Peripheral Arterial Disease in People With DiabetesA MERICAN D IABETES A SSOCIATIONP eripheral arterial disease(PAD)is a condition characterized by athero-sclerotic occlusive disease of the lower extremities.While PAD is a major risk factor for lower-extremity amputa-tion,it is also accompanied by a high likelihood for symptomatic cardiovas-cular and cerebrovascular disease.Al-though much is known regarding PAD in the general population,the assessment and management of PAD in those with diabetes is less clear and poses some special issues.At present,there are no established guidelines regarding the care of patients with both diabetes and PAD.On the7–8of May2003,a Con-sensus Development Conference was held to review the current knowledge regarding PAD in diabetes.After a series of lectures by experts in thefield of endocrinology,cardiology,vascular surgery,orthopedic surgery,podia-try,and nursing,a vascular medicine panel was asked to answer the following questions:1)What is the epidemiology and im-pact of PAD in people with diabetes?2)Is the biology of PAD different in people with diabetes?3)How is PAD in diabetes best diag-nosed and evaluated?4)What are the appropriate treat-ments for PAD in people with diabetes?1)WHAT IS THEEPIDEMIOLOGY ANDIMPACT OF PERIPHERALARTERIAL DISEASE INPEOPLE WITH DIABETES?PAD is a manifestation of atherosclerosischaracterized by atherosclerotic occlusivedisease of the lower extremities and is amarker for atherothrombotic disease inother vascular beds.PAD affectsϳ12mil-lion people in the U.S.;it is uncertain howmany of those have diabetes.Data fromthe Framingham Heart Study(1)revealedthat20%of symptomatic patients withPAD had diabetes,but this probablygreatly underestimates the prevalence,given that many more people with PADare asymptomatic rather than symptom-atic.As well,it has been reported that ofthose with PAD,over one-half are asymp-tomatic or have atypical symptoms,aboutone-third have claudication,and the re-mainder have more severe forms of thedisease(2).The most common symptom of PADis intermittent claudication,defined aspain,cramping,or aching in the calves,thighs,or buttocks that appears repro-ducibly with walking exercise and isrelieved by rest.More extreme presenta-tions of PAD include rest pain,tissue loss,or gangrene;these limb-threatening man-ifestations of PAD are collectively termedcritical limb ischemia(CLI).PAD is also a major risk factor forlower-extremity amputation,especially inpatients with diabetes.Moreover,even forthe asymptomatic patient,PAD is amarker for systemic vascular disease in-volving coronary,cerebral,and renal ves-sels,leading to an elevated risk of events,such as myocardial infarction(MI),stroke,and death.Diabetes and smoking are the stron-gest risk factors for PAD.Other well-known risk factors are advanced age,hypertension,and hyperlipidemia(3).Potential risk factors for PAD includeelevated levels of C-reactive protein(CRP),fibrinogen,homocysteine,apoli-poprotein B,lipoprotein(a),and plasmaviscosity.An inverse relationship hasbeen suggested between PAD and alcoholconsumption.In people with diabetes,the risk ofPAD is increased by age,duration of dia-betes,and presence of peripheral neurop-athy.African Americans and Hispanicswith diabetes have a higher prevalence ofPAD than non-Hispanic whites,even afteradjustment for other known risk factorsand the excess prevalence of diabetes.It isimportant to note that diabetes is moststrongly associated with femoral-popliteal and tibial(below the knee)PAD,whereas other risk factors(e.g.,smokingand hypertension)are associated withmore proximal disease in the aorto-ilio-femoral vessels.The true prevalence of PAD in peoplewith diabetes has been difficult to deter-mine,as most patients are asymptomatic,many do not report their symptoms,screening modalities have not been uni-formly agreed upon,and pain perceptionmay be blunted by the presence of periph-eral neuropathy.For these reasons,a pa-tient with diabetes and PAD may be morelikely to present with an ischemic ulcer organgrene than a patient without diabetes.While amputation has been used by someas a measure for PAD prevalence,medicalcare and local indications for amputationversus revascularization of the patientwith critical limb ischemia widely vary.The nationwide age-adjusted amputationrate in diabetes isϳ8/1,000patient yearswith a prevalence ofϳ3%.However,re-gional patterns differ—there is nearly a●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●From the American Diabetes Association,Alexandria,Virginia.Address correspondence to Nathaniel Clark,MD,MS,RD,American Diabetes