Review

Peripheral Arterial Disease in Diabetic Foot: One Disease with

Multiple Patterns
Marco Meloni 1,2, * and Prashanth R. J. Vas 3,4,5

1 Division of Endocrinology and Diabetology, Department of Medical Sciences, Fondazione Policlinico

“Tor Vergata”, 00133 Rome, Italy
2 Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
3 Diabetes and Diabetic Foot, King’s College NHS Foundation Trust, London SE5 9RS, UK;
[email protected]
4 Diabetes and Endocrinology, Guys and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK
5 School of Life Sciences, King’s College, London SE1 7EH, UK
* Correspondence: [email protected]; Tel.: +39-0620900359

Abstract: Peripheral arterial disease (PAD) is a major complication in individuals with

diabetes and is increasingly prevalent in those with diabetic foot ulcers (DFUs). Despite
this, the characterisation of PAD in diabetic patients remains insufficiently refined, leading
to suboptimal management and outcomes. This review underscores the necessity for
a more nuanced understanding of PAD’s anatomical and biological aspects in diabetic
patients. The distribution of atherosclerotic plaques varies significantly among individuals,
influencing prognosis and treatment efficacy. We describe three key patterns of PAD in
diabetes: pattern 1 PAD—below-the-knee (BTK) disease (with infrageniculate disease where
present); pattern 2—below-the-ankle (BTA) disease; and pattern 3—small artery disease
(SAD), each presenting unique challenges and require tailored therapeutic approaches.
BTK PAD, characterised by occlusions in the anterior tibial, posterior tibial, and peroneal
arteries, necessitates targeted revascularisation to improve foot perfusion. BTA PAD,
involving the pedal and plantar arteries, is associated with higher risks of amputation
and requires advanced revascularisation techniques. SAD, affecting the small arteries
of the foot, remains an enigma and is challenging to treat with the current mechanical
methods, highlighting the potential of autologous cell therapy as a promising alternative. A
refined characterisation of PAD in diabetes is crucial for developing effective, individualised
Academic Editor: Carlo Setacci treatment strategies, ultimately improving patient outcomes, and reducing the burden of
Received: 27 January 2025 diabetic foot complications. In light of these complexities, it is incredulous that we often
Revised: 3 March 2025 use a single term, “peripheral arterial disease”, to describe such a diverse array of disease
Accepted: 12 March 2025 patterns. This oversimplification can be perilous, as it may lead to inadequate therapeutic
Published: 14 March 2025 approaches and suboptimal patient care.
Citation: Meloni, M.; Vas, P.R.J.
Peripheral Arterial Disease in Diabetic Keywords: diabetes; diabetic foot; diabetic foot ulcers; peripheral arterial disease
Foot: One Disease with Multiple
Patterns. J. Clin. Med. 2025, 14, 1987.
https://doi.org/10.3390/
jcm14061987
1. Introduction
Copyright: © 2025 by the authors.
Peripheral arterial disease (PAD) is a well-known chronic complication of diabetes,
Licensee MDPI, Basel, Switzerland.
This article is an open access article
defined by the presence of atherosclerotic plaques along the peripheral vascular tree, from
distributed under the terms and the sub-aortic segment to the foot. PAD is very common in persons with diabetic foot ulcers
conditions of the Creative Commons (DFUs), involving up to 50% of these patients in middle- and high-income countries [1]. The
Attribution (CC BY) license characteristics of individuals affected by DFUs have rapidly evolved in the last two decades,
(https://creativecommons.org/
with a notable concomitant increase in the numbers of those affected by ischaemic DFUs
licenses/by/4.0/).

J. Clin. Med. 2025, 14, 1987 https://doi.org/10.3390/jcm14061987

J. Clin. Med. 2025, 14, 1987 2 of 19

compared to neuropathic DFUs [2,3]. Indeed, a recent retrospective monocentric study

has documented that PAD was present in 70% of patients with a new DFU referring to a
specialised diabetic foot service [4].
PAD in patients with DFU is related to worse outcomes in comparison to pure neu-
ropathic subjects, increasing the risk of non-healing, major amputation, hospital com-
plications and mortality [1,4]. In addition, patients with PAD usually show several
attendant comorbidities, mainly cardiovascular, which influence the management and
prognosis—importantly, the two comorbidities that often coexist with DFU, heart and
renal failure, are independent predictors of amputation and mortality [1,4–6].
Even though the presence of obstructive atherosclerotic disease in the lower extremities
is commonly and generally defined as PAD, the distribution of plaques could slightly
or greatly vary among diabetic subjects with foot ulcers. The different distribution of
arterial disease along the vascular tree is often related to the presence of some concurrent
comorbidity, but the main significant data are that a different location of atherosclerotic
plaques is related to a different prognosis, and the anatomy of PAD has an impact on the
potential outcomes. In addition, each different pattern of PAD often needs a different
treatment, including both surgical and medical approaches. Therefore, adequate study and
recognition of the distribution of PAD and its biological aspect is essential to offer the best
clinical approach.
In this review, we, the authors, aim to derive an overview of the main anatomical
characteristics of PAD in persons with ischaemic DFUs, presenting features and discussing
the different managements useful to restore foot perfusion and achieve good outcomes.
Even though the text describes the different patterns and characteristics of PAD among
individuals with DFU, a section related to treating different patterns is included to help
clinicians for understanding the management options. Each unique pattern requires a
specific mechanical and medical strategy for improving foot perfusion and achieving the
best outcomes.
Although PAD in persons with DFUs is a multisegmental disease, the authors focused
their attention specifically on the main features of atherosclerotic distribution in diabetes
when compared to other vascular risk factors such as smoke, hypertension, dyslipidemia,
etc. Therefore, the description of arterial lesions in iliac, femoral, and popliteal districts is
not reported.
In addition, the authors aim only to describe the different anatomical patterns of PAD
in persons with DFUs without any interference with the classifications already present
in the literature that well describe the characteristics, severity, and treatment of diabetic
patients with PAD [7].

2. Pathophysiology in the Development of PAD

The initial pathophysiological event in the development of PAD begins with atheroge-
nesis and advances towards atherosclerosis, ultimately impacting blood flow dynamics.
Such changes can initiate early and often predate the diagnosis of diabetes [8–10]. This
process is not confined merely to the peripheral arterial vasculature; indeed, the occurrence
of polyvascular disease is common among individuals with diabetes [11,12]
Many mechanisms have been identified as triggers for atherosclerosis, including hyper-
glycaemia [13–15], insulin resistance [16,17], dyslipidaemia [18–20], hypertension [19,20],
and neurovascular dysfunction [21,22]. These can contribute individually, but perhaps
more likely collectively, to stimulating endothelial dysfunction, driving hypercoagulability,
micro thrombosis, and impaired angiogenesis [23–25]. The interplay between these factors
underpins the development and progression of atherosclerosis, promoting the subsequent
transformation of early atherosclerosis into stenotic/occlusive clinical PAD (Figure 1).
J. Clin. Med.Med.
J. Clin. 2025, 14, 14,
2025, 19871987 3 4of of
19 20

Diabetes

(any form, generalised)

Smoking
Neurovascular
Hyperglycaemia Insulin Resistance Dyslipidaemia Hypertension
Dysfunction
Obesity

Endothelial Hypercoagulability Impaired

dysfunction and microthrombosis Angiogenesis

Atherosclerosis

Peripheral Arterial Disease

Figure
Figure 1. 1. Factors
Factors influencing
influencing thethe development
development andand progression
progression of of peripheral
peripheral arterial
arterial disease
disease inin
dia-
diabetic
betic patients.
patients.

