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hich Diabetics Are at Riskor Lower-Extremity Problems and

hat Preventive Measures Can Be Taken?eepak G. Nair, MD, MS, MHA, RVT and Russell Samson, MD, FACS, RVT

Diabetes mellitus is a well-known risk factor for development and progression of peripheralarterial disease. Prospective cardiovascular clinical trials have also clearly demonstratedthat diabetics fare worse than their nondiabetic counterparts. Diabetics also differ fromnondiabetics in that multiple revascularization procedures may be required in order for theclinical outcome to be equivalent to that of a nondiabetic patient. However, by advocatingan aggressive approach to peripheral arterial disease, good results in survival and limbsalvage can be achieved in diabetic patients despite the presence of increased medicalcomorbidities. Key to the management of such patients will be identifying which diabeticpatients will be at most risk so that preventive measures can be undertaken.Semin Vasc Surg 21:154-159 © 2008 Elsevier Inc. All rights reserved.

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IABETES MELLITUS (DM) is a well-known risk factorfor the development and progression of peripheral arte-

ial disease (PAD). Although much is known about the twoonditions as independent processes, the effects of DM onAD is less clear. As the two disease states become morerevalent, vascular specialists will have an increasing burden

n providing care for these individuals. Key to the manage-ent of such patients will be identifying which diabetic pa-

ients will be at most risk so that preventive measures can bendertaken. Accordingly, it is imperative that surgeons areware of the scope and biology of the problem, as well as itsnfluence on medical, endovascular, and open surgical treat-

ent.

cope of the Problemn analysis of the National Health and Nutrition Examina-

ion Survey data showed the prevalence of lower-extremityisease increased significantly with age: from 12.3% in those0 to 59 years old to 26.2% in those 60 to 74 years old, and0.8% in those 75 years and older.1 A more recent review ofhe data focusing on noninstitutionalized United Statesdults older than 60 years revealed an 11.6% prevalence ofAD, defined as an ankle-brachial index of �0.9 in either leg.

arasota Vascular Specialists, Sarasota, FL.ddress reprint requests to Deepak G. Nair, Sarasota Vascular Specialists,

600 N. Cattlemen Road, Suite 220, Sarasota, FL 34232. E-mail:

fdnair@veinsandarteries.com

54 0895-7967/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1053/j.semvascsurg.2008.05.002

n that study, prevalence of DM was significantly higher24.8%) than in those without PAD (14.7%). Age- and gen-er-adjusted odds ratio for DM and PAD was 1.81, suggest-

ng that diabetics are more prone to develop PAD than non-iabetics.2 The Framingham Heart Study estimated that 20%f symptomatic PAD patients had DM and the risk of devel-ping PAD increased with age, duration of their diabetes, andresence of associated neuropathy.3 However, this study mayave greatly underestimated the prevalence of PAD, as many

ndividuals with diabetes have asymptomatic PAD. Further,ertain population groups must be more carefully screenedor the presence of the two disease states. For example, Afri-an Americans and Hispanics with DM have a higher preva-ence of PAD than whites, even after adjustments for knownisk factors.3

Diabetes also impacts the progression of PAD. In a pro-pective population-based study comparing diabetic withondiabetic subjects, there were significantly more stenosesound in the carotid arteries (8.7% v 2.8%), arm arteries2.3% v 0%), and leg arteries (31.8% v 18.4%) and more thanalf the subjects with carotid disease had obstructions inheir lower extremities.4 A Scandinavian study showed thathe rate of progression of claudication to critical limb isch-mia over 6 years was 40% for those with diabetes versus5% for those without diabetes.5

Prospective cardiovascular clinical trials have also clearlyemonstrated that diabetics fare worse than their nondiabeticounterparts. Similarly, PAD patients are at enormous risk

or developing cardiovascular and cerebrovascular events.

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Diabetes and lower-extremity problems 155

uring a 5-year period, 20% of PAD patients will sustain aonfatal myocardial infarction or stroke, and 30% will have aatal event.6 Therefore, diagnosis of these two disease states isot only important to allow for their treatment, but also forrimary prevention of cardiovascular and cerebrovascularvents as well as limb ischemia.

iology of Diabetes in PADhe pathophysiology and anatomical location of PAD is dif-

erent in individuals with diabetes. Those without DM tendo have focal atherosclerotic lesions located in more proximalnd larger arteries, whereas diabetics tend to develop diffuseistal disease (Fig 1). Patients with PAD and DM experienceorse lower-extremity function than those with PAD alone.7

nflammation is enhanced in diabetes and PAD and so ele-

igure 1 Diabetic pattern of tibial disease in PAD.

ated levels of C-reactive protein are seen in patients with l

AD as well as those with impaired glucose tolerance. C-re-ctive protein has been shown to increase procoagulant ac-ivity, prevent regulation of vascular tone, promote vascularmooth muscle cell proliferation, and impair fibrinolysis. Anncrease in the inflammatory state of the vascular system isssociated with an increase in leukocyte chemotaxis, adhe-ion, migration, and transformation into foam cells.8 Theransformation of foam cells is the earliest precursor of ath-roma formation.

