-bosis Prevention Trial31 showed an RR(aspirin vs placebo) of ischemic heartdisease of 0.80 (95% CI, 0.65–0.99),31

and the aspirin component of the Physi-cians Health Survey27 showed an RR(aspirin vs placebo) of myocardialinfarction of 0.56 (95% CI, 0.45–0.70).27 On the other hand, the Pri-mary Prevention Study28 failed toreproduce these results as they wereunable to show a statistically significantdifference in the predefined primaryend point or secondary end point ofmyocardial infarction. However, a sec-ondary end point consisting of the pri-

mary end point with the addition oftransient ischemic attack, peripheralartery disease, revascularization, andangina pectoris showed significantreduction.28 Also negative were theBritish Male Doctors Study,30 whichhad no outcome that reached signifi-cance other than reduction in transientischemic attack, and the Women’sHealth Study,32 which failed to reachsignificance in its primary end point butshowed a significant reduction instroke, a predefined secondary endpoint, with aspirin vs placebo. Thesestudies included populations selectedfor increased cardiovascular risk28,29,31

and populations not selected forincreased cardiovascular risk.27,30,32

A meta-analysis including the BritishMale Doctors Study and PrimaryPrevention Study showed an overallreduction in CVD events drivenentirely by a reduction in the RR ofnonfatal myocardial infarction by 32%(RR, 0.68; 95% CI, 0.59–0.79) for theaspirin group as compared to placebo.Data on stroke and vascular deathremained inconclusive. Among the11,466 females included in this meta-analysis, no statistically significantdifference was shown between aspirinand placebo.33

Figure 2. Effect of aspirin on insulin resistance. Under normal physiologic conditions, the acti-vated insulin receptor phosphorylates signal proteins such as insulin receptor substrate 1 (IRS-1)on tyrosine residues, resulting in their activation. In states with increased circulating tumor necro-sis factor a (TNF-a), such as the cardiometabolic syndrome, IRS-1 is instead serine phosphory-lated, resulting in an inactive form that cannot be acted upon by the insulin receptor. FFAindicates free fatty acids; pSer, phosphoserine; pTyr, phosphotyrosine; ASA, acetyl salicylic acid.

aspirin therapy in patients with CMS JCMS spring 2009 99

The Women’s Health Study32

showed very different results from theother aspirin trials. The risk of vascularevent was not significantly reduced, at9% (RR, 0.91; 95% CI, 0.80–1.03),and the risk of myocardial infarction,which had driven the results of theprevious studies and thus the meta-anal-ysis, was not influenced (RR, 1.02; 95%CI, 0.84–1.25). However, the risk ofstroke was significantly decreased by17% (RR, 0.83; 95% CI, 0.69–0.99).32

Many theories exist about why suchdifferent results were observed in the 2largest trials of reportedly healthy indi-viduals receiving aspirin for primaryprevention, apparently based onsex.27,32 One possibility would be a truesex difference in platelet reactivity.Indeed, a recent study found thatwomen’s platelets are more reactive to10 of 12 common in vitro aggregationagonists and that after treatment withaspirin some of this reactivity remainsunaffected. However, they achievedcomplete suppression of the COX-1pathway, which as stated above is thehypothesized method of cardioprotec-tion.34 Also, the average age of the menand women in these studies was compa-rable, an important fact because athero-sclerosis typically develops about10 years later in women than in men.Indeed, when the Women’s HealthStudy data were analyzed for womenolder than 65 years, there was a signifi-cant reduction of 26% (95% CI, 8%–41%) in the major cardiovascular eventcategory and 34% in myocardial infarc-tion.32 One final possibility is the differ-ence in dosage. The Physicians HealthStudy used 325 mg every other day vsthe Women’s Health Study dosage of100 mg every other day.27,32 Analysisof these and other studies by Dalen35

suggests that the minimum dose of aspi-rin for the primary prevention of myo-cardial infarction in men older than 50is approximately 160 mg and that inwomen the dosage is undetermined butlikely>100 mg/d.