Association,1701N. Beauregard St.,Alexandria,VA22311.E-mail:nclark@.Received and accepted for publication8September2003.This consensus statement has been reviewed and endorsed by the Vascular Disease Foundation.Abbreviations:ABI,ankle-brachial index;CABG,coronary artery bypass graft;CAPRIE,Clopidogrel versus Aspirin in Patients At Risk of Ischemic Events;CLI,critical limb ischemia;CRP,C-reactive protein; eNOS,endothelial cell nitric oxide synthase;FDA,Food and Drug Administration;FFA,free fatty acid;MI, myocardial infarction;MRA,magnetic resonance angiogram;NF-B,nuclear factor-B;PAD,peripheral arterial disease;PAI-1,plasminogen activator inhibitor-1;PI,phosphatidylinositol;PKC,protein kinase C; PVR,pulse volume recording;RAGE,receptor for advanced glycation end products;UKPDS,U.K.Prospec-tive Diabetes Study;VSMC,vascular smooth muscle cell.A table elsewhere in this issue shows conventional and Syste`me International(SI)units and conversion factors for many substances.©2003by the American Diabetes Association.R e v i e w s/C o m m e n t a r i e s/P o s i t i o n S t a t e m e n t sninefold variation of major amputations in people with diabetes across the U.S. Therefore,the incidence and prevalence of amputation may be an imprecise mea-sure of PAD.The reported prevalence of PAD is also affected by the methods by which the diagnosis is sought.Two commonly used tests are the absence of peripheral pulses and the presence of claudication.Both, however,suffer from insensitivity.A more accurate estimation of the prevalence of PAD in diabetes should rely upon a vali-dated and reproducible test.Such a test is the ankle-brachial index(ABI),which in-volves measuring the systolic blood pres-sures in the ankles(dorsalis pedis and posterior tibial arteries)and arms(bra-chial artery)using a hand-held Doppler and then calculating a ratio.Simple to perform,it is a noninvasive,quantitative measurement of the patency of the lower extremity arterial pared with an assessment of pulses or a medical his-tory,the ABI has been found to be more accurate.It has been validated against an-giographically confirmed disease and found to be95%sensitive and almost 100%specific(4).There are some limita-tions,however,in using the ABI.Calci-fied,poorly compressible vessels in the elderly and some patients with diabetes may artificially elevate values.The ABI may also be falsely negative in symptom-atic patients with moderate aortoiliac ste-noses.These issues complicate the evaluation of an individual patient but are not prevalent enough to detract from the usefulness of the ABI as an effective test to screen for and to diagnose PAD in patients with ing the ABI,one recent survey(5)found a prevalence of PAD in people with diabetesϾ40years of age to be20%,a prevalence greater than antici-pated using less reliable measures,such as symptoms or absent pulses.Moreover, another survey of patients with diabetes Ͼ50years of age showed a prevalence of PAD of29%(6).Thus,the prevalence of PAD in diabetes appears higher than pre-viously estimated.Impact of PADThe impact of PAD can be assessed by its progression,the presence of symptoms, and the excess cardiovascular events asso-ciated with systemic atherosclerosis.Ap-proximately27%of patients with PAD demonstrate progression of symptoms over a5-year period,with limb loss oc-curring inϳ4%.While the majority ofpatients remain stable in their lower-limbsymptomatology,there is a striking excesscardiovascular event rate over the same5-year time period,with20%sustainingnonfatal events(MI and stroke)and a30%mortality rate(7).For those withCLI,the outcomes are worse:30%willhave amputations and20%will diewithin6months(8).The natural historyof PAD in patients with diabetes has notspecifically been studied longitudinally,but it is known from prospective clinicaltrials of risk interventions that the cardio-vascular event rates in patients with PADand diabetes are higher than those of theirnondiabetic counterparts.Diagnosis of PADDiagnosing PAD is of clinical importancefor two reasons.Thefirst is to identify apatient who has a high risk of subsequentMI or stroke regardless of whether symp-toms of PAD are present.The second is toelicit and treat symptoms of PAD,whichmay be associated with functional disabil-ity and limb loss.PAD is often more subtlein its presentation in patients with diabe-tes than in those without diabetes.Incontrast to the focal and proximal athero-sclerotic lesions of PAD found typically inother high-risk patients,in diabetic pa-tients the lesions are more likely to bemore diffuse and distal.Importantly,PADin individuals with diabetes