Platelet function is also altered in diabetes. Similar to thathich occurs in the endothelial cell, platelet uptake of glu-

ose is unregulated during periods of hyperglycemia. Thiseads to increased oxidative stress and results in enhancedlatelet aggregation. Platelet glycoprotein Ib and IIb/IIIa re-eptors, which promote thrombosis via their role in adhesionnd aggregation, have increased expression in diabetic pa-ients. Thus, the presence of DM results in a hypercoagulabletate. This is aggravated by an increased production of tissueactor, factor VII, and plasminogen activator inhibitor-1, asell as a decrease in antithrombin, protein C, and fibrinolytic

unction.9,10

reventive Interventionn Diabetics with PADiven the significant increased cardio- and peripheral vascu-

ar risk that is associated with PAD and DM, early interven-ion is strongly suggested. These interventions should in-lude lifestyle changes, medications, and optimal foot care.he goal is to reduce cardiovascular and cerebrovascularvents as well as the need for peripheral revascularization andmputations. Ultimately, endovascular or open revascular-zation procedures may be required to prevent amputation.

ifestyle Modificationessation of cigarette smoking is the most important singleodifiable risk factor for prevention and/or progression of

AD in diabetics and nondiabetics. The amount and durationf tobacco use are directly associated with development androgression of PAD.11 Ankle pressure improvement and in-reased exercise tolerance are observed as early as a fewonths after smoking is stopped.12 Patients with symptom-

tic PAD who quit smoking have almost twice the chance ofurviving 5 years as compared with those who continue tomoke.13 Smoking also impacts the prognosis of lower-xtremity revascularization. Continued tobacco use is asso-iated with a threefold increase in the risk of graft failuremong patients who continue to smoke after lower-limb by-ass surgery, regardless of the type of graft used. The greaterhe duration and amount of tobacco use, the lower the rate ofraft patency.14

Excellent glycemic control (hemoglobin A1c �7.0%)hould be sought in all patients, but especially those withAD. Prospective data providing evidence of this benefit is,owever, lacking. In the United Kingdom Prospective Diabe-es Study, intensive glycemic control reduced diabetes-re-

ated deaths, but it did not significantly reduce risk of ampu-

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156 D.G. Nair and R. Samson

ation. The one qualification is that the prevalence of PADas not defined; therefore, conclusions from the study mayot be directly applicable to patients with DM and PAD.15

Supervised exercise programs have been the cornerstonef therapy in symptomatic patients with claudication. Manyandomized clinical trials have concluded that such a benefitxists,16 however, to be effective, such programs require ateast 3 months of intermittent treadmill walking three times aeek. There is no evidence to suggest that diabetes negativelyecreases the efficacy of such programs, however, carefullytted shoes are mandatory if patients are to avoid foot traumand subsequent skin ulceration.

reatment of Foot Lesionsiabetic foot ulcers, which can occur in the absence of majorrterial disease, require particular medical attention. The areaf involvement must be off-loaded, relieving the damagedissue from weight-bearing or pressure. Many techniques ex-st to offload the diabetic foot, including but not limited topecial shoes with pressure-relieving inserts or sandals thatncorporate a rocker-bottom sole. Local wound care can beccomplished with treatments ranging from moist salineressing changes to expensive dressings or recombinantound healing factor therapies, such as Becaplermin (Re-ranex; Ortho-McNeill, New Brunswick, NJ). However, re-ently the latter has come under some scrutiny with sugges-ions that there may be more cancer-related deaths in patientsho have had more than their treatments with these growth

actor topical applications.17 The choice of dressing is vari-ble, but the goals include maintaining a moist wound bed,bsorbing exudates, and creating a barrier against contami-ation. All necrotic tissue must be removed from the wounded, and surrounding callus needs to be pared down to allowpithelialization. Antibiotic treatment may be helpful whenocal cellulitis or purulence is noted. These wounds are usu-lly polymicrobial, with aerobic and anaerobic Gram-ositive and Gram-negative bacteria involved. Superficialultures often lead to a confusing clinical picture because ofhis polymicrobial involvement. Therefore, obtaining deepissue cultures leads to better characterization of the offend-ng organisms. Culture-directed antibiotics can then be cho-en. In the early stages, oral antibiotics are often sufficient;owever, when involvement is more complex, parenteral an-ibiotics under the guidance of an infectious disease specialistay be necessary. If vascular inflow to the foot is inadequate,

hen antibiotic treatment is unlikely to be successful. In thisetting, vascular interventions may be necessary to create auitable environment for healing.

