FB 133.

1001

DIABETICMedicine

DOI: 10.1111/j.1464-5491.2009.02866.x

Review Article
Peripheral arterial disease in diabetesa review
E. B. Jude, I. Eleftheriadou* and N. Tentolouris*
Tameside General Hospital, Ashton-Under-Lyne, UK and *Athens University Medical School, Athens, Greece
Accepted 23 September 2009

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Abstract
Diabetic patients are at high risk for peripheral arterial disease (PAD) characterized by symptoms of intermittent
claudication or critical limb ischaemia. Given the inconsistencies of clinical findings in the diagnosis of PAD in the
diabetic patient, measurement of ankle-brachial pressure index (ABI) has emerged as the relatively simple, non-invasive
and inexpensive diagnostic tool of choice. An ABI < 0.9 is not only diagnostic of PAD even in the asymptomatic patient,
but is also an independent marker of increased morbidity and mortality from cardiovascular diseases. With better
understanding of the process of atherosclerosis, avenues for treatment have increased. Modification of lifestyle and
effective management of the established risk factors such as smoking, dyslipidaemia, hyperglycaemia and hypertension
retard the progression of the disease and reduce cardiovascular events in these patients. Newer risk factors such as
insulin resistance, hyperfibrinogenaemia, hyperhomocysteinaemia and low-grade inflammation have been identified,
but the advantages of modifying them in patients with PAD are yet to be proven. Therapeutic angiogenesis, on the
other hand, represents a promising therapeutic adjunct in the management of PAD in these patients. Outcomes after
revascularization procedures, such as percutaneous transluminal angioplasty and surgical bypasses in diabetic
patients, are poorer, with increased perioperative morbidity and mortality compared with that in non-diabetic
patients. Amputation rates are higher due to the distal nature of the disease. Efforts towards increasing
awareness and intensive treatment of the risk factors will help to reduce morbidity and mortality in diabetic patients
with PAD.
Diabet. Med. 27, 414 (2010)
Keywords ankle-brachial pressure index, diabetes, peripheral arterial disease, risk factors, treatment
Abbreviations ABI, ankle-brachial pressure index; bFGF, basic fibroblast growth factor; cAMP, cyclic adenosine-3,5monophosphate; CRP, C-reactive protein; DM, diabetes mellitus; HGF, hepatocyte growth factor; HTN, hypertension;
LDL, low-density lipoprotein; MI, myocardial infarction; NGF, nerve growth factor; NO, nitric oxide; PAD, peripheral
arterial disease; PAI, plasminogen activator inhibitor; PCTA, percutaneous transluminal balloon angioplasty; SBP,
systolic blood pressure; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; TcPO2, transcutaneous
partial pressure of oxygen; UKPDS, United Kingdom Prospective Diabetes Study; VEGF, vascular endothelial growth
factor; vWF, von Willebrand factor

Introduction
Peripheral arterial disease (PAD) is a group of disorders
characterized by narrowing or occlusion of the arteries
resulting in gradual reduction of blood supply to the limbs.
Patients with PAD may be asymptomatic or may develop
symptoms of intermittent claudication or symptoms of critical
limb ischaemia, characterized by pain in the peripheries at rest,

Correspondence to: Edward B. Jude, MD, Tameside General

Hospital, Ashton-Under-Lyne, Lancashire OL6 9RW, UK.
E-mail: edward.jude@tgh.nhs.uk

ischaemic ulceration or gangrene. Diabetic patients with PAD are

at high risk of increased morbidity and mortality from
cardiovascular diseases. Considering that between 120 and
140 million people suffer from diabetes mellitus (DM)
worldwide and that diabetic patients are at excess risk of
developing PAD [1], the implications of the problem are
enormous.
The importance of PAD in DM is several-fold. PAD may be
asymptomatic until it reaches an advanced stage [2]. It presents at
an earlier age and progresses more rapidly than in non-diabetic
patients. It is usually more severe in extent [3] and often not all
patients may be offered a revascularization procedure when

2010 The Authors.

Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

DIABETICMedicine

Incidence

needed. Furthermore, the outcome after revascularization

procedures is poorer and many patients progress to a major
amputation [3]. The presence of PAD is in itself an independent
factor for increased mortality due to associated cardiovascular
and cerebrovascular diseases [1]. Finally, early detection of PAD
helps in risk factor modification, which reduces progression and
improves outcome.