is usually ac-companied by peripheral neuropathywith impaired sensory feedback.Thus,aclassic history of claudication may be lesscommon.However,a patient may elicitmore subtle symptoms,such as leg fatigueand slow walking velocity,and simply at-tribute it to getting older.It has beenreported that patients with PAD and dia-betes experience worse lower-extremityfunction than those with PAD alone(9).Also,diabetic patients who have beenidentified with PAD are more prone to thesudden ischemia of arterial thrombosis(10)or may have a pivotal event leadingto neuroischemic ulceration or infectionthat rapidly results in an acute presenta-tion with critical limb ischemia and risk ofamputation.By identifying a patient withsubclinical disease and instituting preventa-tive measures,it may be possible to avoidacute,limb-threatening ischemia.PAD in diabetes also adversely affectsquality of life,contributing to long-termdisability and functional impairment thatis often severe.Patients with claudicationhave a slower walking speed(generallyϽ2mph)and a limited walking distance.This may result in a“cycle of disability”with progressive deconditioning and lossof function.Finally,there are significanteconomic costs of health care,reducedproductivity,and personal expenses asso-ciated with a chronic manifestation of ath-erosclerotic disease such as PAD.2)IS THE BIOLOGY OF PADDIFFERENT IN PEOPLEWITH DIABETES?Diabetes affects nearly every vascular bed;however,the pervasive influence of dia-betes on the atherothrombotic milieu ofthe peripheral vasculature is unique.Theabnormal metabolic state accompanyingdiabetes results in changes in the state ofarterial structure and function.The onsetof these changes may even predate theclinical diagnosis of diabetes.Relativelylittle is known about the biology of PADin individuals with diabetes in particular.However,it is felt that the atherogenicchanges observed with other manifesta-tions of atherosclerotic disease,such ascoronary and carotid artery disease,aregenerally applicable to patients with bothPAD and diabetes.The proatherogenic changes associ-ated with diabetes include increases invascular inflammation and derangementsin the cellular components of the vascu-lature,as well as alterations in blood cellsand hemostatic factors.These changes areassociated with an increased risk for ac-celerated atherogenesis as well as pooroutcomes.Given the large size of the pe-ripheral vascular bed,the potential im-pact of these abnormalities is great.Diabetes,inflammation,and risk forPADInflammation has been established asboth a risk marker and perhaps a risk fac-tor for atherothrombotic disease states,including PAD(11).Elevated levels ofCRP are strongly associated with the de-velopment of PAD(12).In addition,lev-els of CRP are abnormally elevated inpatients with impaired glucose regulationsyndromes,including impaired glucosetolerance and diabetes.In addition to being a marker of dis-ease presence,elevation of CRP may alsobe a culprit in the causation or exacerba-tion of PAD.CRP has been found to bindto endothelial cell receptors promotingapoptosis and has been shown to colocal-Peripheral arterial disease in people with diabetesize with oxidized LDL in atherosclerotic plaques.CRP also stimulates endothelial production of procoagulant tissue factor, leukocyte adhesion molecules,and che-motactic substances and inhibits endo-thelial cell nitric oxide(NO)synthase (eNOS),resulting in abnormalities in the regulation of vascular tone.Finally,CRP may increase the local production of com-pounds impairingfibrinolysis,such as plasminogen activator inhibitor(PAI)-1.Diabetes and endothelial cell dysfunctionThe endothelial cell lining of the arterial vasculature is a biologically active organ. It modulates the relationship between the cellular elements of the blood and the vas-cular wall,mediating the normal balance between thrombosis andfibrinolysis,and plays an integral role in leukocyte/cell wall interactions.Abnormalities of endo-thelial function can render the arterial system susceptible to atherosclerosis and its associated adverse outcomes.Most patients with diabetes,including those with PAD,demonstrate abnormalities of endothelial function and vascular regula-tion(13).The mediators of endothelial cell dysfunction in diabetes are numerous,but an importantfinal common pathway is de-rangement of NO bioavailability.NO is a potent stimulus for vasodilatation and lim-its inflammation via its modulation of leu-kocyte-vascular wall interaction. Furthermore,NO inhibits vascular smooth muscle cell(VSMC)migration and prolifer-ation and limits platelet