edicationsiabetics with uncontrolled hypertension are more at risk for

ignificant cardiovascular events, so there is a consensus rec-mmendation that blood pressure be strictly controlled�130/80 mmHg).18 However there is no direct evidencehat treating hypertension reduces the incidence and severity

f PAD in diabetics. t

The lower-extremity arterial benefit of dyslipidemia treat-ent for diabetics is also not clearly defined. For patientsith preexisting PAD, the Heart Protection Study demon-

trated the benefit of cholesterol-lowering statin therapy oneducing the incidence of myocardial infarction, coronaryeath, stroke, and revascularization (coronary and noncoro-ary). This was independent of whether the patients wereiabetic. However, there was no apparent effect on the inci-ence of death, aneurysm repairs, and major amputations.19

espite the failure to effect amputation, the addition of st-tins would appear to be beneficial and this is supported byhe National Cholesterol Education Program Adult Treat-ent Panel III update in 2004, which stated that presence ofiabetes may have a moderate rather than high risk for de-elopment of cardiovascular disease20 and the American Di-betes Association guidelines, which recommend use of st-tins for secondary prevention of cardiovascular events in allatients with DM.18 These recommendations were furtherustained by results of the Stop Atherosclerosis in Nativeiabetics Study (SANDS) randomized trial, which comparedrogression of subclinical atherosclerosis, as evaluated byarotid ultrasonography, in Native Americans with type 2M. Participants randomized to aggressive targets of low-ensity lipoprotein cholesterol (�70 mg/dL) and systoliclood pressure (�115 mmHg) had regression of their carotid

ntimal medial thickness.21

Antiplatelet agents, such as aspirin, also have a role iniabetics with PAD. Those with DM and PAD may derivedditional benefit by taking clopidogrel. The Clopidogrel versusspirin in Patients at Risk of Ischemic Events (CAPRIE) studyvaluated �19,000 patients with recent stroke, myocardialnfarction, or stable PAD. Approximately one-third of pa-ients in the PAD group had diabetes and in those patients,lopidogrel was superior to aspirin therapy.22

Pentoxifylline was widely used to enable people with de-ilitating intermittent claudication to walk farther. However,

t has been shown to offer no significant difference comparedo placebo.20 Further, it has not been shown to influence theeed for revascularization or to decrease amputation rate. Onhe other hand, cilastazol has been shown to significantlymprove maximal and pain-free walking distance in patientsith and without diabetes. Cilastazol has antiplatelet, anti-

hrombotic, and vasodilating properties, but its exact mech-nism of action in patients is unknown. Patients with diabe-es showed no significant differences from those withoutiabetes in a pooled analysis of phase III controlled clinicalrials. However, the increase in walking distance is slightlyess in patients with diabetes, but these patients have a loweraseline walking distance and a higher incidence of cardiacisease.23

ndovascular Treatmentdvances in endovascular technology and techniques have

ncreased the probability of patients, especially diabetics, un-ergoing percutaneous treatment as first-line therapy forheir cardiovascular disease. However, randomized clinical

rials in endovascular coronary revascularization have clearly

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Diabetes and lower-extremity problems 157

hown that diabetics achieve inferior results.24,25 Whetherhis translates to peripheral endovascular interventions re-ains controversial. The technical feasibility, safety, and im-ediate success of percutaneous transluminal peripheral an-

ioplasty in diabetic patients has been well-established.26,27

urthermore, diabetic patients with chronic limb ischemiaave been shown to benefit from endovascular revasculariza-ion. However, they differ from nondiabetics in that multipleevascularization procedures may be required in order for thelinical outcome to be equivalent to that of a nondiabeticatient.28 Reasons for this include advancing atherosclerosisnd earlier and more aggressive development of neointimalyperplasia.29 The prospective, randomized, controlled mul-icenter Bypass Versus Angioplasty in Severe Ischemia of theeg (BASIL) trial compared surgery versus angioplasty as therst-line treatment in severe limb ischemia.30 Neither modal-