21.3 1000 for men

17.6 1000 for women
NA
NA
NA
NA
NA
2 1000 at 30 years of age
6 1000 at 60 years of age
7 1000 at 70 years of age
12.6 1000 for men
8.4 1000 for women
13 1000

Review article

2010 The Authors.

Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

NA
586
2002
UK
11

ABI, ankle-brachial pressure index; IC, intermittent claudication; NA, not available.

IC, foot ulcer, lower

extremity amputation

NA
5209
IC

General population
(26% with diabetes mellitus)
Type 1 diabetes mellitus
Framingham
4

1985

17.3%
38.0%
23.5%
8.7%
33.0%
3% in age < 60 years
20% in age 75 years
173
1084
864
213
48
642
ABI < 0.9
IC or pulse deficit
ABI < 0.9
ABI < 0.9
ABI < 0.9
IC, pulse deficit,
non-invasive testing
Type 1 and Type 2 diabetes mellitus
Type 1 and Type 2 diabetes mellitus
Type 2 diabetes mellitus
Type 1 diabetes mellitus
Type 1 and Type 2 diabetes mellitus
General population
Hoorn study
Australia
UK
UK
UK
North America
6
8
9
9
7
10

1995
1984
1992
1992
1999
1985

1073
Pulse deficit
Type 1 and Type 2 diabetes mellitus

Population
Years

19451969
USA, Minnesota
5

In the Rochester study [5], the cumulative incidence of PAD in

DM was 21.3 1000 person-years for men and 17.6 1000
person-years for women. In this study, the cumulative
incidence of PAD was 15% 10 years after the diagnosis of
DM, which increased to 45% 20 years later. In the Framingham
study [4] the incidence of PAD in the diabetic population was
12.6 1000 person-years for men and 8.4 1000 person-years for
women, while the figures in non-diabetic people were 3.3 and
1.1 1000 person-years for men and women, respectively.
One single study examined the incidence of PAD in patients
with T1DM [11]; the incidence was 13 events 1000 person-

Country

Incidence

References

Large population-based studies have shown that the prevalence

of PAD is higher in patients with DM. The Framingham study [4]
showed that there was a 3.5- and 8.6-fold excess risk among men
and women, respectively, of developing PAD in patients with
DM. In the Rochester study the prevalence of PAD at the time of
diagnosis of DM was 8% between the years 1945 and 1969,
while it was 10.5% in 1970 [5]. The Hoorn study found that the
prevalence of ABI < 0.9 in individuals with normal glucose
tolerance was 7% and increased to 20.9% in diabetic patients
[6], while a pilot study found a prevalence of asymptomatic PAD
of 33% [7].
One study showed that the type of DM does not affect the
prevalence of PAD, identical prevalences being found in
patients with Type 1 (T1DM) and Type 2 DM (T2DM) [8].
However, another study found a much higher prevalence of
PAD (23.5%) in patients with T2DM than in those with
T1DM (8.7%) [9].

Table 1 Epidemiological data for peripheral arterial disease in patients with and without diabetes mellitus

Prevalence

Diagnostic criterion

Number of
patients

Prevalence

The true incidence of PAD is difficult to ascertain and

estimates can be erroneous due to several reasons. A
significant number of patients with PAD are unlikely to
complain of intermittent claudication because the presence of
peripheral neuropathy may mask the symptoms of claudication
[2]. Furthermore, the method used to diagnose PAD
[symptoms of claudication, palpation of peripheral pulses or
ankle-brachial pressure index (ABI)] has a major influence on
statistics. The results of various clinical trials [411] on the
prevalence and incidence of PAD in DM are summarized in
Table 1.

8.0%

Epidemiology

DIABETICMedicine

years with no gender difference and was similar to that in patients

with T2DM.

Amputation rate

Diabetic patients have increased risk of lower-extremity

amputations in comparison with non-diabetic subjects and
there is no convincing evidence that revascularization
procedures are effective in preventing amputation [3].
Moreover, the severity of PAD in DM assessed
angiographically has been associated with major amputations
[12].

Mortality

Large population-based studies have shown that diabetic

patients with PAD have a three- to four-fold increased
mortality compared with healthy individuals [6], and patients
with critical limb ischaemia and DM have a shorter amputationfree survival period than patients with critical ischaemia but
without DM [13]. The 5-year mortality in diabetic patients with
critical limb ischaemia is 30% [14].