A highlight feature of atherosclerosis in diabetes is the presence of endothelial dys-

3.function
Common Characteristics
leading to reduced nitricand
oxideAnatomical
(NO) synthesis.Distribution ofsimply
However, it is not PAD unique
in
Persons with Diabetic
to the condition, Foot
being present in multiple conditions which are often coexistent, such as
hypertension
PAD in personsand dyslipidaemia.
with diabetes Atherogenesis
is defined by leads
the to the subendothelial
presence accumulation
of obstructive atheroscle-
rotic disease in lower extremities arteries. PAD in diabetics affects younger form
of lipid-rich monocyte-derived foam cells and associated T cells, which coalesce to a
subjects,
non-stenotic fatty streak [26]. As the deposition progresses, a necrotic
shows a multisegmental distribution, and a faster progression in comparison to persons core of cholesterol
esters is formed, covered by a fibrous cap containing vascular smooth muscle cells (VSMC)
without diabetes [36,37]. The arterial vessels are often characterised by widespread calci-
and inflammatory cells (T cells, mast cells, and some macrophages). Evidence has shown
fication, and occlusions are more frequent than stenosis [36–38]. Diabetes affects neoangi-
abnormal neovascularisation around atherosclerotic lesions and calcium hydroxyapatite
ogenesis, and the presence of collateral vessels is often reduced [36,37]. Even though PAD
deposition [16,26].
in diabetic persons shows a multi-level distribution from the iliac segments to the foot, the
Chronic hyperglycaemia may also drive the production of advanced glycation end
distribution of atherosclerotic plaques and arterial lesions in diabetic subjects is greatly
products (AGEs) [27], activating protein kinase C, which downstream activates multiple
characterised
pro-inflammatory by thegenes.
involvement
This canofreduce
below-the-knee
NO synthesis (BTK)
andarteries
further (anterior tibial artery,
impair vasodilation.
posterior tibial artery,
Insulin resistance canandalsoperoneal artery) vascular
directly impair when compared
endothelial to PAD in persons
function without
by disturbing
diabetes [39–41].
subcellular Basedpathways
signalling on the aim of this to
common review,
insulinthis kind
action andof nitrate
PAD with
oxidethe involvement
production.
of BTKDiabetic
arteriesvascular
(with orsmooth
without the involvement of iliac, femoral, and popliteal
muscle cells also exhibit a higher predisposition to undergo arteries)
will be defined
osteogenic in the text as
transformation pattern
[28,29]. The1 increased
(Table 1, Figure
calcium2a,b).
and phosphate deposition stiffens
the arterial walls. The end result, medial arterial calcification (Mönckeberg sclerosis), is
Table 1. Pattern
a common of peripheral
finding arterial disease
in individuals in patients
with diabetes, with ischaemic
reducing diabetic
vessel wall foot ulcers.
compliance [30,31].
The presence of autonomic neuropathy in diabetes can affect blood vessel wall blood flow
Pattern 1 Pattern 2 Pattern 3
regulation. Impaired sympathetic control has its own potential to reduce vasodilation,
 Presence of below-the-kneetherebyarterialexacerbating the ischaemic effects [32].
 Presence of below-the-ankle ar-
disease (anterior tibial artery, poste-
Moreover, exogenous factors suchartery,
as obesity  Presence of small artery disease
terial disease (pedal me-and smoking, which often coexist, can
rior tibial artery, and peroneal artery)
trigger a cascade of independent mechanisms that lead to (plantar arch, of
the formation digital, metatar-
atherosclerotic
dial plantar artery, and lateral
 Presence or absence of above-the-knee
plaques. The interaction of harmful toxins released in cigarette sal, tarsal, and acalcaneal
smoke, genetic predis-
plantar artery)
arterial disease (iliac arteries, femoral
position, and the influence of other risk factors in an individual branches)with diabetes can further
 Presence or absence of below-
arteries, popliteal artery, and tibio-pe-
accelerate the manifestation of peripheral arterial disease  Presence or absence
[33]. Abnormal of below-
catecholamine
the-knee and above-the-knee ar-
roneal trunk) the-ankle and below-the-knee
terial disease
 Absence of below-the-ankle arterial arterial disease
 Absence of small arterial disease
disease
 J. Clin. Med. 2025, 14, 1987 4 of 19

release stimulates the endothelial ‘alpha-adrenergic’ receptors and diminishes nitric oxide
availability in these cells.
While atherosclerosis was once considered a degenerative, progressive condition,
recent evidence indicates that many atherosclerotic regions are actually supported by
a dynamic inflammatory process that can be modified [26]. Supporting this, trials
of lipid-lowering agents (e.g., statins) and more recent antidiabetic medications (e.g.,
SGLT2 inhibitors and GLP-1 analogues) designed for anti-hyperglycaemic purposes
have demonstrated improved clinical outcomes for individuals with peripheral arterial
disease [34,35].

3. Common Characteristics and Anatomical Distribution of PAD in

Persons with Diabetic Foot
PAD in persons with diabetes is defined by the presence of obstructive atherosclerotic
disease in lower extremities arteries. PAD in diabetics affects younger subjects, shows a
multisegmental distribution, and a faster progression in comparison to persons without
diabetes [36,37]. The arterial vessels are often characterised by widespread calcification,
and occlusions are more frequent than stenosis [36–38]. Diabetes affects neoangiogenesis,
and the presence of collateral vessels is often reduced [36,37]. Even though PAD in diabetic
persons shows a multi-level distribution from the iliac segments to the foot, the distribution
J. Clin. Med. 2025, 14, 1987 5 of 20
of atherosclerotic plaques and arterial lesions in diabetic subjects is greatly characterised
by the involvement of below-the-knee (BTK) arteries (anterior tibial artery, posterior tibial
artery, and peroneal artery) when compared to PAD in persons without diabetes [39–41].
Theoninvolvement
Based of infra-popliteal
the aim of this review, this kindvessels
of PADin diabetes
with the has been associated
involvement of BTK with a
arteries
higher risk
(with or of major
without theamputation
involvementinofcomparison to and
iliac, femoral, PADpopliteal
exclusively characterised
arteries) by thein
will be defined
involvement of above-the-knee
the text as pattern (ATK)2a,b).
1 (Table 1, Figure arteries [39].

(a) (b)

Figure
Figure2.2. (a).
(a). Arterial disease with
Arterial disease withocclusion
occlusionofofanterior
anterior tibial
tibial (ATA)
(ATA) andand posterior
posterior tibialtibial
arteryartery
(PTA).
Foot perfusion is partially ensured by the peroneal artery (PA). (b). Arterial disease
(PTA). Foot perfusion is partially ensured by the peroneal artery (PA). (b). Arterial disease with with occlusion
of the posterior
occlusion tibial artery
of the posterior (PTA)
tibial and
artery stenosis
(PTA) and of the distal
stenosis partdistal
of the of the peroneal
part of the artery
peroneal(PA). Foot
artery
perfusion is partially ensured by the anterior tibial artery (ATA) presenting some distal
(PA). Foot perfusion is partially ensured by the anterior tibial artery (ATA) presenting some distal stenosis.
stenosis.

4. Evolution and New Pattern of PAD in Patients with Diabetic Foot

Ulcers
 J. Clin. Med. 2025, 14, 1987 5 of 19

Table 1. Pattern of peripheral arterial disease in patients with ischaemic diabetic foot ulcers.

Pattern 1 Pattern 2 Pattern 3

• Presence of below-the-knee arterial
• Presence of below-the-ankle • Presence of small artery
disease (anterior tibial artery, posterior
arterial disease (pedal artery, disease (plantar arch,
tibial artery, and peroneal artery)
medial plantar artery, and digital, metatarsal, tarsal,
• Presence or absence of above-the-knee
lateral plantar artery) and calcaneal branches)
arterial disease (iliac arteries, femoral
• Presence or absence of • Presence or absence of
arteries, popliteal artery, and
below-the-knee and below-the-ankle and
tibio-peroneal trunk)
above-the-knee arterial disease below-the-knee arterial
• Absence of below-the-ankle arterial
• Absence of small arterial disease disease
disease

The involvement of infra-popliteal vessels in diabetes has been associated with a

higher risk of major amputation in comparison to PAD exclusively characterised by the
involvement of above-the-knee (ATK) arteries [39].

