PHERIPHERAL ARTERY DISEASE IN DIABETES

DR. S.K.SHARMA

CONSULTANT ENDOCRINOLOGIST

JAIPUR.

ADA Guidelines for PAD care in ADA Guidelines for PAD care in DiabeticsDiabetics

29% prevalence of PAD in diabetics over 29% prevalence of PAD in diabetics over 50 years50 years

Failing to detect PAD may lead to lower Failing to detect PAD may lead to lower limb amputations and increased five-year limb amputations and increased five-year risk of myocardial infarction (MI) or stroke, risk of myocardial infarction (MI) or stroke, with a mortality rate of about 33%. with a mortality rate of about 33%.

PAD underdiagnosed in PAD underdiagnosed in DiabeticsDiabetics

Of all patients with PAD, half are Of all patients with PAD, half are asymptomatic asymptomatic

One third have claudication One third have claudication Remaining patients have severe disease Remaining patients have severe disease Peripheral Neuropathy in the diabetics Peripheral Neuropathy in the diabetics

make the condition asymptomaticmake the condition asymptomatic

Goals Of TreatmentGoals Of Treatment

Symptom controlSymptom control Prevention of Limb lossPrevention of Limb loss Reduction of other macrovascular diseaseReduction of other macrovascular disease

Screening & DiagnosisScreening & Diagnosis

ABI is recommended in all diabetic patients ABI is recommended in all diabetic patients older than 50 years and in those younger older than 50 years and in those younger than 50 years if there is coexisting than 50 years if there is coexisting hypertension, smoking, hypercholesterolemia, hypertension, smoking, hypercholesterolemia, or diabetes for more than 10 yearsor diabetes for more than 10 years

If normal, ABI should be repeated every 5 If normal, ABI should be repeated every 5 years.years.

The ABI is 95% sensitive and almost The ABI is 95% sensitive and almost 100%100% specific compared with angiographyspecific compared with angiography

Screening & Diagnosis(cont.)Screening & Diagnosis(cont.)

Functional testing with a graded treadmill is Functional testing with a graded treadmill is useful for evaluating treatment efficacy.useful for evaluating treatment efficacy.

Duplex ultrasonography or magnetic Duplex ultrasonography or magnetic resonance angiography visualize vessels and resonance angiography visualize vessels and help in surveillance for graft or stent patencyhelp in surveillance for graft or stent patency

X-ray angiography is the gold standard, but X-ray angiography is the gold standard, but the small risk of contrast-induced the small risk of contrast-induced nephrotoxicity precludes its routine use for nephrotoxicity precludes its routine use for diagnosisdiagnosis

Treatment of Asymtomatic PAD Treatment of Asymtomatic PAD in Diabeticsin Diabetics

Smoking cessationSmoking cessation Preventive foot carePreventive foot care Maintaining HbAMaintaining HbA1C1C at less than 7% at less than 7% Blood pressure should be aggressively Blood pressure should be aggressively

managed, maintaining levels at less than managed, maintaining levels at less than 130/80 mm Hg 130/80 mm Hg

LDL cholesterol levels should be maintained at LDL cholesterol levels should be maintained at less than 100 mg/dL less than 100 mg/dL

Antiplatelet therapy : 75 mg daily of Antiplatelet therapy : 75 mg daily of clopidogrelclopidogrel better reduces risk of ischemic events better reduces risk of ischemic events compared with 325 mg daily of aspirin compared with 325 mg daily of aspirin

Treatment of Symptomatic PAD Treatment of Symptomatic PAD in Diabeticsin Diabetics

Customized footwear to reduce pressure for Customized footwear to reduce pressure for neuroischemic limbsneuroischemic limbs

Supervised exercise therapy (intermittent Supervised exercise therapy (intermittent treadmill walking 3 times per week) treadmill walking 3 times per week)

CilostazolCilostazol is the drug of choice over is the drug of choice over pentoxifylline for improvement of walking pentoxifylline for improvement of walking distance, functional status, and quality of lifedistance, functional status, and quality of life

CLI requires surgical treatment when medical CLI requires surgical treatment when medical management with debridement, nonadherent management with debridement, nonadherent dressings, and adjunctive wound healing dressings, and adjunctive wound healing techniques failstechniques fails

Treatment of Symptomatic PAD Treatment of Symptomatic PAD in Diabetics(cont.)in Diabetics(cont.)