Risk factors for PAD in diabetes

Various risk factors have been described for the increased
predisposition to the development of PAD in DM. Many studies
[4,5,911,1527] have attempted to resolve this complicated
issue by comparing diabetic patients with PAD with non-diabetic
patients with PAD and between diabetic patients with and
without PAD.
Increasing age correlates strongly with PAD in patients with
both T1DM and T2DM [9]. Although in the Framingham study
[4] much of the excess risk associated with DM was found in
those < 75 years old, the Framingham-offspring study found that
for each 10 years of age, the odds ratio of PAD was 2.6 [15].
In the Framingham and Rochester studies, the incidence of
PAD was higher in men than in women [4,5]. Diabetic women
are more likely to have PAD compared with non-diabetic women
of similar age [16]. While premenopausal women in the general
population enjoy relative protection from atherosclerosis due to
their hormonal status, DM blunts the benefit of the female gender
[10], especially in the elderly group.
In the United Kingdom Prospective Diabetes Study (UKPDS)
[17], duration and degree of hyperglycaemia were associated
with an increased risk for incident PAD independently of other
factors. Each 1% increase in HbA1c was associated with a 28%
excess risk for incident PAD at the end of 18 years. In another
study, the odds ratio of PAD was 28.9 and 51.1 for a DM
duration of 2029 years and > 30 years, respectively, in patients
with T1DM, while it was 3.8 and 4.3 for a DM duration of 10
19 years and > 20 years, respectively, in patients with T2DM
[18].
The UKPDS found that increased systolic blood pressure (SBP)
was an independent risk factor for PAD and each 10-mmHg

Peripheral arterial disease in diabetes E. B. Jude et al.

increase in SBP was associated with a 25% increased risk for

development of PAD at the end of 18 years [17]. Tight BP control
was also associated with lower prevalence of PAD at long-term
follow-up in the UKPDS [19]. Other factors have also been
associated independently with PAD in patients with both T1DM
and T2DM. These are summarized in Table 2.

Pathogenesis of PAD in diabetes

Vascular disease in DM affects both the microcirculation and
large vessels. Microangiopathy is characterized by involvement
of blood vessels at the level of the arterioles and capillaries,
causing thickening of the basement membrane and making it
more permeable to plasma solutes. PAD in diabetic patients is
due to the angiopathy affecting the medium-sized arteries
predominantly and is due to the abnormal metabolic state that
prevails in DM. The most important metabolic aberrations are
chronic hyperglycaemia, insulin resistance and dyslipidaemia,
which render the arteries susceptible to atherosclerosis. Various
types of affected cells work in tandem to create atheroma, the
hallmark of atherosclerosis. In brief, some of the cellular events in
the process of atherosclerosis are as follows.
DM impairs endothelial function, through hyperglycaemia,
excess circulating free fatty acids, increased oxidative stress and
inhibition of endothelial nitric oxide (MO) synthase. Thus, there is
a decrease in NO and prostacyclin and an increase in endothelin-I
and angiotensin-II, which are potent vasoconstrictors [28].
DM augments the process of atheroma formation. There is an
increase in plasma and cellular concentration of histamine, which
may contribute to the increased endothelial permeability in
diabetic patients with PAD [28]. The migration of T lymphocytes
into the intima, their activation and secretion of cytokines is
enhanced. Monocytes ingest oxidized low-density lipoprotein
(LDL) molecules on reaching the subendothelial space and
become foam cells, which lead to fatty streak formation, the
precursors of the atheroma. The atheromatous plaque so formed
is unstable as diabetic endothelial cells secrete cytokines that
inhibit production of collagen by smooth muscle cells [29]. They
also secrete metalloproteinases, which break down the collagen
in the fibrous cap of atheromas, leading to a tendency to plaque
rupture and thrombus formation [30]. Endothelial cells produce
increased amounts of tissue factor, a major procoagulant factor.
Migration of medial vascular smooth muscle cells into the intimal
fatty streak lesion is enhanced. These cells then produce
extracellular matrix, aggravating atheroma formation.
Hyperglycaemia also increases intracellular concentration of
glucose in platelets as its uptake is non-insulin dependent. This
leads to decreased production of platelet-derived NO and excess
production of oxygen free radicals [29].
Calcium haemostasis regulating platelet shape, secretion,
aggregation and thromboxane production is disturbed in DM
[31]. Platelet expression of receptor proteins for von Willebrand
factor (vWF) and fibrin products is increased in DM, which could
be the result of decreased production of the antiaggregants NO
and prostacyclin, and increased production of fibrinogen and

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Table 2 Risk factors for peripheral arterial disease in diabetes mellitus