The evidence supporting a cardio-protective effect of aspirin in T2DM iscontroversial. Although no large trialhas specifically examined the use ofaspirin as secondary prevention only in

patients with diabetes and prior vascu-lar events, diabetic patients in the stud-ies reported in the AntithromboticTrialists’ Collaborative26 meta-analysishad risk reductions similar to those innondiabetics.26 The AntithromboticTrialists’ Collaborative26 meta-analysislooked at a subset of 9 trials comparingantiplatelet therapy to control therapyin 4961 diabetics and showed anonsignificant reduction of 7% inserious vascular events.26 The EarlyTreatment in Diabetic RetinopathyStudy (ETDRS),36 which contributedthe bulk of the patients to this analysis,had particularly interesting findings.Because approximately 30% of theparticipants in both the aspirin andplacebo groups had evidence ofmacrovascular disease at study entry, itcan be viewed as a mixed primary andsecondary outcome trial in diabetics.When the primary outcome of all-cause mortality between the aspirinand placebo groups was evaluated at 5and 7 years, no difference wasobserved. Analysis at 5 years revealed asignificant reduction in the predeter-mined secondary end point of fatal andnonfatal myocardial infarction (RR,0.72; 99% CI, 0.55–0.95). However,at 7 years this effect was no longer sta-tistically significant. A caveat of thisstudy is that all patients had to haveproliferative retinopathy and thus mayhave had diabetes for a longer period oftime and may have had a history ofworse glycemic and blood pressurecontrol.

Collectively, available data demon-strate a variable response to aspirin inpatients with CMS. Platelets fromaffected individuals exhibit increasedactivation via thromboxane-dependentand thromboxane-independent path-ways as well as resistance to normalantiaggregating influences. One exam-ple of this is the increased microaggre-gates due to P2Y12 activation that werereversed with ticlopidine but not aspi-rin.9 Also, aspirin does not affect PAI-1levels,37 one of the major componentsof poor fibrinolysis in CMS, though itmay reduce plasmin-induced PAI-1activity,38 nor does it directly affect ele-ments of the extrinsic pathway.37

Aspirin resistance is a problematicterm that is sometimes used to describethe variable results seen with aspirin ther-apy. It is defined either clinically as con-tinued ischemic events in patientsreceiving aspirin or as in vitro failure ofthe antiaggregatory effect of aspirin onplatelets as measured by various tech-niques. Prevalence estimates range fromabout 6% to 60% depending on thetechnique used, with wide variationbetween techniques even within the samesample. ‘‘Sensitivity’’ to aspirin alsoappears to vary within an individualdepending on their current physiologicstatus and changing with parameters suchas blood pressure and state of health.39

In summary, there are limited dataon the utility of aspirin treatment inpatients with CMS. Although aspirinhas been shown to be beneficial in high-risk individuals, most of these personshad ischemic heart disease or T2DM.The benefits in individuals with CMSwere not assessed, but without estab-lished T2DM or ischemic heart disease.While the benefit in patients withT2DM and no ischemic heart diseaseseems well documented, most of thedata come from the ETDRS and mostof the patients included had long-stand-ing T2DM and likely poor glycemicand blood pressure control, as evi-denced by their degree of retinopathy;they were also less likely to be receivingaggressive lipid therapy.

Many of the factors resulting in thehypercoagulable state of CMS are not sig-nificantly affected by acetylsalicylic acidtherapy, and thus benefit cannot beassumed. At present, the low cost andgood side effect profile for low-dose aspi-rin and its benefit in diabetic and otherhigh-risk patients likely justifies its use inpatients with CMS. On the other hand,prospective controlled trials are needed inpatients who have CMS but no vasculardisease or T2DM, and their results willcertainly help to better characterize theimpact of aspirin in patients with CMS.