For all infections, incision and drainage is the For all infections, incision and drainage is the treatment of choicetreatment of choice

Major amputation is indicated only when there Major amputation is indicated only when there is overwhelming infection threatening the is overwhelming infection threatening the patient's lifepatient's life

Limb revascularization indicated inLimb revascularization indicated in

a) CLI resistant to conservative therapya) CLI resistant to conservative therapy

b) Availability of autologous veinb) Availability of autologous vein

c) Absence of irreversible gangrenec) Absence of irreversible gangrene

SUMMARYSUMMARY

Screening with ABI should be conducted in all Screening with ABI should be conducted in all diabetic patients older than 50 years and in those diabetic patients older than 50 years and in those younger than 50 years with other risk factors younger than 50 years with other risk factors (hypertension and smoking, hypercholesterolemia, (hypertension and smoking, hypercholesterolemia, and diabetes for more than 10 years). and diabetes for more than 10 years).

Primary prevention is key and achieved by Primary prevention is key and achieved by addressing other risk factors, including smoking, addressing other risk factors, including smoking, hypertension, glycemic control, antiplatelet therapy, hypertension, glycemic control, antiplatelet therapy, and foot care. and foot care.

CilostazolCilostazol is the drug of choice over pentoxifylline for is the drug of choice over pentoxifylline for improvement of walking distance, functional status, improvement of walking distance, functional status, and quality of life and quality of life

PAD Atherosclerotic occlusive disease of the lower extremities

EpidemiologyUSA – 12 million people suffering from PAD

20% of symptomatic PAD had diabetes and many more asymptomatic

At the time of diagnosis of diabetes PAD-8%

10 years after PAD- 15%

20 years after PAD –45%

Risk factor

Lower extremity amputation

Marker of atherothrombotic disease in systemic vascular accompanied by

CAD

CVD

RENAL VESSEL

Amputation prevalence in diabetes –3% I.e.8/1000 pts./year.

PAD IN DIABETES

In diabetes risk of PAD

Age

Duration of diabetes

Pheripheral Neuropathy

Ethnic group– African, American & Hispanics

PREVALENCE OF PAD IN INDIAPREVALENCE OF PAD IN INDIA CUPS; n=631CUPS; n=631 Overall prevalence of PAD=3.2%Overall prevalence of PAD=3.2%

PAD prevalencePAD prevalence

Normal glucose Normal glucose Impaired glucoseImpaired glucose DiabetesDiabetes

tolerance (n=517)tolerance (n=517) tolerance (n=34)tolerance (n=34) (n=80)(n=80)

2.7%2.7% 2.9%2.9% 6.3% 6.3%

Prevalence of PAD in newly diagnosed Prevalence of PAD in newly diagnosed subjects was 3.5% vs 7.8% in known subjects was 3.5% vs 7.8% in known diabetic subjectsdiabetic subjects

Diabetes Care 2000; 23: 1295-1300

PREVALENCE OF PAD IN INDIA PREVALENCE OF PAD IN INDIA (contd)(contd)

Age groupAge group Normal glucose Normal glucose Glucose Glucose (yrs)(yrs) tolerance intolerancetolerance intolerance

31-5031-50 1.5%1.5% 2.1% 2.1%

51-7051-70 3.4%3.4% 6.3% 6.3%

>70>70 12.5%12.5% 17.6% 17.6%

Diabetes Care 2000; 23: 1295-1300

In diabetes - Femoral,popliteal & tibial vessel (below the knee)

In smokers - More proximal disease Aorta-ilio femoral vessel

In diabetes – Prevelence of PAD mostly asymptomatic

Pain perception blunted by neuropathy

More changes of ischemic ulcers or gangrene

IMPORTANCE OF DIAGNOSIS OF PAD IN DIABETES

Identify patient with high risk of MI,Stroke

Treat symptoms of PAD- functional disability and limb loss

To identify subclinical disease & preventive measures to avoid limb threatning ischemia

Presentation more subtle in diabetes

Lesions are more diffuse and distal v/s in non diabetics

BIOLOGY OF PAD IN DIABETES

Changes in arterial structure & function

Increase vascular inflammation

Derangement of the cellular component of vasculature

Alteration in blood cells- haemostatic factors

Accelerated atherosclerosis – poor outcome

Increase CRP – marker

Endothelial cell receptors -- apoptosis

oxidised LDL

procoagulants

decrease e-NOS

PAI-I

ENDOTHELIAL DYSFUNCTION IN PAD

Increased TNF-alpha, IL-6 & circulating adhesion molecules e.g.. VCAM,Increased PAI-1

Chronic hyperglycemia results in glycosylation of protein formation of AGE, increased oxidative stress induced vascular inflammation via receptar for AGE(RAGE)

PHYSICAL EXAMINATION

Visual inspection of the lower extremities

Atrophy of skin,alopecia,dystrophy of nails,coldness of the toes & change in color

Hypoxia – vasodilation in the dependent position(rubor)

Rapid balancing with elevation

Feeble or absent pulsation –femoral,paplioteal,dorselis pedis and posterior tibial