References

Risk factor

Type of diabetes mellitus

1,4,5,9,15,17,28
4,5,10
1,5,11,17,18,21,28
17,28
4,15,17
4,11,15,17,19
9,11,15,17,18,20,21
22
23
9,15,21
11,24
1,15
25
9,11,18
26
26
27

Increasing age
Male gender
Duration of diabetes mellitus
Degree of hyperglycaemia
Smoking
Hypertension
Dyslipidaemia
Increased serum lipoprotein (a) levels
Reduced serum apolipoprotein (a) levels
Obesity, central body fat distribution
Insulin resistance
Increased serum fibrinogen levels
Hyperhomocysteinaemia
Microalbuminuria
Increased levels of von Willebrand factor
Increased levels of thrombinantithrombin complexes
Increased levels of intercellular adhesion molecules

1, 2
2
1, 2
2
2
1, 2
1, 2
1, 2
2
2
1, 2
2
Non-diabetics
1, 2
2
2
2

platelet activators such as thrombin and vWF [32]. This increase

in intrinsic platelet activity contributes to the state of enhanced
thrombotic potential.
Diabetic patients have impaired fibrinolytic activity [1]. In
addition, there are increased circulating levels of procoagulants
such as tissue factor, factor VII and decreased levels of
anticoagulants such as antithrombin-III and protein C, thus
favouring a tendency to coagulation, impaired fibrinolysis and
persistence of thrombi [33].
Patients with impaired glucose tolerance have elevated levels of
C-reactive protein (CRP), which is strongly associated with PAD.
CRP inhibits endothelial NO synthase and stimulates the
production of procoagulant tissue factor, leucocyte adhesion
molecules, chemotactic substances and plasminogen activator
inhibitor (PAI)-1 and thus contributes to a thrombotic
environment [28].

Profile of PAD in diabetes

The pattern of PAD involvement differs between diabetic and
non-diabetic patients. Diabetic patients with PAD commonly
show involvement of the arteries below the knee, especially at
the tibial and peroneal arteries, and involvement of the
profunda femoris [3]. Also, it is more commonly symmetrical
and multi-segmental, and stenoses can be seen even in the
collateral vessels. Non-diabetic patients with PAD usually
present with single, unilateral, proximal arterial involvement.
Some, but not all studies, reported that PAD progresses more
rapidly in DM.

Clinical presentation
The majority of diabetic patients with PAD are asymptomatic
(up to 75%) when ABI < 0.9 is the criterion for the diagnosis. The

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Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

PARTNERS programme [34] showed that 48% of the 6369

patients, of whom 41% had DM, were aware of their condition.
Some data suggest that patients with DM develop more
symptomatic forms of PAD such as intermittent claudication,
foot ulcers and critical limb ischaemia symptoms [35], while
other studies have found no difference in the frequency of
symptoms between diabetic and non-diabetic patients [9].
Diabetic patients with decreased pain perception due to
peripheral neuropathy may delay the recognition of PAD [2].
Peripheral neuropathy and PAD are known risk factors for
foot ulceration [36]; almost 4060% of diabetic patients with
foot ulcers have PAD, which is associated with a higher
amputation rate and mortality [36]. With impaired circulation
and sensation, foot ulceration and infection develop commonly.
Development of dry gangrene is the end-stage presentation of
PAD, indicating that in the absence of a revascularization
procedure a major amputation is unavoidable.
Diabetic patients with PAD have poorer lower extremity
function compared with non-diabetic subjects with PAD; they
have shorter mean walking distance and slower fast pace
velocities than non-diabetic patients with PAD. This was due
to the associated peripheral neuropathy, differences in exertional
leg symptoms and greater cardiovascular disease in diabetic
patients [37].

Diagnosis of PAD
A history of intermittent claudication or absence of peripheral
pulses on palpation is unreliable for detection of PAD. The
dorsalis pedis pulse is absent congenitally in about 1015% of the
population. However, a history of claudication, presence of
bruits proximally and findings of chronic ischaemia in the
peripheries such as cold feet, pallor on limb elevation and
dependent rubor, trophic skin changes and distal gangrene are all

Peripheral arterial disease in diabetes E. B. Jude et al.