activation.There-fore,the loss of normal NO homeostasis can result in a cascade of events in the vascula-ture leading to atherosclerosis and its con-sequent complications.Several mechanisms contribute to the loss of NO homeostasis,including hyper-glycemia,insulin resistance,and free fatty acid(FFA)production.Hyperglycemia blocks the function of endothelial eNOS and boosts the production of reactive ox-ygen species,which impairs the vasodila-tor homeostasis fostered by endothelium. This oxidative stress is amplified because, in endothelial cells,glucose transport is not downregulated by hyperglycemia.In addition to hyperglycemia,insulin resistance plays a role in the loss of normal NO homeostasis(14).One consequence of insulin resistance is excess liberation of FFAs.FFAs may have numerous deleteri-ous effects on normal vascular homeostasis, including activation of protein kinase C (PKC),inhibition of phosphatidylinositol(PI)-3kinase(an eNOS agonist pathway),and production of reactive oxygen species.The sum effect of all these leads to the loss ofNO homeostasis.The effects of endothelial cell dys-function,along with activation of the re-ceptor for advanced glycation endproducts(RAGE),increase the local in-flammatory state of the vascular wall,me-diated in part by increased production ofthe transcription factors,nuclear fac-tor-B(NF-B),and activator protein1.Local increases in these proinflammatoryfactors,together with the loss of normalNO function is associated with increasedleukocyte chemotaxis,adhesion,transmi-gration,and transformation into foamcells.This latter process is further aug-mented by increased local oxidative stress(15).Foam cell transformation is the ear-liest precursor of atheroma formation.Diabetes and the VSMCThe presence of diabetes is also associatedwith significant abnormalities in VSMCfunction.Diabetes stimulates pro-atherogenic activity in VSMC via mecha-nisms similar to that in endothelial cells,including reductions in PI-3kinase,as wellas local increases in oxidative stress and up-regulation of PKC,RAGE,and NF-B.Thesum total of these changes might be ex-pected to promote the formation of athero-sclerotic lesions.These effects may alsoincrease VSMC apoptosis and tissue factorproduction,while reducing de novo syn-thesis of plaque stabilizing compounds,such as collagen.Thus,the above events ac-celerate atherosclerosis and are also associ-ated with plaque destabilization andprecipitation of clinical events(16).Diabetes and the plateletPlatelets play an integral role in the con-nection between vascular function andthrombosis.Abnormalities in platelet bi-ology may not only promote the progres-sion of atherosclerosis,but also influencethe consequence of plaque disruption andatherothrombosis.As in the endothelialcell,platelet uptake of glucose is un-checked in the setting of hyperglycemiaand results in increased oxidative stress.Consequently,platelet aggregation isenhanced in patients with diabetes.Plate-lets in diabetic patients also have in-creased expression of glycoprotein Ib andIIb/IIIa receptors,which are important inthrombosis via their role in adhesion andaggregation.Diabetes,coagulation,and rheologyDiabetes leads to a hypercoagulable state(17).It is associated with the increasedproduction of tissue factor by endothelialcells and VSMCs,as well as increasedplasma concentrations of factor VII.Hy-perglycemia is also associated with a de-creased concentration of antithrombinand protein C,impairedfibrinolytic func-tion,and excess production of PAI-1.Finally,abnormalities in rheology areseen in diabetic patients as an elevation inblood viscosity andfibrinogen.Elevatedviscosity andfibrinogen are both correla-tive with abnormalities in ABI among pa-tients with PAD,and elevatedfibrinogen(or its degradation products)has been as-sociated with the development,presence,and complications of PAD.In summary,diabetes increases therisk for atherogenesis via deleterious ef-fects on the vessel wall,as well as effectson blood cells and rheology.The vascularabnormalities leading to atherosclerosisin patients with diabetes may be evidentbefore the diagnosis of diabetes,and theyincrease with duration of diabetes andworsening blood glucose control.Furtherstudies of the diabetes-specific mecha-nisms responsible for the development ofatherosclerosis,as well as the specificpathways responsible for PAD in this pop-ulation,are needed.3)HOW IS PAD INDIABETES BESTDIAGNOSED ANDEVALUATED?Clinical evaluation:history andphysicalThe initial assessment of PAD in patientswith diabetes should begin with a thor-ough medical history and physical exam-ination to