4. Evolution and New Pattern of PAD in Patients with Diabetic

Foot Ulcers
While the involvement of infra-popliteal vessels in diabetes is a well-established
concept, the pattern of PAD in persons with diabetes and ischaemic foot ulcers appears to
include certain distinct and more aggressive forms. In recent years, it has been documented
that PAD can often present more distally, profoundly involving the foot arteries that were
previously under-considered in diabetic subjects [42]. Foot arteries, such as the dorsalis
pedal artery, medial plantar artery, and lateral plantar artery, are now recognised as major
arteries of the foot, primarily responsible for delivering blood to various areas of the
J. Clin. Med. 2025, 14, 1987 6 of 20
foot [42]. Authors consider this kind of PAD a severe pattern of PAD, and it will be defined
in the text as pattern 2 of PAD (Table 1, Figure 3).

Figure 3. Below-the-ankle arterial disease with the absence/occlusion of the pedal and plantar
Figure 3. Below-the-ankle arterial disease with the absence/occlusion of the pedal and plantar arter-
arteries in a patient presenting an open tibial artery.
ies in a patient presenting an open tibial artery.

In a very large retrospective study, Ferraresi et al. documented that among 1915 an-
giograms of patients affected by chronic limb-threatening ischaemia (CLTI), approxi-
mately 80% of them were affected by the arterial disease of foot arteries [42]. The presence
J. Clin. Med. 2025, 14, 1987 6 of 19

In a very large retrospective study, Ferraresi et al. documented that among 1915 an-
giograms of patients affected by chronic limb-threatening ischaemia (CLTI), approximately
80% of them were affected by the arterial disease of foot arteries [42]. The presence of
below-the-ankle [BTA] arterial disease was found to be the more aggressive clinical pattern
of CLTI, being associated with foot gangrene and increased risk of amputation. Further-
more, diabetes and end-stage renal disease (ESRD) emerged as significant factors associated
with BTA arterial disease [42]. Another recent study focusing on individuals with is-
chaemic DFUs analysed the prevalence of BTA disease and its relationship with clinical
outcomes [43]. Among 272 patients with ischaemic DFUs who underwent lower limb
revascularisation, BTA arterial disease was retrospectively identified in 44% of the cases.
Patients with BTA arterial disease exhibited higher rates of cardiovascular risk factors such
as ischaemic heart disease, ESRD, and hypertension. Notably, individuals with BTA in-
volvement experienced higher rates of non-healing, minor amputation, major amputation,
mortality, and revascularisation failure compared to those without BTA involvement [43].
Additionally, the presence of BTA arterial disease was found to be an independent predictor
of non-healing and secondary minor amputation [43].
While PAD in diabetes is generally associated with atherosclerotic disease in other
vascular districts, this specific pattern of PAD involving foot arteries appears to be more
closely associated with the presence of CAD. One recent study compared the prevalence
of CAD in patients with ischaemic DFUs presenting with BTK disease without BTA in-
volvement and those with BTA arterial disease. The results indicated that the presence of
foot artery disease was more strongly associated with CAD [44]. In this study, the overall
prevalence of CAD in the entire population was 63.4%. However, within the BTA group,
the prevalence was significantly higher at 75.4%, compared to 54.1% in the BTK group [44].
Patients with BTA arterial disease reported more cases of acute myocardial infarction (AMI)
(5%) during 1 year of follow-up when compared to BTK patients in which AMI occurred in
1.3% of the cases. In addition, BTA arterial disease (compared to BTK arterial disease) was
independently associated with the presence of CAD [44]
We believe this reinforces the need for screening CAD in all individuals with DFUs and
PAD, suggesting a much lower threshold for investigation in those with foot artery disease.

5. The Small Artery Disease: A Mysterious Pattern of PAD

The major foot arteries, including the dorsalis pedis and the lateral and medial plantar
arteries, are responsible for blood transmission to the foot. In contrast, the smaller arteries,
which are referred to as the small vessels of the foot, facilitate blood distribution into
the foot tissue. The small arteries of the foot comprise the plantar arch and the arteries
originating from it such as the tarsal arteries, metatarsal arteries, and digital arteries, but
also the calcaneal branches of the plantar arteries (Figure 4).
Small artery disease (SAD) is, therefore, an arterial disease involving the above-
mentioned arteries. SAD is confirmed by a global angiographic evaluation of the plantar
arch and small arteries. SAD can be present in different grades of severity: (1) patent
with the absence of disease or mild disease with a preserved network of the forefoot and
calcaneal branches; (2) diffuse disease with the narrowing or poverty of digital, metatarsal,
tarsal, and calcaneal branches; (3) extreme poverty or absence of plantar arch, digital,
metatarsal, tarsal, and calcaneal branches. The authors consider this kind of PAD as an
extremely severe pattern of PAD, and it will be defined as pattern 3 of PAD (Table 1,
Figure 5).
 tar arteries, are responsible for blood transmission to the foot. In contrast, the smaller ar-
teries, which are referred to as the small vessels of the foot, facilitate blood distribution
into the foot tissue. The small arteries of the foot comprise the plantar arch and the arteries
J. Clin. Med. 2025, 14, 1987 originating from it such as the tarsal arteries, metatarsal arteries, and digital arteries,7 of
but19
also the calcaneal branches of the plantar arteries (Figure 4).

J. Clin. Med. 2025, 14, 1987 8 of 20

Figure
Figure 4.
4. Normal
Normal distribution
distribution of
of small
small arteries
arteries into
into the
the foot.
foot.

Small artery disease (SAD) is, therefore, an arterial disease involving the above-men-
tioned arteries. SAD is confirmed by a global angiographic evaluation of the plantar arch
and small arteries. SAD can be present in different grades of severity: (1) patent with the
absence of disease or mild disease with a preserved network of the forefoot and calcaneal
branches; (2) diffuse disease with the narrowing or poverty of digital, metatarsal, tarsal,
and calcaneal branches; (3) extreme poverty or absence of plantar arch, digital, metatarsal,
tarsal, and calcaneal branches. The authors consider this kind of PAD as an extremely
severe pattern of PAD, and it will be defined as pattern 3 of PAD (Table 1, Figure 5).

(a) (b)

Figure 5.
Figure 5. (a)
(a) Gangrene
Gangrene of of forefoot
forefoot in a patient
in a patient with
with small
small artery
artery disease
disease (grade
(grade 3)
3) with
with preserved
preserved
footarteries
major foot arteriesafter
afterrevascularisation
revascularisation procedure
procedure (b).(b). Despite
Despite revascularisation,
revascularisation, there
there is anisabsence
an ab-
sence
of of visible
visible flowthe
flow into into the digital
digital and metatarsal
and metatarsal arteries.
arteries. (b). (b).

It is estimated that up to 25% of individuals with diabetes and PAD demonstrate the
presence of SAD, which often coexists with BTA disease [42,45]. Diabetes is a powerful
risk factor for SAD (relative risk > 2 times in comparison to the absence of diabetes), while
other factors associated with the presence of SAD are ESRD and obesity [42].
Even though the definition of SAD could be not so precise and requires specialised
J. Clin. Med. 2025, 14, 1987 8 of 19

It is estimated that up to 25% of individuals with diabetes and PAD demonstrate the
presence of SAD, which often coexists with BTA disease [42,45]. Diabetes is a powerful
risk factor for SAD (relative risk > 2 times in comparison to the absence of diabetes), while
other factors associated with the presence of SAD are ESRD and obesity [42].
Even though the definition of SAD could be not so precise and requires specialised
expertise for its evaluation, it seems to play a crucial role in the scenario of PAD, resulting
in being independently associated with CLTI which represents the most severe clinical
pattern of PAD [42]. Even though there is a paucity of clinical studies, the presence of SAD
could play a significant role in tissue lesions.