DIABETICMedicine

diagnostic of PAD. Peripheral Doppler ultrasonography, colour

duplex scanning, ABI measurement, plethysmography,
transcutaneous oximetry [transcutaneous partial pressure of
oxygen (TcPO2)] and magnetic resonance angiography are the
battery of non-invasive tests currently available.
An ABI < 0.9 has been used as a criterion for diagnosis in most
studies on PAD, because of its simplicity and non-invasiveness
(Table 3). However, studies on resting ABI and post-exercise ABI
have been conflicting. An arteriographically controlled study
showed that significant stenoses (> 50%) were present in diabetic
patients with palpable foot pulses and ABI > 1 [12]. Questions
have been raised about the reliability of ABI in the diagnosis of
PAD as it was found that ABI was high in hypotensive or
normotensive patients and low in hypertensive patients [38]. The
sensitivity and specificity of ABI were 70.6% and 88.5%,
respectively, in patients with PAD diagnosed by colour duplex
ultrasound [1].
Measurement of pre- and post-exercise ABI is currently
recommended for the screening and diagnosis of PAD, until
more reliable diagnostic tools become available. The ABI
measured with ankle SBP just before and after 5 min of
exercise may reveal significant PAD before resting ABI
becomes abnormal. A drop in ankle BP > 20% indicates
significant PAD, while an absence of such a fall virtually rules
out PAD [1]. Medial arterial calcification (Monckebergs
sclerosis), found in up to 47% of patients with T1DM in one
study [39], is common in patients with DM or renal failure and in
heavy smokers and this can falsely raise ABI to values > 1.3 [1],
masking the presence of PAD [40]. A recent study suggested that
diabetic patients with an ABI 1.4 should be considered as
PAD-equivalent [40]. Medial arterial calcification may also
render the artery non-compressible and hence ankle BP may not
be assessable. However, the presence of calcification is not a
measure of the severity of the disease or the extent of
stenosis occlusion. An alternative approach in these patients is
to measure the great toe BP using a strain gauge sensor or a
photoplethysmograph [2]. Determination of TcPO2 may help
assess healing of ischaemic skin lesions, but is not reliable for the
diagnosis of PAD in DM [2]. Continuous-wave Doppler may
identify occlusive PAD but is a qualitative test only. Colour

duplex ultrasound and magnetic resonance angiography help in

localizing PAD lesions and planning intervention. Traditional or
digital subtraction angiography remains the gold standard
against which all other diagnostic modalities should be
compared. It is to be used when a vascular intervention is
planned [1]. A proposed protocol for the diagnosis of PAD in
patients with and without DM is depicted in Fig. 1.

Treatment
The aims in the management of the diabetic patient with PAD are
to improve symptoms and to prevent cardiovascular morbidity
and mortality. Treatment of PAD can be considered in three
stages: lifestyle and risk factor modifications, drug therapy and
vascular interventions.

Lifestyle modifications

Lifestyle modifications are the first mode of therapy as metabolic

and lipid abnormalities improve with smoking cessation,
exercise, weight loss and dietary modifications.
Cigarette smoking is the single most important risk factor for
the development of atherosclerosis and smoking cessation may
halt the progression of disease [28]. Smoking increases the risk
and reduces the success of peripheral vascular intervention [15].
Physical exercise improves exercise tolerance and most of the
studies have shown at least a doubling in walking distance [41].
Noteworthy, these changes were found without significant
improvement in blood flow, but exercise increases
cardiovascular fitness, oxidative enzyme activities, NO
production and insulin sensitivity [29], enhances utilization of
fatty acids in calf muscles, and improves walking biomechanics
as well as blood rheology. Exercise training leads to modest
reductions in BP, cholesterol and glucose levels.

Risk factor modifications

Glycaemic control

There is no conclusive evidence to suggest that optimal glycaemic

control lowers the risk of PAD [42]. In the presence of an

Table 3 The role of ankle-brachial pressure index (ABI) for the diagnosis of peripheral arterial disease (PAD) in patients with diabetes mellitus

Advantages

References

Disadvantages

References

Simple

1,28

28,40

Non-invasive

1,28

Reproducible

1,28

ABI 1.4 (medial arterial calcification) unreliable,

should be considered as PAD equivalent
Arteriographically evident stenoses > 50%
with resting ABI > 1
ABI in hypotensive or normotensive patients
ABI in hypertensive patients

Sensitivity of 90% and specificity 98%

for the detection of haemodynamically
significant (> 50%) stenosis in leg arteries
Post-exercise ABI: drop of ankle-blood
pressure > 20% indicates PAD

1,28

12
38

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Review article

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FIGURE 1 Proposed protocol for the diagnosis of peripheral arterial disease (PAD) in patients with and without diabetes mellitus. Reprinted with
permission from N Engl J Med 2001; 344: 16081621. ABI, ankle-brachial index; TBI, toe-brachial index.