Arterial bruits

ANKLE BRACHIAL INDEX It is a simple test to asses lower extremities circulation with Doppler ultrasound probe & blood pressure cuff

In which systolic pressure of both brachial arteries of arms & posterior tibial & dorselis pedis arteries of both lower limb is measured

ABI is ratio of Ankle systolic pressure

Brachial systolic pressure

ABI Sevearity of PAD

0.90—1.30 Normal

0.70--- 0.89 Mild

0.40--- 0.69 Moderate

< 0.40 Severe

Sometime it is useful to measure ABI before and after exercise

In some diabetic patient because of sclerosis,arteries are noncompressible and show abnormal high ABI(>1.3)

In such patient arterial duplex ultrasound,pulse volume waveform analysis or toe brachial index in measured

KEY POINTS FOR PAD PATIENTS MANAGEMENT

Screen for CAD & aggressive management for CAD risk factors e.g. H.T.,Dyslipedemia, Glucose intolerance & Smoking

No pharmacological therapy e.g. Weight loss,Smoking Cessation & structured exercise programme including walking programme

ACE-I Antihypertensive agent of choice(renal function should be followed closely because atherosclerotic renal artery sclerosis / HOPE-14.1% v/s 17.7% with placebo ; 40% and 10% bilateral renal artery stenosis)

Treatment of H.T. in PAD patients reduces the risk of MI,Stroke,HF & death

All patients with PAD should be on an antiplatlet agent

BENEFITS OF EXERCISE IN PAD

Lowers the blood pressure

Improve claudication symptoms

Increase pain free & maximal walking distance

Improve quality of life

Improve survival

Lowers TG’s and raises HDL – Chloe.

Improves Glucose tolerance and Insulin resistance

CAD IN PAD PATIENTS

Mortality rate 30% at 5 years, 50% at 10yrs. & 75% at 15yrs.

90% deaths are due to MI and Stroke

Relative risk of dying of CAD in patientswith PAD is 6-7 times

ABI prediction of cardiovascular mortality –25% mortality rate at 4 yrs. In women with ABI of <0.9

DIABETES AND PAD

35-40% of patients with PAD have Diabetes mellitus

EFFECT OF TYPE 2 DIABETES & ITS EFFECT OF TYPE 2 DIABETES & ITS DURATION ON THE RISK OF PAD IN DURATION ON THE RISK OF PAD IN

MENMEN

Am J Med. 2004;116:236-240Am J Med. 2004;116:236-240

BACKGROUNDBACKGROUND

PAD is associated withPAD is associated with morbiditymorbidity risk of MI & strokerisk of MI & stroke risk of amputationrisk of amputation

Incidence of PAD is linked with incidence Incidence of PAD is linked with incidence of DMof DM

What about duration of diabetes & PAD?What about duration of diabetes & PAD?

AIMAIM

To assess the risk of developing PAD in To assess the risk of developing PAD in relation to the duration of diabetes among relation to the duration of diabetes among men in the Health Professionals Follow-up men in the Health Professionals Follow-up StudyStudy

RESULTS(cont.)RESULTS(cont.)

387 cases of PAD among 48, 607 men387 cases of PAD among 48, 607 men Men who developed PAD were older, consumed Men who developed PAD were older, consumed

more alcohol, smoked more, took more aspirin, more alcohol, smoked more, took more aspirin, physically less active and more likely to have physically less active and more likely to have hypertension and hypercholesterolemiahypertension and hypercholesterolemia

The age adjusted RR of PAD among diabetic The age adjusted RR of PAD among diabetic compared with non diabetic is 3.39 (95% CI)compared with non diabetic is 3.39 (95% CI)

If all other risks are adjusted the RR became If all other risks are adjusted the RR became 2.61 (95% CI)2.61 (95% CI)

CONCLUSIONCONCLUSION

The results indicate that duration of Type 2 The results indicate that duration of Type 2 diabetes is associated strongly with the risk of diabetes is associated strongly with the risk of developing PADdeveloping PAD

SUMMARYSUMMARY

PAD is not a major cause of mortality althoughPAD is not a major cause of mortality although Diabetes increases the risk of amputation 3 folds Diabetes increases the risk of amputation 3 folds

compared to non-diabeticscompared to non-diabetics PAD is strongly associated in diabetics with PAD is strongly associated in diabetics with

hypertension and smoking habitshypertension and smoking habits An advantage of this study was the relatively long An advantage of this study was the relatively long

follow-ups (12 years)follow-ups (12 years) Awareness of these effects by patients and health Awareness of these effects by patients and health

professionals will lead to earlier detection of PAD professionals will lead to earlier detection of PAD and its effective managementand its effective management

HOW COMMON IS INTERMITTENT HOW COMMON IS INTERMITTENT CLAUDICATION?CLAUDICATION?