6. Diagnostic Assessment
The detection of PAD typically involves a sequence of diagnostic steps. Firstly, a broad
clinical evaluation is required to identify potential risk factors for lower limb atherosclerotic
disease, including age, diabetes duration, obesity, hypertension, dyslipidemia, ESRD, and
smoking. For instance, the presence of ESRD could indicate the potential presence of BTA
arterial disease and SAD [42], while obesity seems to be related to SAD [42].
Clinical history should be followed by the identification of peripheral pulses (femoral,
popliteal, dorsalis pedal, and posterior tibial artery): the absence of pulses could be re-
lated to the presence of PAD in different levels of the vascular tree, while their presence
cannot completely exclude the presence of PAD, especially in the case of several cardio-
vascular risk factors and/or the presence of signs of ischaemic wounds such as necrosis or
gangrene [46,47].
The diagnosis of PAD is ultimately determined through a comprehensive set of labo-
ratory tests. Diagnostic assessment includes first-level tests such as ankle-brachial index
(ABI), ankle pressure (AP), toe-brachial index (TBI), toe pressure (TP), transcutaneous
oxygen pressure (TcPO2), and ultrasound (US) colour duplex, while magnetic resonance
imaging (MRI) and computed tomography (CT) are defined as second-level tests [7].
PAD is highly suspected in subjects with DFUs presenting ABI < 0.9 or >1.3 and
TBI < 0.70 [47]. Normal ABI values are considered between 0.9 and 1.3, and in the case of
incompressible arteries due to the presence of calcifications, ABI values could be falsely
normal or higher in patients with DFUs [48]. AP and ABI are also considered weak
predictors of healing: AP < 50 mmHg or ABI < 0.5 could be associated with reduced
chances of healing and increased risk of major amputation [49].
TP and TBI can assess the distal blood flow, specifically in the forefoot and toes [50].
They also predict the potential probability of wound healing: TP values > 30 mmHg
increases the chance of healing up to 30%; otherwise, TP values < 30 mmHg increase the
risk of major amputation nearly to 20% [51].
TcPO2 is a useful tool for identifying a PAD condition and its grade of severity. In
addition, TcPO2 is usually considered in the clinical practice to predict the chance of
healing in patients with DFUs [7]. TcPO2 values between 30 and 50 mmHg are suggestive
of mild/moderate PAD, while TcPO2 values < 30 mmHg are considered a condition of
CLTI and, in this case, lower limb revascularisation should be mandatory [52].
In addition, TcPO2 values > 50 mmHg are a good predictor of wound healing in
patients with DFUs, while values < 25 mmHg are suggestive of non-healing [7]. The
chances of healing should be considered uncertain in the case of values between 25 and
50 mmHg, and additional variables of the wound, such as the size, depth, and presence of
infection, should be taken into account before considering revascularisation options [7,53].
TcPO2 is also a reliable tool for evaluating the wound angiosome blood perfusion and
can be tested in different areas of the foot according to the ulcer location [54]. Accordingly,
TcPO2 could help clinicians decide whether they should perform a revascularisation proce-
J. Clin. Med. 2025, 14, 1987 9 of 19

dure. Different conditions could interfere with the sensitivity of TcPO2, mainly peripheral
oedema and infection, two conditions that can reduce oxygen values [54]. TcPO2 is not able
to define the location of atherosclerotic disease in the vascular tree but it can greatly help
clinicians to define the grade of blood supply in the wound angiosome area in the case of
incomplete revascularisation (BTK or BTA). In the case of persistent ischaemia in the wound
angiosome area, a new revascularisation (if technically feasible) or the use of some different
adjuvant therapies could be considered [55]. The same concept could be evaluated in the
case of SAD. If, in the case of SAD, TcPO2 identifies the persistence of foot/angiosome
ischemia, the use of new regenerative therapies should be closely considered due to its
effectiveness in modifying the vascular condition in the case of SAD, by increasing TcPO2
levels and promoting wound healing [55,56].
Although the test are reliable and accurate in a large part of the population, there
is a potential risk of several errors, which could influence the sensitivity and specificity
of each functional assessment. Therefore, the above-mentioned bedside tests should be
performed by trained health care professionals in a standardised protocol [47]. In addition,
even though they can identify the potential presence of PAD (individually or combined),
these tests do not indicate the site of atherosclerotic disease in the vascular tree.
US colour duplex is a very good tool to define the anatomical distribution of atheroscle-
rotic plaques across the vascular tree and its impact on foot perfusion [7,57]. When ex-
pert vascular professionals perform the analysis, the information acquired can locate the
stenotic/occlusive PAD region, reliably identifying the presence of BTK and/or BTA arterial
disease. Nonetheless, the same exam is not useful for screening the presence of SAD. US
colour duplex, in association with clinical parameters, can help clinicians to define the need
for revascularisation procedure and map the type of approach and which vessel deserves
recanalisation or not [56,57].
MRI and CT are the gold standard for studying and describing PAD. Both provide a
clear framework of arterial lesions and their distribution. They can often better define the
presence of BTK and BTA arterial disease and, in some cases, detect the presence of SAD.
Their use can help vascular surgeons or interventional radiologists/cardiologists in some
specific circumstances to plan the vascular approach, especially in the case of some doubt
on US evaluation, atherosclerotic disease involving iliac arteries or common femoral artery,
and previous vascular interventions (especially bypass [7,58,59]).
Angiography should not be commonly used as a diagnostic test, but only when a
revascularisation procedure by endovascular approach is already planned [7,60]. In this
specific case, it can be considered the final diagnostic step just before the revascularisation
procedure, allowing one to better identify the type of PAD (BTK and/or BTA), the precise
location of atherosclerotic plaques, the characteristics of plaques, and finally, the presence
of SAD [42,60].

7. Treatment
In persons with ischaemic DFUs and PAD who are suitable for peripheral revasculari-
sation, it is essential to evaluate the entire lower extremity arterial circulation (from iliac
segments to the foot) with detailed visualisation of BTK and BTA arteries [7]. The aim of
revascularisation procedures should be to restore in-line blood flow to at least one of the
foot arteries [46]. Recovering the optimal blood flow increases the chance of healing and
reduces the risk of amputation. Otherwise, incomplete revascularisation can impact the
chance of wound healing and healing time [7].
Basically, revascularisation should be addressed to recanalise the wound-related artery
which supplies the anatomical region of the ulcer when this approach is feasible [7]. In
the case of ischaemic DFUs requiring restoration of blood perfusion, early revascularisa-
J. Clin. Med. 2025, 14, 1987 10 of 19