help identify those patientswith PAD risk factors,symptoms of clau-dication,rest pain,and/or functional im-pairment.Alternative causes of leg painon exercise are many,including spinalstenosis,and should be excluded.PADpatients present along a spectrum of se-verity ranging from no symptoms,inter-mittent claudication,rest pain,andfinallyto nonhealing wounds and gangrene.A thorough walking history will elicitclassic claudication symptoms and varia-tions thereof.As these symptoms are of-American Diabetes Associationten not reported,patients should be asked specifically about them.Two important components of the physical examination are visual inspection of the foot and pal-pation of peripheral pulses.Dependent rubor,pallor on elevation,absence of hair growth,dystrophic toenails,and cool, dry,fissured skin are signs of vascular in-sufficiency and should be noted.The in-terdigital spaces should be inspected for fissures,ulcerations,and infections(18).Palpation of peripheral pulses should be a routine component of the physical exam and should include assessment of the femoral,popliteal,and pedal vessels. It should be noted that pulse assessment is a learned skill and has a high degree of interobserver variability,with high false-positive and false-negative rates.The dor-salis pedis pulse is reported to be absent in8.1%of healthy individuals,and the posterior tibial pulse is absent in2.0%. Nevertheless,the absence of both pedal pulses,when assessed by a person expe-rienced in this technique,strongly sug-gests the presence of vascular disease.Noninvasive evaluation for PAD:ABI In contrast to the variability of pulse assess-ment and the often nonspecific nature of information obtained via history and other components of the physical exam,the ABI is a reproducible and reasonably accurate, noninvasive measurement for the detection of PAD and the determination of disease se-verity(19).The ABI is defined,as noted pre-viously,as the ratio of the systolic blood pressure in the ankle divided by the systolic blood pressure at the arm.The tools re-quired to perform the ABI measurement in-clude a hand-held5–10MHz Doppler probe and a blood pressure cuff.The ABI is measured by placing the pa-tient in a supine position for5min.Systolic blood pressure is measured in both arms, and the higher value is used as the denom-inator of the ABI.Systolic blood pressure is then measured in the dorsalis pedis and posterior tibial arteries by placing the cuff just above the ankle.The higher value is the numerator of the ABI in each limb.The diagnostic criteria for PAD based on the ABI are interpreted as follows:●Normal if0.91–1.30●Mild obstruction if0.70–0.90●Moderate obstruction if0.40–0.69●Severe obstruction ifϽ0.40●Poorly compressible ifϾ1.30An ABI valueϾ1.3suggests poorly com-pressible arteries at the ankle level due tothe presence of medial arterial calcifica-tion.This renders the diagnosis of PAD byABI alone less reliable.Due to the high estimated prevalence ofPAD in patients with diabetes,a screeningABI should be performed in patientsϾ50years of age who have diabetes.If normal,the test should be repeated every5years.Ascreening ABI should be considered in dia-betic patientsϽ50years of age who haveother PAD risk factors(e.g.,smoking,hy-pertension,hyperlipidemia,or duration ofdiabetesϾ10years).A diagnostic ABIshould be performed in any patient withsymptoms of PAD.It should be noted thatin the evaluation of the individual patientthere may be errors and that the reliability ofany diagnostic test is dependent on the priorprobability of disease(Bayes’Theorem).Vascular lab evaluation:segmentalpressures and pulse volumerecordingsIn the patient with a confirmed diagnosis ofPAD in whom an assessment of the locationand severity is desired,the next step wouldbe a vascular laboratory evaluation for seg-mental pressures and pulse volume record-ings(PVRs).These tests should also beconsidered for patients with poorly com-pressible vessels or those with a normal ABIwhere there is high suspicion of PAD.Seg-mental pressures and PVRs are determinedat the toe,ankle,calf,low thigh,and highthigh.Segmental pressures help with lesionlocalization,while PVRs provide segmentalwaveform analysis,a qualitative assessmentof bloodflow.Treadmill functional testingFor patients with atypical symptoms or anormal ABI with typical symptoms of clau-dication,functional testing with a gradedtreadmill may help with diagnosis.Patientswith claudication will typically exhibit aϾ20-mmHg drop in ankle pressure afterexercise.Treadmill testing may also be usedas an evaluation of treatment efficacy and asan assessment