increased risk of cardiovascular events with increasing levels of

glycaemia [17] and hyperglycaemia being the important
metabolic factor in atherogenesis, optimal glycaemic control
would be sensible in patients with PAD. Medications that
improve insulin resistance may have advantages over other
hypoglycaemic agents, since insulin resistance is a risk factor for
PAD. However, metformin was not superior to sulphonylureas
or insulin in the prevention of PAD in DM [42]. In the
PROACTIVE study only patients without PAD at baseline
benefited from treatment with pioglitazone [43].
Dyslipidaemia

Aggressive management of dyslipidaemia in patients with DM

and PAD is warranted and the primary aim is LDL-cholesterol
levels < 2.6 mmol l or even lower (< 1.8 mmol l) [28]. Statins
are the treatment of choice in such patients. The 4S-Study [44]
showed that simvastatin reduced claudication in patients with
PAD, although there were no specific data regarding diabetic
patients. The Heart Protection Study showed that lowering LDLcholesterol with simvastatin reduces cardiovascular mortality
and morbidity in diabetic patients by almost 25% [45], while the
Collaborative Atorvastatin Diabetes Study showed that
aggressive treatment with atorvastatin in diabetic patients

2010 The Authors.

Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

reduced major cardiovascular events by 37%, irrespective of

pretreatment LDL-cholesterol levels [46].
Hypertension

Optimal control of hypertension (HTN) to 130 80 mmHg

reduces stroke and death rates. Long-term tight BP control was
associated with a 50% lower risk for PAD in the UKPDS with no
difference between the primary medications (captopril and
atenolol) used for the management of HTN [19]. The HOPE
study [47] showed that ramipril decreased the rates of
myocardial infarction (MI), stroke and death in diabetic
patients with cardiovascular disease. The reduction of
cardiovascular morbidity and mortality in patients with PAD
was 25%. A recent study also showed that intensive BP control
reduces the risk for cardiovascular events in diabetic patients
with PAD [48].
There have been no reports of worsening of symptoms after
control of HTN in patients with PAD. A meta-analysis concluded
that b-blockade was not associated with reduced treadmill
walking performance in PAD patients with intermittent
claudication [49]. Currently, it is recommended that b-blockers
be used as and when indicated, except in patients with critical
limb ishaemia.

DIABETICMedicine

Drug therapy
Antiplatelet agents

Antiplatelet agents are of benefit in patients with PAD, as platelet

hyperactivity leads to formation of thrombus at sites of
atherosclerotic plaques. Antiplatelet agents produce
angiographic improvement, increase walking distance, reduce
the need for vascular intervention, improve patency rates after
vascular interventions and reduce cardiovascular mortality. The
Anti-platelet Trialists Collaboration has shown that an
antiplatelet agent, usually aspirin, reduces cardiovascular
deaths by 25% in patients with symptomatic atherosclerotic
disease. This reduction in death rates was 18% in the subset of
patients with intermittent claudication [50]. However, these
studies have not reported data separately in diabetic patients with
PAD.
Aspirin alone is as effective as aspirin combined with
dipyridamole, sulphinpyrazone or ticlopidine in preventing
graft occlusion or reduction in risk of death from
cardiovascular events [51]. However, aspirin with dipyridamole
resulted in least progression of PAD compared with aspirin alone
or placebo in an arteriographically controlled trial [52]. A dose of
325 mg did not show any additional benefit over a dose of 75 mg.
Ticlopidine, an antiplatelet thienopyridine agent, improves
clinical outcomes in patients with PAD but is not recommended
because of adverse effects (neutropenia and thrombotic
thrombocytopenic purpura).
Clopidogrel is a second-generation thienopyridine drug with
fewer side-effects. The CAPRIE study [53] compared
clopidogrel with aspirin in > 19 000 patients and found that
the overall decrease in the primary endpoints of MI, stroke or
vascular deaths was 8.7%, and clopidogrel decreased the endpoint of MI by 19.2% over that of aspirin irrespective of the
primary cardiovascular disease. The study also showed that in
the subgroup (about 30% of the 19 000 patients) with PAD at
baseline, those who received clopidogrel had 24% lower
primary end-points of MI, stroke or vascular death in
comparison with aspirin. However, there was no particular
reference to DM.
Intermittent claudication