Occurs in 40-50% of PAD patientsOccurs in 40-50% of PAD patients Relatively common; occurs in 5% of Relatively common; occurs in 5% of

adults > 65 yearsadults > 65 years Higher rates in older adults, smokers and Higher rates in older adults, smokers and

diabeticsdiabetics Annual incidence is 2% in people aged > Annual incidence is 2% in people aged >

65 years65 years

Curr Med Res Opin 2002; 18: 479-487Curr Med Res Opin 2002; 18: 479-487

Am J Cardiol 2001; 87 (Suppl): 14 D-18 DAm J Cardiol 2001; 87 (Suppl): 14 D-18 D

MANAGEMENTMANAGEMENT

Risk factor modificationRisk factor modification Exercise therapyExercise therapy Antiplatelet therapyAntiplatelet therapy Medical therapy targeted at symptomsMedical therapy targeted at symptoms Revascularisation proceduresRevascularisation procedures

PENTOXIFYLLINEPENTOXIFYLLINE Hemorrheologic agentHemorrheologic agent Improves erythrocyte deformability, reduces blood viscosity and Improves erythrocyte deformability, reduces blood viscosity and

decreases platelet reactivity and plasma hypercoagulabilitydecreases platelet reactivity and plasma hypercoagulability First drug approved for intermittent claudication in 1984First drug approved for intermittent claudication in 1984 ‘‘De factoDe facto’ standard’ standard

““Pentoxifylline is no longer recommended for first-line therapy for Pentoxifylline is no longer recommended for first-line therapy for most patients with intermittent claudication”most patients with intermittent claudication”

1996 AHA Scientific Statement1996 AHA Scientific Statement

Am J Med 2002; 112: 49-57Am J Med 2002; 112: 49-57

Am J Cardiol 2001; 87 (suppl): 14D-18D

CILOSTAZOLCILOSTAZOL

Novel agentNovel agent Approved by US FDA in 1999Approved by US FDA in 1999 Only drug besides pentoxifylline Only drug besides pentoxifylline

specifically indicated for intermittent specifically indicated for intermittent claudicationclaudication

UNIQUE MECHANISM OF ACTIONUNIQUE MECHANISM OF ACTION

CilostazolCilostazol

Phosphodiesterase III inhibitorPhosphodiesterase III inhibitor

cAMP levelscAMP levels

PlateletsPlatelets Vascular smooth Vascular smooth musclemuscle

Lipoprotein Lipoprotein lipase activitylipase activity TG synthesisTG synthesis

Platelet Platelet aggregationaggregation

VasodilationVasodilation peripheral blood flowperipheral blood flow Antiproliferative effectAntiproliferative effect TGTG

HDL HDL

NO EFFECT ON BLEEDING TIMENO EFFECT ON BLEEDING TIME

BENEFICIAL EFFECTS ON LIPIDSBENEFICIAL EFFECTS ON LIPIDS

EXERTS ANTIPROLIFERATIVE EFFECTSEXERTS ANTIPROLIFERATIVE EFFECTS

CAUSES REGRESSION OF CAROTID CAUSES REGRESSION OF CAROTID ATHEROSCLEROSISATHEROSCLEROSIS

Hemostasis 1999;29:269-276

““The unique combination of antiplatelet, The unique combination of antiplatelet, vasodilatory, antiproliferative and lipid-vasodilatory, antiproliferative and lipid-modifying effects of cilostazol make it an modifying effects of cilostazol make it an attractive agent for use in PAD patients attractive agent for use in PAD patients with intermittent claudication”with intermittent claudication”

Ann Pharmacother 2001; 35: 48-56Ann Pharmacother 2001; 35: 48-56

Dawson et al.Circulation 1998; 98: 678-686

GREATER IMPROVEMENT IN MAXIMAL GREATER IMPROVEMENT IN MAXIMAL WALKING DISTANCE EVEN AT TROUGHWALKING DISTANCE EVEN AT TROUGH

IMPROVES ANKLE-BRACHIAL INDEXIMPROVES ANKLE-BRACHIAL INDEX

INCREASE PAIN FREE AND MAXIMAL INCREASE PAIN FREE AND MAXIMAL WALKING DISTANCEWALKING DISTANCE

IMPROVE FUNCTIONAL ABILITY & IMPROVE FUNCTIONAL ABILITY & QUALITY OF LIFE (ASSESSED BY QUALITY OF LIFE (ASSESSED BY QUESTIONNAIRES)QUESTIONNAIRES)

CONTRAINDICATIONSCONTRAINDICATIONS

Hypersensitivity to the drugHypersensitivity to the drug Congestive heart failureCongestive heart failure

WARNINGS & PRECAUTIONSWARNINGS & PRECAUTIONS Pregnancy: Category CPregnancy: Category C Nursing mothersNursing mothers