tion (preferably within two weeks from the assessment) is essential to achieve the best
outcomes [61,62].
Nonetheless, revascularisation procedures should be performed according to the
characteristics of PAD, considering the anatomical distribution of atherosclerotic plaques
and the wound location. According to the preliminary assessment of PAD, revasculari-
sation procedures (both surgical bypass and endovascular) should aim to recanalise all
the stenotic/occluded arteries that could influence the foot perfusion, including also iliac,
femoral, and popliteal arteries [7]. Even though iliac arteries and ATK arteries are not
deeply described in the current review based on the aim of the authors, the mentioned
vessels deserve the same careful consideration and need to be recanalised in the case of
significant stenosis and occlusion, regardless of the baseline angiographic pattern [63,64]
It is established that PAD in diabetes is a multi-level disease; until a few years ago,
the main severe pattern of PAD was considered the pattern 1 involving BTK arteries, and
the revascularisation was targeted to recanalise infra-popliteal vessels. As reported in a
large study by Faglia et al. [65], the recanalisation of at least a vessel BTK (mainly anterior
tibial arteries, and as a second option the peroneal artery) was mandatory to achieve the
recovery of blood perfusion into the foot tissues and promote wound healing. Opening
one BTK vessel more seemed to ensure better results than the revascularisation of a single
BTK vessel [65]. This result can be achieved regardless of the kind of approach, surgically
(open bypass) or endovascular (percutaneous transluminal angioplasty).
Nonetheless, considering the high prevalence of BTA arterial disease, nowadays in sev-
eral cases, the recanalisation of BTK vessels is not sufficient to ensure good outcomes. Even
though Huzing et al. did not find any significant difference in limb salvage and amputation-
free survival between BTA and BTK angioplasty [66], the role and the management of BTA
arterial disease remains an open debate. More recently, it has been documented that in the
case of BTA arterial disease, the revascularisation of foot arteries is crucial for achieving
wound healing and avoiding major amputation [41,67]. In a recent study on this specific
topic, patients with BTA arterial disease receiving a complete recanalisation of foot arteries
allowed up to 89% of healing and only 2.1% of major amputation at 1 year of follow-up,
while a failed foot revascularisation led to less chance of healing (9.1%) and higher risk of
major amputation (36.3%) [67]. In addition, failed foot revascularisation is an independent
predictor of non-healing, minor amputation, and major amputation.
Given the increased prevalence of BTA arterial disease in patients with DFUs and its
significant impact on wound healing, several advanced vascular techniques have been
developed to recanalise foot arteries. These techniques include plantar-loop techniques,
retrograde revascularisation, and bifurcated bypass, among others [68–71], which appear
to yield better results, particularly when standard revascularisation fails. However, the
revascularisation of BTA arteries is not always feasible and proves to be more challenging
than BTK revascularisation, with a consistent rate of revascularisation failure [72–74].
More recently, an endovascular or percutaneous deep venous arterialisation (pDVA)
has been developed, wherein anastomosis of arterial inflow and venous outflow permits
oxygenated blood to enter the veins and perfuse devitalised tissues via the retrograde
route [75,76] (Figure 6).
 pDVA [77] reported a technical success rate of 97% (95% confidence interval [CI] 96.2–
97.9%) and a major amputation rate of 21.8% (95% CI 21.1–22.4%) at one year. The rate of
wound healing was 69.5% (95% CI 67.9–71.0%), the reintervention rate was 37.4% (95% CI
J. Clin. Med. 2025, 14, 1987 34.9–39.9%), and the all-cause mortality rate was 15.7% (95% CI 14.1–17.2%). 11 of 19

(a) (b)

Figure6.6. Presence
Figure Presence of
of pattern
pattern 22 and
and pattern
pattern 33 PAD
PADin
inan
anindividual
individualwith
withdiabetes
diabetes(a)
(a)treated
treatedwith
with
percutaneous
percutaneousdeep
deepvenous
venousarterialisation
arterialisation(b).
(b).

A recent
Even systematic
though review
peripheral of 233 participants
ischaemia with no-option
and its characteristics ischemia
severely impact undergo-
the prog-
ing pDVA
nosis [77] reported
of patients a technical
with DFUs, success
the presence rate of
of other 97% (95%variables
significant confidence
suchinterval [CI]
as infection,
96.2–97.9%) and a major amputation rate of 21.8% (95% CI 21.1–22.4%) at one year.
depth (bone involvement), size, inability to stand or walk without help (frailty), dialysis, The
rate
andof wound
heart healing
failure couldwas 69.5%the
reduce (95% CI 67.9–71.0%),
probability of woundthe healing
reintervention rate was
and should 37.4%
be always
(95% CI 34.9–39.9%),
considered [1,4,6]. and the all-cause mortality rate was 15.7% (95% CI 14.1–17.2%).
Even
Whilethough peripheral
BTK arteries ischaemia
and major BTAand its characteristics
arteries can potentiallyseverely impact the
be approached prog-
mechani-
nosis of patients with DFUs, the presence of other significant variables such as
cally through a bypass procedure or an endovascular technique, the mechanical treatment infection,
depth (bone involvement), size, inability to stand or walk without help (frailty), dialysis,
and heart failure could reduce the probability of wound healing and should be always
considered [1,4,6].
While BTK arteries and major BTA arteries can potentially be approached mechanically
through a bypass procedure or an endovascular technique, the mechanical treatment of
small arteries remains hugely challenging due to their anatomy and distribution. Therefore,
SAD is often a real burden in revascularisation strategies, even in the case of the successful
recanalisation of the larger foot arteries.
SAD has often been found in patients with no-option limb ischaemia who presented a
failure of mechanical revascularisation procedure [41,44] or in those patients who receive
indirect revascularisation and show the persistence of wound angiosome ischaemia despite
the successful recanalisation of one of the foot arteries [78–81]. In the first mentioned
framework, SAD is usually associated with the absence of big foot arteries (pedal artery
and plantar arteries) defining the so-termed condition of “desert foot” in which there is a
complete or almost absence of blood flow below the ankle. This condition, without recourse
to rescue treatment, is associated with the highest risk of major amputation [81,82].
The second framework is otherwise related to a partial recanalisation of the foot but
not of the wound-related artery (indirect revascularisation). In the case of SAD, there are no
active collateral vessels that can supply the absence of direct flow to the wound angiosome
area which could remain in a persistent or partially ischaemic status. The absence of viable
collateral vessels increases the risk of non-healing, longer healing time, and higher risk
of amputation when compared to indirect revascularisation with the presence of good
collateral vessels [78–83].
Until a few years ago, the treatment of conditions such as desert foot or indirect
revascularisation was considered not feasible and often, major amputation was the clinical
J. Clin. Med. 2025, 14, 1987 12 of 19

choice. In recent years, new frontiers for treating these severe frameworks of PAD have
been opened offering new solutions for clinicians involved in the field.
Particularly, the use of autologous cell therapy (ACT), mainly mononuclear cell ther-
apy collected from the peripheral blood (PB-MNC) or from the bone marrow (BM-MNC),
seemed to change the natural history of untreatable limb ischaemia in persons with
DFUs [84]. Even though more consistent studies and the largest clinical trials are re-
quired, ACT has been documented to improve foot ischaemia, reduce foot ischaemic pain,
increase the chance of healing and limb salvage, and reduce mortality [84–87]. Scatena
et al. have documented that ACT was associated with a significantly higher rate of ulcer
healing (>80%), greater increase of TcPO2 and ABI values, and reduction in pain at 2 years
of follow-up in comparison to conventional therapy in persons with DFUs and no-option
CLTI [88]. Panunzi et al. have documented similar clinical results in a single-arm study
documenting that ACT was effective in the case of SAD by the increase in the local factors
involved in the paracrine neoangiogenesis [89]. Monami et al. showed a positive impact on
limb salvage and improvement in ischaemic parameters (TcPO2) by the use of PB-MNCs in
diabetic patients with no-option CLTI and SAD. The same study recorded 20% of major
amputations at 1-year follow-up and amputees were those presenting the most severe
pattern of SAD with the complete absence of small arteries [56].
Meloni et al. documented a reduction of major amputaton nearly to 50% at 1-year of
follow-up in patients with DFUs and NO-CLI by using PB-MNCs in comparison to patients
treated by conventional therapy [90]. Afterwards, the same research group documented
the effectiveness of PB-MNC therapy in patients with DFUs and SAD receiving indirect
revascularisation with the persistence of wound angiosome ischaemia. At 1-year of follow-
J. Clin. Med. 2025, 14, 1987 13 of 20
up, wound healing was achieved in more than 80% of cases and any amputation was
recorded [55]
An easy algorithm reported in Figure 7 suggests a summary of the treatment of the
three different patterns.

Figure 7. Suggested algorithm of treatment

Figure 7. treatment according
according to
to the
the different
different patterns
patterns of
of PAD.
PAD.