Acknowledgements: This research wassupported by National Institutes of Healthgrants R01 HL73101-01A1 (to JRS) andthe Veterans Affairs Merit System (0018to JRS).

aspirin therapy in patients with CMS JCMS spring 2009100

REFERENCES

1 Barr ELM, Zimmet PZ, Welborn TA, et al.Risk of cardiovascular and all-cause mortalityin individuals with diabetes mellitus, impairedfasting glucose, and impaired glucose toler-ance: the Australian Diabetes, Obesity, andLifestyle Study (AusDiab). Circulation. 2007;116:151–157.

2 Baigent C. ISIS-2: 10 year survival amongpatients with suspected acute myocardialinfarction in randomised comparison of intra-venous streptokinase, oral aspirin, both, orneither. The ISIS-2 (Second InternationalStudy of Infarct Survival) CollaborativeGroup. BMJ. 1998;316:1337–1343.

3 Schellinger PD. Stroke: advances in therapy.Lancet Neurology. 2005;4:2.

4 Offermanns S. Activation of platelet functionthrough G protein-coupled receptors. CircRes. 2006;99:1293–1304.

5 Huo Y. Circulating activated platelets exacer-bate atherosclerosis in mice deficient in apoli-poprotein E. Nat Med. 2003;9:61–67.

6 Shechter M. Blood glucose and platelet-dependent thrombosis in patients with coro-nary artery disease. J Am Coll Cardiol.2000;35:300–307.

7 Davi G. Platelet activation in obese women:role of inflammation and oxidant stress.JAMA. 2002;288:2008–2014.

8 Maruyama I. Effect of leptin in platelet andendothelial cells. Obesity and arterialthrombosis. Ann NY Acad Sci. 2000;902:315–319.

9 Matsuno H, Tokuda H, Ishisaki A, et al.P2Y12 receptors play a significant role in thedevelopment of platelet microaggregation inpatients with diabetes. J Clin EndocrinolMetab. 2005;90:920–927.

10 Kakafika AI, Liberopoulos EN, KaragiannisA, et al. Dyslipidaemia, hypercoagulabilityand the metabolic syndrome. Curr Vasc Phar-macol. 2006;4:175–183.

11 Yan Y. Aspirin response and failure in diabeticpatients with cardiovascular disease. CurrOpin Pharmacol. 2005;5:190–197.

12 Anfossi G. Impaired synthesis and action ofantiaggregating cyclic nucleotides in plateletsfrom obese subjects: possible role in platelethyperactivation in obesity. Eur J Clin Invest.2004;34:482–489.

13 Westerbacka J. Inhibition of platelet-collageninteraction: an in vivo action of insulinabolished by insulin resistance in obesity.Arterioscler Thromb Vasc Biol. 2002;22:167–172.

14 Colwell JA, Nesto RW. The Platelet in Diabe-tes: Focus on prevention of ischemic events.Diabetes Care. 2003;26:2181–2188.

15 Stegenga ME, van der Crabben SN, Levi M,et al. Hyperglycemia stimulates coagulation,whereas hyperinsulinemia impairs fibrinolysisin healthy humans. Diabetes. 2006;55:1807–1812.

16 Lau DCW, Dhillon B, Yan H, et al.Adipokines: molecular links betweenobesity and atheroslcerosis. Am J Phys-iol Heart Circ Physiol. 2005;288:H2031–H2041.

17 Undas A, Brummel-Ziedins KE, Mann KG.Antithrombotic properties of aspirin andresistance to aspirin: beyond strictlyantiplatelet actions. Blood. 2007;109:2285–2292.

18 Antovic A. Marked increase of fibrin gel per-meability with very low dose ASA treatment.Thromb Res. 2005;116:509–517.

19 Ebstein W. Zur therapie des diabetes mell-itus, insbesondere uber die anwendungdes salicylsauren natron bei demselben.Berliner Klinische Wochenschrift. 1877;24:337–340.

20 Hotamisligil GS. IRS-1-mediated inhibitionof insulin receptor tyrosine kinase activity inTNF-alpha- and obesity-induced insulinresistance. Science. 1996;271:665–668.