Two agents are available for the treatment of intermittent

claudication: pentoxifylline and cilostazol. Pentoxifylline, a
methylxanthine derivative is a haemorheological agent that
reduces blood viscosity. It also has antiplatelet action and reduces
serum fibrinogen levels. Results of pentoxifylline in claudication
varied in different studies, with some suggesting favourable
results in diabetic patients but most demonstrating a modest
improvement in symptoms suggesting that pentoxifylline is not
justified for routine use [28]. Pentoxifylline may benefit patients
with severe claudication symptoms and those in whom exercise
and or cilostazol is not effective or is contraindicated.
Cilostazol, a quinolone derivative, is a selective
phosphodiesterase-III inhibitor that suppresses cyclic adenosine3,5-monophosphate(cAMP)degradation. Increasedintraplatelet

10

Peripheral arterial disease in diabetes E. B. Jude et al.

cAMP inhibits thromboxane A2 production and platelet

aggregation by inhibiting phospholipase and cyclooxygenase.
Cilostazol induces vasodilation by inhibiting calcium-induced
contractions of smooth muscle cells.
Treatment with cilostazol increases pain-free and maximal
treadmill walking distances and improves quality of life
significantly more than pentoxifylline [54]. A pooled analysis
of eight Phase III trials of 436 diabetic patients with intermittent
claudication showed that patients who received cilostazol
increased their maximal walking distances, initial claudication
distance and absolute claudication distance more than those with
placebo [55]. Response rates and safety data were similar in
patients with and without DM.
Cilostazol is contraindicated in patients with congestive heart
failure and severe hepatic or renal impairment. Cilostazol is a
promising therapy for patients with claudication and DM among
the limited options available for these patients [2].
The above drugs for intermittent claudication are
recommended in the event of failure of lifestyle modifications.
Clinical trials have shown no efficacy of vasodilator drugs such as
papavarine in PAD and they are not recommended.
Drugs of possible benefit

Iloprost, a prostacyclin derivative, reduces levels of PAI-1 (which

is associated with increased fibrinogen levels and
hypercoaguability) and also increases walking capacity in
diabetic patients with PAD [56]. Further studies are required
before iloprost could be recommended for use.
Critical leg ischaemia

In patients with critical leg ischaemia a revascularization

procedure should always be considered. In addition,
appropriate foot care, sufficient footwear, debridement of foot
ulcers, non-adherent dressings and treatment of infections with
antibiotics are essential for preventing amputation [1].
Therapeutic angiogenesis

Therapeutic angiogenesis represents a novel approach to increase

blood flow to ischaemic tissues by induction of a collateral
vascular network. This can be achieved by administration of
angiogenic factors such as vascular endothelial growth factor
(VEGF), basic fibroblast growth factor (bFGF), hepatocyte
growth factor (HGF) and nerve growth factor (NGF). Two
modes of angiogenesis are emerging; the first is the topical (into
the muscles or arteries of the lower limbs) administration of the
recombinant growth factor protein, and the second is
incorporation of genes encoding angiogenic growth factors into
a vector (virus or plasmid) to deliver DNA to human cells [57].
Topical, rather than intravenous, administration of these factors
is preferred because systemic toxicity is low and higher
concentrations of the growth factors are achieved locally.
Intramuscular administration of VEGF and intra-arterial
administration of bFGF resulted in clinical improvement.
Importantly, both treatments were safe and well tolerated [57].
Treatment with bFGF gene therapy by intramuscular injection

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Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

Review article

DIABETICMedicine

FIGURE 2 Proposed protocol for the management of peripheral arterial disease (PAD) in patients with diabetes mellitus (DM). AE, adverse effects; VEGF,
vascular endothelial growth factor; bFGF, basic fibroblast growth factor; HGF, hepatocyte growth factor; NGF, nerve growth factor; PCTA, percutaneous
transluminal balloon angioplasty; BG, bypass grafting.

into thigh and calf muscles in patients with severe limb ischaemia
resulted in improvement in clinical outcomes [57]. However,
only a few patients with DM were included in these studies and
we must wait to gain confidence in the efficacy of these treatments
in patients with DM. HGF and NGF promote neovascularization
in experimental DM [57] and experience in humans is limited.
Human bone-marrow cells contain stem cells that have the
potential for differentiation into a variety of tissues, including
endothelium. Transplantation of autologous bone-marrow stem
cells in 10 patients with severe PAD into the common femoral
artery and the thigh and calf muscles resulted in clinical
improvement and increase in ABI. In another study, autologous
peripheral blood stem cells in 62 patients with severe PAD were