8. Early Detection of PAD and Global Management

Early diagnosis of PAD is mandatory for improving outcomes in terms of healing
and limb salvage, but also to reduce cardiovascular morbidity and mortality [90]. The as-
sessment of foot blood perfusion should be ensured being PAD one of the main reasons
for non-healing or delayed healing in persons with DFU [1]. When PAD is detected and
blood flow to the foot is not sufficient for wound healing, early revascularisation should
be performed to improve outcomes [61,62].
J. Clin. Med. 2025, 14, 1987 13 of 19

8. Early Detection of PAD and Global Management

Early diagnosis of PAD is mandatory for improving outcomes in terms of healing
and limb salvage, but also to reduce cardiovascular morbidity and mortality [90]. The
assessment of foot blood perfusion should be ensured being PAD one of the main reasons
for non-healing or delayed healing in persons with DFU [1]. When PAD is detected and
blood flow to the foot is not sufficient for wound healing, early revascularisation should be
performed to improve outcomes [61,62].
PAD is a well-known severe risk factor for cardiovascular events [35], and the global
management of all cardiovascular aspects should be required, including glycemic control,
smoking, lipids, and blood pressure. Glycemic control should be firstly considered to reduce
the progression of atherosclerotic disease over time [46,91]. In addition, impaired control of
diabetes could negatively impact the wound-healing process and limb salvage [92], as well
as mortality in admitted patients [93]. Usually, HbA1c values < 7.0% should be ensured
with the goal of reducing the progression of lower limb atherosclerotic disease, even if this
target needs to be adapted according to any individual condition [93].
Smoking cessation is also mandatory to reduce the worsening of PAD and the risk of
any related cardiovascular events [94]. In addition, smoking is associated with a high risk of
revascularisation failure and the recurrence of limb ischaemia post-revascularisation [95,96].
Dyslipidaemia, including total cholesterol, low-density lipoprotein cholesterol (LDL-
C), triglycerides, and lipoprotein a, is closely associated with PAD and the promotion of
atherosclerotic disease in several vascular districts [97]. In patients with PAD and those
managed by lower limb revascularisation procedures, the use of statin therapy is widely
recommended [94,98].
At the same time, the adequate management of blood pressure should be ensured
to further reduce the progression of PAD. Usually, in patients with diabetes pressure
values < 130/80 mmHg are the target required, but in older persons, higher values are
recommended for avoiding severe hypotension events [94,99].
Any available drug for reducing hypertension could be used, even though in patients
with diabetes, angiotensin-converting enzyme (ACE) and angiotensin receptor are con-
sidered the first-line treatment for their positive effects on cardiovascular morbidity and
events [95,100]. In addition, the use of ACE and/or ARB has documented a reduction in
long-term mortality in patients affected by DFUs [100].
Diabetic foot syndrome is considered a complex disease and technical vascular aspects
are only an element to be considered. All cardiovascular risk factors, such as screening
and education of patients in their personal foot care, deserve the same attention to reduce
the risk of impairment of both PAD and foot ulcers [7]. Accordingly, global management
by a multi-disciplinary team is recommended for improving outcomes also in ischaemic
subjects [101].

9. Conclusions
PAD in patients with ischaemic diabetic foot is not a single disease, showing three
main patterns defined by the involvement of BTK arteries, BTA arteries, and small foot
arteries, respectively. Each pattern has a different severity, with BTA arterial disease and
SAD presenting the highest risk of being unsuccessful in their respective treatment. While
BTK arterial disease needs the recanalisation of infra-popliteal vessels, preferably of the
artery direct to the wound angiosome area, to achieve wound healing and avoid major
amputation, BTA arterial disease requires the recanalisation of foot big arteries (pedal and
plantar arteries). SAD is not still treatable by revascularisation procedures but seems to
improve using ACT, specifically mononuclear cell therapy, which ensures the creation of
small new vessels in the area of ischaemia.
J. Clin. Med. 2025, 14, 1987 14 of 19

Further studies will be useful to better define the diagnosis of SAD by non-invasive
tools (nowadays evaluable only by the angiographic evaluation) and identify the response
to each medical approach to decide what could be the best management of ischaemic DFUs.
As reported in the introduction, the authors aim only to describe the different anatom-
ical patterns of PAD in persons with DFUs without underestimating or substituting the
classifications on the severity of PAD in diabetic patients and its treatment widely and well
reported by the recent guidelines of IWGDF.
The authors state that the patterns described in the text are related to the extension
of PAD and merely report their point of view based on the angiographic distribution of
arterial lesions in patients with DFUs. Outcomes related to the different patterns represent
data collected by a few papers available in the literature, and the majority of them are
retrospective studies with different kinds of populations. This point could be a bias and
other research could be useful to reinforce this kind of description.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Conflicts of Interest: The authors declare no conflicts of interest.

References
1. Prompers, L.; Schaper, N.; Apelqvist, J.; Edmonds, M.; Jude, E.; Mauricio, D.; Uccioli, L.; Urbancic, V.; Bakker, K.; Holstein, P.; et al.
Prediction of outcome in individuals with diabetic foot ulcers: Focus on the differences between individuals with and without
peripheral arterial disease. The EURODIALE Study. Diabetologia 2008, 51, 747–755. [CrossRef] [PubMed] [PubMed Central]
2. Armstrong, D.G.; Cohen, K.; Courric, S.; Bharara, M.; Marston, W. Diabetic foot ulcers and vascular insufficiency: Our population
has changed, but our methods have not. J. Diabetes Sci. Technol. 2011, 5, 1591–1595. [CrossRef] [PubMed] [PubMed Central]
3. Meloni, M.; Piaggesi, A.; Uccioli, L. From a Spark to a Flame: The Evolution of Diabetic Foot Disease in the Last Two Decades. Int.
J. Low. Extrem. Wounds, 2024; ahead of print. 15347346241238480. [CrossRef]
4. Meloni, M.; Izzo, V.; Giurato, L.; Lázaro-Martínez, J.L.; Uccioli, L. Prevalence, Clinical Aspects and Outcomes in a Large Cohort of
Persons with Diabetic Foot Disease: Comparison between Neuropathic and Ischemic Ulcers. J. Clin. Med. 2020, 9, 1780. [CrossRef]
[PubMed] [PubMed Central]
5. Faglia, E.; Clerici, G.; Clerissi, J.; Gabrielli, L.; Losa, S.; Mantero, M.; Caminiti, M.; Curci, V.; Quarantiello, A.; Lupattelli, T.; et al.
Long-term prognosis of diabetic patients with critical limb ischemia: A population-based cohort study. Diabetes Care 2009, 32,
822–827, Erratum in Diabetes Care 2009, 32, 1355. [CrossRef] [PubMed] [PubMed Central]
6. Meloni, M.; Izzo, V.; Giurato, L.; Cervelli, V.; Gandini, R.; Uccioli, L. Impact of heart failure and dialysis in the prognosis of
diabetic patients with ischemic foot ulcers. J. Clin. Transl. Endocrinol. 2018, 11, 31–35. [CrossRef] [PubMed] [PubMed Central]
7. Fitridge, R.; Chuter, V.; Mills, J.; Hinchliffe, R.; Azuma, N.; Behrendt, C.A.; Boyko, E.J.; Conte, M.S.; Humphries, M.; Kirksey,
L.; et al. The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer.
Diabetes Metab. Res. Rev. 2024, 40, e3686. [CrossRef] [PubMed]
8. Soyoye, D.O.; Abiodun, O.O.; Ikem, R.T.; Kolawole, B.A.; Akintomide, A.O. Diabetes and peripheral artery disease: A review.
World J. Diabetes 2021, 12, 827–838. [CrossRef]
9. Rask-Madsen, C.; King, G.L. Mechanisms of Disease: Endothelial dysfunction in insulin resistance and diabetes. Nat. Clin. Pract.
Endocrinol. Metab. 2007, 3, 46–56. [CrossRef]
10. Drexel, H.; Aczel, S.; Marte, T.; Benzer, W.; Langer, P.; Moll, W.; Saely, C.H. Is atherosclerosis in diabetes and impaired fasting
glucose driven by elevated LDL cholesterol or by decreased HDL cholesterol? Diabetes Care 2005, 28, 101–107. [CrossRef]
11. Gutierrez, J.A.; Scirica, B.M.; Bonaca, M.P.; Steg, P.G.; Mosenzon, O.; Hirshberg, B.; Im, K.; Raz, I.; Braunwald, E.; Bhatt, D.L.
Prevalence and outcomes of polyvascular (coronary, peripheral, or cerebrovascular) disease in patients with diabetes mellitus
(from the SAVOR-TIMI 53 trial). Am. J. Cardiol. 2019, 123, 145–152. [CrossRef]
12. Aday, A.W.; Matsushita, K. Epidemiology of peripheral artery disease and polyvascular disease. Circ. Res. 2021, 128, 1818–1832.
[CrossRef] [PubMed]
13. Khan, A.W.; Jandeleit-Dahm, K.A.M. Atherosclerosis in diabetes mellitus: Novel mechanisms and mechanism-based therapeutic
approaches. Nat. Rev. Cardiol. 2025; ahead of print. [CrossRef] [PubMed]
J. Clin. Med. 2025, 14, 1987 15 of 19