of physical function.Additional evaluationIn patients with possible CLI,furthernoninvasive studies may help with clini-cal decision making regarding revascular-ization.A toe pressureϽ40mmHg or atoe waveformϽ4mm may predict im-paired wound healing and is often used inthe evaluation of ischemic ulcers.Systolictoe pressure is also useful in the evalua-tion of the patient with medial arterial cal-cification,where the ABI is less accurate.Another method of predicting healing isthe measurement of the transcutaneouspartial pressure of oxygen(TcPO2).AvalueϽ30mmHg is associated with poorhealing of wounds or amputations.Anatomic studies:duplexsonography,magnetic resonanceangiogram,and contrastangiographyFor those patients in whom revasculariza-tion is considered and anatomical local-ization of stenoses or occlusions isimportant,an evaluation with a duplexultrasound or a magnetic resonance an-giogram(MRA)may be valuable.Duplexultrasound can directly visualize vesselsand is also useful in the surveillance ofpostprocedure patients for graft or stentpatency.MRA is noninvasive with mini-mal risk of renal insult.It may give imagesthat are comparable with conventional X-ray angiography,especially in occultpedal vessels,and may be used for ana-tomical diagnosis.While MRA is a safe and promising newtechnology,the gold standard for vascularimaging is X-ray angiography,and it is in-dicated primarily for the anatomical evalu-ation of the patient in whom arevascularization procedure is intended.Because it is an invasive test with a small riskof contrast-induced nephrotoxicity,“ex-ploratory”angiography should not be per-formed for diagnosing PAD.For patientswith suspected pedal ischemia,the angiog-raphy should include an aortogram with se-lective unilateral runoff and a magnifiedlateral view of the foot.It should be notedthat the decision to perform an angiogram ismade on a clinical basis and the need forrevascularization,sometimes independentof any prior noninvasive tests.4)WHAT ARE THEAPPROPRIATE MEDICALTREATMENTS FOR PAD INPEOPLE WITH DIABETES?Treatment of systemicatherosclerosis associated with PADMost cardiovascular risk factors for indi-viduals with PAD are similar to those forpeople with diabetes alone.Althoughthere is little prospective data showingthat treating these risk factors will im-prove cardiovascular outcomes in peoplePeripheral arterial disease in people with diabeteswith both PAD and diabetes specifically, consensus strongly supports such inter-ventions,given that both PAD and diabe-tes are associated with significantly increased risks of cardiovascular events. Cigarette smoking.Cigarette smoking is the single most important modifiable risk factor for the development and exac-erbation of PAD.In patients with PAD, tobacco use is associated with increased progression of atherosclerosis as well as increased risk of amputation(20).Thus, tobacco cessation counseling and avoid-ance of all tobacco products is absolutely essential.Glycemic control.Hyperglycemia may be a cardiovascular risk factor in individ-uals with PAD;however,evidence for the benefit of tight glycemic control in ame-liorating PAD is lacking.In the U.K.Pro-spective Diabetes Study(UKPDS), intensive glycemic control reduced diabe-tes-related endpoints and diabetes-related deaths(21).However,it was not associated with a significant reduction in the risk of amputation due to PAD.In fact, the major reduction in adverse end points was due to improved microvascular rather than macrovascular end points.An additional caveat is that,although it is likely that many patients with PAD were included in the UKPDS study,the preva-lence of PAD was not defined,therefore conclusions from this study may not di-rectly relate to patients with diabetes and PAD.Nevertheless,good glycemic con-trol(A1CϽ7.0%)should be a goal of therapy in all patients with PAD and dia-betes in order to prevent microvascular complications.Hypertension.Hypertension is associ-ated with the development of atheroscle-rosis as well as with a two-to threefold increased risk of claudication(22).In the UKPDS,diabetes endpoints and risks of strokes were significantly reduced and risk of MI was nonsignificantly reduced by tight blood pressure control(23).Risk for amputation due to PAD was not re-duced.In general,the effects of treating hypertension on atherosclerotic disease or on cardiovascular events have not been directly evaluated in patients with both PAD and diabetes.Nevertheless,consen-sus still strongly supports aggressive blood pressure control(Ͻ130/80mmHg) in patients with PAD and diabetes in or-der to reduce cardiovascular