2010 The Authors.

Journal compilation 2010 Diabetes UK. Diabetic Medicine, 27, 414

transplanted into the lower limb muscles. All indices of blood

flow improved, while pain was reduced in 87% of the patients
[58]. Although clinical experience is limited, stem cell therapy
represents a promising therapeutic adjunct in the management of
PAD and further research is needed.
It is early to conclude on the position of the novel therapies in
the management of PAD in DM and more data from randomized
controlled trials are necessary to establish their efficacy and
safety. However, given that the tibial arteries are predominantly
involved in diabetes, and that revascularization procedures are
not usually performed at this site, their indication may be for the
management of severe limb ischaemia not amenable to
revascularization surgery. They may also be useful for the

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DIABETICMedicine

management of PAD in patients at high surgical risk due to severe

comorbidities.

Revascularization procedures

Classically, the indications for a revascularization procedure in

PAD are disabling claudication affecting quality of life after
medical therapy has failed to improve symptoms, and critical
limb ischaemia symptoms. The revascularization procedures
currently available are percutaneous transluminal balloon
angioplasty (PCTA) with or without stenting and surgical
revascularization by means of bypass grafting using
autogenous vein or a synthetic graft or endarterectomy for
localized lesions.
The number of revascularization procedures for PAD is about
8- to16-fold higher in diabetic compared with non-diabetic
patients. Additionally, patients with DM have distal
revascularization procedures more often than non-diabetic
patients [1]. The choice of a procedure depends on many
factors such as site and extent of the disease, distal run off and
surgical risk due to associated cardiovascular disease. Proximal,
short segment disease in the iliac and femoral segments is
amenable to PCTA, with results comparable to that in nondiabetic patients. More distal disease in the popliteal and tibial
arteries is better managed by bypass grafting, but with a higher
peri-procedural morbidity and mortality [1]. PCTA below the
knee is restricted to patients with critical limb ischaemia who are
at high risk during surgical revascularization because of
comorbidities. They may achieve satisfactory limb salvage rates
at least in the short term. However, in view of the distal and
diffuse nature of the disease in diabetic patients, the procedures
are technically difficult to perform. The distal run off tends to be
poor and hence the results are worse, revascularization is often
not possible and amputation rates are much higher in diabetic
patients with critical limb ischaemia [14].

Outcomes

The results of PCTA with or without stenting are better for

proximal lesions, with reported primary patency rates of 90% at
1 year [10] and 85% at 4 years for iliac angioplasty, and 80% at
1 year for femoral angioplasty. Re-stenosis rates are higher in
diabetic compared with non-diabetic patients after
femoropopliteal PCTA [59] and high lipoprotein(a) levels [59]
predict restenosis. Antiplatelet agents and cilostazol reduce
restenosis rates after PCTA.
Graft occlusion after peripheral revascularization procedures
is higher and limb salvage rates are lower in patients with DM [1].
However, limb salvage rates were similar in diabetic and nondiabetic patients after distal revascularization in some studies
[60]. Peripheral neuropathy and foot ulceration are associated
with lower limb salvage rates in diabetic patients.
Survival of diabetic patients following a surgical
revascularization procedure is slightly lower than that in nondiabetic patients, but similar for more proximal procedures [1].

12

Peripheral arterial disease in diabetes E. B. Jude et al.

However, the outcome after amputation in diabetic patients with

PAD is poorer. The 3-year survival after an amputation is < 50%
and a second amputation is exceedingly common after the first;
survival is lower than in non-diabetic subjects undergoing
successful revascularization [3]. A proposed protocol for the
management of PAD in patients with DM is depicted in Fig. 2.

Summary
Patients with DM are prone to develop PAD. PAD begins
earlier, progresses more rapidly and is more commonly
asymptomatic in DM. Distal arterial involvement of the tibial
and peroneal arteries is the predominant pattern. Lifestyle
modifications are of benefit. Drug therapy is advised in patients
who do not respond to lifestyle modification. Antiplatelet
therapy can retard the onset and progression of PAD and reduce
cardiovascular events in diabetic patients. Therapeutic
angiogenesis represents a promising therapeutic adjunct in the
management of PAD and further research is needed. The results
of revascularization procedures for proximal lesions are similar
to those in non-diabetic patients, but results in distal bypasses
are poor in the long term. Amputation rates after
revascularization are much higher in diabetic than in nondiabetic patients. Mortality in general and perioperative
mortality are also high in diabetic patients. Early, aggressive
management of the risk factors and timely referral for
revascularization might improve outcome in patients with PAD.

Competing interests
Nothing to declare.

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