14. Magri, C.J.; Mintoff, D.; Camilleri, L.; Xuereb, R.G.; Galea, J.; Fava, S. Relationship of hyperglycaemia, hypoglycaemia, and
glucose variability to atherosclerotic disease in type 2 diabetes. J. Diabetes Res. 2018, 2018, 7464320. [CrossRef] [PubMed]
15. Forsythe, R.; Brownrigg, J.; Hinchliffe, R. Peripheral arterial disease and revascularization of the diabetic foot. Diabetes Obes.
Metab. 2015, 17, 435–444. [CrossRef] [PubMed]
16. Beverly, J.K.; Budoff, M.J. Atherosclerosis: Pathophysiology of insulin resistance, hyperglycemia, hyperlipidemia, and inflamma-
tion. J. Diabetes 2020, 12, 102–104. [CrossRef]
17. Adeva-Andany, M.M.; Ameneiros-Rodríguez, E.; Fernández-Fernández, C.; Domínguez-Montero, A.; Funcasta-Calderón, R.
Insulin resistance is associated with subclinical vascular disease in humans. World J. Diabetes 2019, 10, 63. [CrossRef]
18. Frak,
˛ W.; Wojtasińska, A.; Lisińska, W.; Młynarska, E.; Franczyk, B.; Rysz, J. Pathophysiology of cardiovascular diseases: New
insights into molecular mechanisms of atherosclerosis, arterial hypertension, and coronary artery disease. Biomedicines 2022,
10, 1938. [CrossRef]
19. Hurtubise, J.; McLellan, K.; Durr, K.; Onasanya, O.; Nwabuko, D.; Ndisang, J.F. The different facets of dyslipidemia and
hypertension in atherosclerosis. Curr. Atheroscler. Rep. 2016, 18, 1–12. [CrossRef]
20. Murakami, T. Atherosclerosis and arteriosclerosis. Hypertens. Res. 2023, 46, 1810–1811. [CrossRef]
21. Owens, C.D.; Mukli, P.; Csipo, T.; Lipecz, A.; Silva-Palacios, F.; Dasari, T.W.; Tarantini, S.; Gardner, A.W.; Montgomery, P.S.;
Waldstein, S.R.; et al. Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease,
increasing the risk of cognitive decline in older adults. Am. J. Physiol. Heart Circ. Physiol. 2022, 322, H924–H935. [CrossRef]
22. Forst, T.; Pfützner, A.; Kunt, T.; Pohlmann, T.; Schenk, U.; Bauersachs, R.; Küstner, E.; Beyer, J. Skin microcirculation in patients
with type I diabetes with and without neuropathy after neurovascular stimulation. Clin. Sci. 1998, 94, 255–261. [CrossRef]
23. Li, Y.; Liu, Y.; Liu, S.; Gao, M.; Wang, W.; Chen, K.; Huang, L.; Liu, Y. Diabetic vascular diseases: Molecular mechanisms and
therapeutic strategies. Signal Transduct. Target. Ther. 2023, 8, 152. [CrossRef]
24. Mota, A.P.; de Castro Santos, M.E.; Lima e Silva Fd de Carvalho Schachnik, N.C.; de Oliveira Sousa, M.; das Graças Carvalho, M.
Hypercoagulability markers in patients with peripheral arterial disease: Association to ankle-brachial index. Angiology 2009, 60,
529–535.
25. Vaidya, A.R.; Wolska, N.; Vara, D.; Mailer, R.K.; Schröder, K.; Pula, G. Diabetes and thrombosis: A central role for vascular
oxidative stress. Antioxidants 2021, 10, 706. [CrossRef]
26. Weissberg, P.L. Atherogenesis: Current understanding of the causes of atheroma. Heart 2000, 83, 247. [CrossRef] [PubMed]
27. Yamagishi, S.-I.; Matsui, T. Role of hyperglycemia-induced advanced glycation end product (AGE) accumulation in atherosclerosis.
Ann. Vasc. Dis. 2018, 11, 253–258. [CrossRef] [PubMed]
28. Sinha, A.; Vyavahare, N.R. High-glucose levels and elastin degradation products accelerate osteogenesis in vascular smooth
muscle cells. Diabetes Vasc. Dis. Res. 2013, 10, 410–419. [CrossRef] [PubMed]
29. Molinuevo, M.S.; Cortizo, A.M.; Sedlinsky, C. Effects of advanced glycation end-products, diabetes and metformin on the
osteoblastic transdifferentiation capacity of vascular smooth muscle cells: In Vivo and In Vitro studies. J. Diabetes Its Complicat.
2023, 37, 108626. [CrossRef]
30. Ndip, A.; Williams, A.; Jude, E.B.; Serracino-Inglott, F.; Richardson, S.; Smyth, J.V.; Boulton, A.J.; Alexander, M.Y. The
RANKL/RANK/OPG Signaling Pathway Mediates Medial Arterial Calcification in Diabetic Charcot Neuroarthropathy. Diabetes
2011, 60, 2187–2196. [CrossRef]
31. Edmonds, M. Medial arterial calcification and diabetes mellitus. Z. Für Kardiol. 2000, 89 (Suppl. 2), S101–S104. [CrossRef]
32. Veves, A.; Akbari, C.M.; Primavera, J.; Donaghue, V.M.; Zacharoulis, D.; Chrzan, J.S.; DeGirolami, U.; LoGerfo, F.W.; Freeman, R.
Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and
foot ulceration. Diabetes 1998, 47, 457–463. [CrossRef]
33. Messner, B.; Bernhard, D. Smoking and Cardiovascular Disease. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 509–515. [CrossRef]
[PubMed]
34. Skeik, N.; Elejla, S.A.; Sethi, A.; Manunga, J.; Mirza, A. Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular
and limb events in peripheral artery disease: A review. Vasc. Med. 2023, 28, 62–76. [CrossRef] [PubMed]
35. Lamacchia, O.; Sorrentino, M.R. Diabetes mellitus, arterial stiffness and cardiovascular disease: Clinical implications and the
influence of SGLT2i. Curr. Vasc. Pharmacol. 2021, 19, 233–240. [CrossRef]
36. Golledge, J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat. Rev. Cardiol. 2022, 19,
456–474. [CrossRef] [PubMed]
37. Low Wang, C.C.; Blomster, J.I.; Heizer, G.; Berger, J.S.; Baumgartner, I.; Fowkes, F.G.R.; Held, P.; Katona, B.G.; Norgren, L.; Jones,
W.S.; et al. Cardiovascular and Limb Outcomes in Patients with Diabetes and Peripheral Artery Disease: The EUCLID Trial. J.
Am. Coll. Cardiol. 2018, 72, 3274–3284. [CrossRef]
38. Ix, J.H.; Miller, R.G.; Criqui, M.H.; Orchard, T.J. Test characteristics of the ankle-brachial index and ankle-brachial difference for
medial arterial calcification on X-ray in type 1 diabetes. J. Vasc. Surg. 2012, 56, 721–727. [CrossRef]
J. Clin. Med. 2025, 14, 1987 16 of 19