ty was shown to be superior to the other. This indicated thatercutaneous intervention was at least equivalent to surgicaleconstruction. Although not designed to specifically addresshe issue of DM, diabetic patients in that study also required

higher rate of repeated interventions. Similarly, a moreecent analysis of percutaneous therapy for superficial femo-al artery disease comparing patients with and without DMresenting with claudication showed no significant differ-nce in primary patency among the groups, but assisted-atency was significantly worse in patients with insulin-de-endent DM.31 Interestingly, there was no significantifference in assisted patency between nondiabetics and non-

nsulin�dependent diabetics. Among patients presentingith chronic limb ischemia (ie, rest pain, tissue loss), limb-

alvage rates were worse in diabetics despite equivalent pa-ency and restenosis rates.29

A multitude of technological innovations have been devel-ped for peripheral arterial endovascular interventions. Per-utaneous atherectomy, using a laser or a rotational cuttinglade, fare significantly worse in diabetics as compared tohose without DM.32,33 It has been a setback for this technol-gy, which had been intended to champion the difficult an-tomic patterns of disease characteristic of diabetic patients.lthough atherectomy results in decreased primary patency

n this population, it has allowed for improved limb salvagen patients with critical limb ischemia not undergoing sur-ery34 (Fig 2). Subintimal angioplasty and cryoplasty, in con-rast, have been shown to have similar benefit in diabeticsnd nondiabetics alike.35,36 However, vascular calcification,ore commonly noted in diabetics, will often make theserocedures technically unfeasible.

pen Surgical Treatmentatients with DM and PAD are often perceived as “high-risk”or open lower-extremity revascularization due to the higherates of amputation, increased incidence and severity of cor-nary artery disease, and higher cardiovascular mortalityeen in this population.4 These risk factors are seen as sug-esting a poorer outcome and sometimes may discouragereatment in this group. This may be due, in part, to the

redominantly tibial distribution of disease in diabetics. t

owever, a national survey in the United Kingdom foundhat 60% of diabetic patients with symptomatic PAD wereuitable for revascularization. Only 20% needed a primarymputation.37 Further, many studies have demonstratedong-term bypass graft patency, limb salvage, and survivalates to be comparable between diabetic and nondiabeticroups with PAD.37-40 However, insulin-dependent DM doesignificantly increase the chance of a major amputation (non-nsulin–dependent DM did not) in the early as well as lateeriod after revascularization.39 Females or those with a base-

ine ankle-brachial index �0.44 may have a reduced proba-ility of clinical improvement.39 However, in these studies,resence of DM did not lead to increased risk of postopera-ive death or early graft thrombosis. Nevertheless, it is appro-riate to be cautious in offering surgery for stable diabeticlaudicants. These patients should be advised that they areess likely to improve than other patients with similar symp-oms. On the other hand, our experience, as well as that ofthers, highlights the importance of intervening for limb-

igure 2 Recanalized tibial arteries after percutaneous artherectomy.

hreatening situations (ie, rest pain, ulceration, gangrene).

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158 D.G. Nair and R. Samson

onclusionrterial involvement of leg arteries presents differently iniabetic patients and diabetics are more likely to developAD than the general population.41-43 The high prevalence oferipheral neuropathy results in less symptomatology, suchhat PAD often goes undetected. Symptomatic diabetic (clau-icants) patients are more likely to progress to ischemic restain. Asymptomatic diabetics with PAD are also more likelyo progress to foot ulcers, gangrene, and amputation.

By advocating an aggressive approach to PAD, good results inurvival and limb salvage can be achieved in diabetic patients,espite the presence of increased medical comorbidities. Activeanagement of comorbidities, such as hypertension, coronary

rtery disease, diabetes, and hypercholesterolemia, are likely toontribute to improved outcomes. The presence of DM doesmpact the current revascularization practice in patients withAD. Insulin-dependent diabetics fare worse after percutaneous

ower-extremity interventions than non-insulin–dependent di-betics. However, given a similar limb-salvage rate in those pa-ients undergoing revascularization procedures, diabeticshould not be biased against. The decision to treat conserva-ively rather than by endovascular intervention or bypass sur-ery should be based on suitability for revascularization, appro-riate anatomy, and presence of medical conditions other thaniabetes. Percutaneous therapy and surgery for the treatment ofAD in the face of DM are not mutually exclusive, and, in mostases, the former does not preclude the latter.

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