risk.Results of the Heart Outcomes Pre-vention Evaluation(HOPE)study showed that ramipril,an ACE inhibitor,significantly reduced the rate of cardio-vascular death,MI,and stroke in a broadrange of high-risk patients without hyper-tension(24).Of the9,297patients in thisstudy,4,051had PAD.Patients with PADhad a similar reduction in the cardiovas-cular endpoints when compared withthose without PAD,thus demonstratingthat ramipril was effective in lowering therisk of fatal and nonfatal ischemic eventsamong all patients.Nonetheless,the po-tential benefit of ACE inhibitors has notbeen studied in prospective,randomizedtrials in patients with PAD.Such trials areneeded before making definite treatmentrecommendations regarding the use of anACE inhibitor as a unique pharmacologicagent in the treatment of PAD.Dyslipidemia.Although treating dyslip-idemia decreases cardiovascular morbid-ity and mortality in general,no studieshave directly studied the treatment oflipid disorders in patients with PAD.In ameta-analysis of randomized trials in pa-tients with PAD and dyslipidemia whowere treated by a variety of therapies,Leng et al.(25)reported a nonsignificantreduction in mortality and no change innonfatal cardiovascular events.However,the severity of claudication was reducedby lipid-lowering treatment.Similarly,ina subgroup analysis of the ScandinavianSimvastatin Survival Study(4S),the re-duction in cholesterol level by simvastatinwas associated with a38%reduction inthe risk of new or worsening symptoms ofintermittent claudication(26,27).In theHeart Protection Study,adults with coro-nary disease,other occlusive arterial dis-ease,or diabetes were randomly allocatedto receive simvastatin or placebo(28).Asignificant reduction in coronary deathrate was observed in people with PAD,but the reduction was no greater than theeffect of the drug on other subgroups.Thus,although there are no data showingdirect benefits of treating dyslipidemia inindividuals with both PAD and diabetes,dyslipidemia in diabetic patients shouldbe treated according to published guide-lines,which recommend a target LDLcholesterol levelϽ100mg/dl.Followingthis guideline,it is our belief that lipid-lowering treatment may not only decreasecardiovascular deaths,but may also slowthe progression of PAD in diabetes.Antiplatelet therapy.The AntiplateletTrialists’Collaboration reviewed145ran-domized studies in an effort to evaluatethe efficacy of prolonged treatment withantiplatelet agents(in most cases,aspirin)(29).This meta-analysis combined datafromϾ100,000patients,includingϳ70,000high-risk patients with evi-dence of cardiovascular disease.A27%reduction in odds ratio(OR)in the com-posite primary endpoint(MI,stroke,andvascular death)was found for high-riskpatients compared with control subjects.However,when a subset ofϾ3,000pa-tients with claudication was analyzed,ef-fects of antiplatelet therapy were notsignificant.Thus,the use of aspirin to pre-vent cardiovascular events and death inpatients with PAD is considered equivo-cal;however,aspirin therapy for peoplewith diabetes is recommended(30).The Clopidogrel Versus Aspirin in Pa-tients At Risk of Ischemic Events(CAP-RIE)Study evaluated aspirin versusclopidogrel inϾ19,000patients with re-cent stroke,MI,or stable PAD(31).Thestudy results showed that75mg of clopi-dogrel per day was associated with a rel-ative risk reduction of8.7%comparedwith the benefits of325mg of aspirin perday for a composite endpoint(MI,isch-emic stroke,and vascular death).Morestriking,in a subgroup analysis ofϾ6,000patients with PAD,clopidogrel was asso-ciated with a risk reduction of24%com-pared with aspirin.Clopidogrel wasshown to be as well tolerated as aspirin.Based on these results,clopidogrel wasapproved by the Food and Drug Admin-istration(FDA)for the reduction of isch-emic events in all patients with PAD.Inthe CAPRIE study,about one-third of thepatients in the PAD group had diabetes.In those patients,clopidogrel was also su-perior to aspirin therapy.In summary,patients with diabetesshould be on an antiplatelet agent(e.g.,aspirin or clopidogrel)according to cur-rent guidelines(30).Those with diabetesand PAD may benefit more by takingclopidogrel.Treatment of symptomatic PADMedical therapy for intermittent claudica-tion currently suggests exercise rehabili-tation as the cornerstone therapy,as wellas the potential use of pharmacologicagents.Exercise rehabilitation.Since1966,many randomized controlled trials havedemonstrated the benefit of supervisedexercise training in individuals with PADAmerican Diabetes Association。
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