21 Kanety H. Tumor necrosis factor alpha-induced phosphorylation of insulin receptorsubstrate-1 (IRS-1). Possible mechanism forsuppression of insulin-stimulated tyrosinephosphorylation of IRS-1. J Biol Chem.1995;270:23780–23784.

22 Sesti G. Defects of the insulin receptorsubstrate (IRS) system in human meta-bolic disorders. FASEB J. 2001;15:2099–2111.

23 Gao Z, Zuberi A, Quon MJ, et al. Aspirininhibits serine phosphorylation of insulinreceptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serinekinases. J Biol Chem. 2003;278:24944–24950.

24 Yuan M, Konstantopoulos N, Lee J, et al.Reversal of obesity- and diet-induced insulinresistance with salicylates or targeted disrup-tion of ikkbeta. Science. 2001;293:1673–1677.

25 Hundal RS, Petersen KF, Mayerson AB,et al. Mechanism by which high-doseaspirin improves glucose metabolism in type2 diabetes. J Clin Invest. 2002;109:1321–1326.

26 Collaboration AT. Collaborative meta-analy-sis of randomised trials of antiplatelet therapyfor prevention of death, myocardial infarc-tion, and stroke in high risk patients. BMJ.2002;324:71–86.

27 anonymous. Final report on the aspirin com-ponent of the ongoing Physicians’ HealthStudy. Steering Committee of the Physicians’Health Study Research Group. N Engl J Med.1989;321:129–135.

28 Roncaglioni MC. Low-dose aspirin and vita-min E in people at cardiovascular risk: arandomised trial in general practice. The Lan-cet. 2001;357:89–95.

29 Hansson L. Effects of intensive blood-pres-sure lowering and low-dose aspirin in patientswith hypertension: principal results of thehypertension optimal treatment (HOT)randomised trial. HOT Study Group. Lancet.1998;351:1755–1762.

30 Peto R, Collins R, Wheatley R, et al. Rando-mised trial of prophylactic daily aspirin inBritish male doctors. British Medical JournalClinical Research Ed. 1988;296:313–316.

31 anonymous. Thrombosis prevention trial:randomised trial of low-intensity oral antico-agulation with warfarin and low-dose aspirinin the primary prevention of ischaemic heartdisease in men at increased risk. The MedicalResearch Council’s General Practice ResearchFramework. Lancet. 1998;351:233–241.

32 Ridker PM, Cook NR, Lee IM, et al. A ran-domized trial of low-dose aspirin in the pri-mary prevention of cardiovascular disease inwomen. N Engl J Med. 2005;352:1293–1304.

33 Eidelman R, Hebert Patricia, Weisman Ste-ven, et al. An update on aspirin in the primaryprevention of cardiovascular disease. ArchIntern Med. 2003;163:2006–2010.

34 Becker DM. Sex differences in platelet reactiv-ity and response to low-dose aspirin therapy.JAMA. 2006;295:1420–1427.

35 Dalen JE. Aspirin to prevent heart attack andstroke: what’s the right dose? Am J Med.2006;119:198–202.

36 anonymous. Aspirin effects on mortality andmorbidity in patients with diabetes mellitus.Early Treatment Diabetic Retinopathy StudyReport 14. ETDRS Investigators. JAMA.1992;268:1292–1300.

37 Zhao L. Effect of aspirin, clopidogrel anddipyridamole on soluble markers of vascularfunction in normal volunteers and patientswith prior ischaemic stroke. Platelets.2006;17:100–104.

38 Shi G, Wang SJ, Chang BI, et al. Regulationof plasminogen activator inhibitor activity byplasmin in endothelial cells. Thromb Res.1996;81:75–84.

39 Gasparyan AY, Watson T, Lip GYH. The roleof aspirin in cardiovascular prevention: impli-cations of aspirin resistance. J Am CollCardiol. 2008;51:1829–1843.

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