39. Jude, E.B.; Oyibo, S.O.; Chalmers, N.; Boulton, A.J.M. Peripheral arterial disease in diabetic and nondiabetic patient A comparison
of severity and outcome. Diabetes Care 2001, 24, 1433–1437. [CrossRef]
40. Ciavarella, A.; Silletti, A.; Mustacchio, A.; Gargiulo, M.; Galaverni, M.C.; Stella, A.; Vannini, P. Angiographic evaluation of the
anatomic pattern of arterial obstructions in diabetic patients with critical limb ischemia. Diabet. Med. 1993, 19, 586–589.
41. Graziani, L.; Silvestro, A.; Bertone, V.; Manara, E.; Andreini, R.; Sigala, A.; Mingardi, R.; De Giglio, R. Vascular involvement in
diabetic subjects with ischemic foot ulcer: A new morphologic categorization of disease severity. Eur. J. Vasc. Endovasc. Surg.
2007, 33, 453–460. [CrossRef]
42. Ferraresi, R.; Mauri, G.; Losurdo, F.; Troisi, N.; Brancaccio, D.; Caravaggi, C.; Neri, L. BAD transmission and SAD distribution:
A new scenario for critical limb ischemia. J. Cardiovasc. Surg. 2018, 59, 655–664. [CrossRef] [PubMed]
43. Meloni, M.; Izzo, V.; Giurato, L.; Gandini, R.; Uccioli, L. Below-the-ankle arterial disease severely impairs the outcomes of diabetic
patients with ischemic foot ulcers. Diabetes Res. Clin. Pract. 2019, 152, 9–15. [CrossRef] [PubMed]
44. Meloni, M.; Bellia, A.; Giurato, L.; Lauro, D.; Uccioli, L. Below-the-ankle arterial disease: A new marker of coronary artery disease
in patients with diabetes and foot ulcers. Acta Diabetol. 2022, 59, 1331–1338. [CrossRef] [PubMed]
45. Ferraresi, R.; Ucci, A.; Pizzuto, A.; Losurdo, F.; Caminiti, M.; Minnella, D.; Casini, A.; Clerici, G.; Montero-Baker, M.; Mills, J. A
Novel Scoring System for Small Artery Disease and Medial Arterial Calcification Is Strongly Associated with Major Adverse
Limb Events in Patients with Chronic Limb-Threatening Ischemia. J. Endovasc. Ther. 2021, 28, 194–207. [CrossRef] [PubMed]
46. Leibson, C.L.; Ransom, J.E.; Olson, W.; Zimmerman, B.R.; O’Fallon, W.M.; Palumbo, P.J. Peripheral arterial disease, diabetes, and
mortality. Diabetes Care 2004, 27, 2843–2849. [CrossRef]
47. Chuter, V.; Schaper, N.; Mills, J.; Hinchliffe, R.; Russell, D.; Azuma, N.; Behrendt, C.A.; Boyko, E.J.; Conte, M.S.; Humphries,
M.; et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus:
A systematic review. Diabetes Metab. Res. Rev. 2024, 40, e3683. [CrossRef] [PubMed]
48. Young, M.J.; Adams, J.E.; Anderson, G.F.; Boulton, A.J.; Cavanagh, P.R. Medial arterial calcification in the feet of diabetic patients
and matched non-diabetic control subjects. Diabetologia 1993, 36, 10. [CrossRef] [PubMed]
49. Conte, M.S.; Bradbury, A.W.; Kolh, P.; White, J.V.; Dick, F.; Fitridge, R.; Mills, J.L.; Ricco, J.B.; Suresh, K.R.; Murad, M.H.
Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur. J. Vasc. Endovasc. Surg. 2019, 69,
3S–125S.e40.
50. Pickwell, K.M.; Siersma, V.D.; Kars, M.; Holstein, P.E.; Schaper, N.C. Diabetic foot disease: Impact of ulcer location on ulcer
healing. Diabetes Metab. Res. Rev. 2013, 29, 377–383. [CrossRef]
51. Kalani, M.; Brismar, K.; Fagrell, B.; Ostergren, J.; Jörneskog, G. Transcutaneous oxygen tension and toe blood pressure as
predictors for outcome of diabetic foot ulcers. Diabetes Care 1999, 22, 147–151. [CrossRef]
52. Norgren, L.; Hiatt, W.R.; Dormandy, J.A.; Nehler, M.R.; Harris, K.A.; Fowkes, F.G.; TASC II Working Group. Inter-Society
Consensus for the Management of Peripheral Arterial Disease (TASC II). J. Vasc. Surg. 2007, 45 (Suppl. S), S5–S67. [CrossRef]
[PubMed]
53. Barshes, N.R.; Flores, E.; Belkin, M.; Kougias, P.; Armstrong, D.G.; Mills, J.L.S. The accuracy and cost-effectiveness of strategies
used to identify peripheral artery disease among patients with diabetic foot ulcers. YMVA 2016, 64, 1682. [CrossRef] [PubMed]
54. Izzo, V.; Meloni, M.; Fabiano, S.; Morosetti, D.; Giurato, L.; Chiaravalloti, A.; Ruotolo, V.; Gandini, R.; Uccioli, L. Rearfoot
Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel. Cardiovasc. Interv. Radiol. 2017, 40, 120–124.
[CrossRef] [PubMed]
55. Marco, M.; Luigi, U.; Valeria, R.; Ermanno, B.; Carlo, M.; Maria, R.; Aikaterini, A.; Laura, G.; Alfonso, B.; Davide, L. Effectiveness
of autologous mononuclear cells as adjuvant therapy in patients with ischaemic diabetic foot ulcers receiving indirect lower limb
revascularization. Acta Diabetol. 2024; ahead of print. [CrossRef] [PubMed]
56. Ragghianti, B.; Berardi, B.M.; Mannucci, E.; Monami, M. Autologous Peripheral Blood Mononuclear Cells in Patients with Small
Artery Disease and Diabetic Foot Ulcers: Efficacy, Safety, and Economic Evaluation. J. Clin. Med. 2023, 12, 4148. [CrossRef]
[PubMed] [PubMed Central]
57. Berchiolli, R.; Bertagna, G.; Adami, D.; Piaggesi, A.; Iacopi, E.; Giangreco, F.; Torri, L.; Troisi, N. Peripheral Interventional
Strategy Assessment (PISA) for Diabetic Foot Ulcer Revascularization: Preliminary Outcomes of a Multidisciplinary Pilot Study.
Diagnostics 2023, 13, 2879. [CrossRef] [PubMed] [PubMed Central]
58. Collins, R.; Burch, J.; Cranny, G.; Aguiar-Ibáñez, R.; Craig, D.; Wright, K.; Berry, E.; Gough, M.; Kleijnen, J.; Westwood, M. Duplex
ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of
symptomatic, lower limb peripheral arterial disease: Systematic review. BMJ 2007, 334, 1257e66. [CrossRef]
59. Bradbury, A.W.; Adam, D.J. Diagnosis of peripheral arterial disease of the lower limb. BMJ 2007, 334, 1229–1230. [CrossRef]
60. Aiello, A.; Anichini, R.; Brocco, E.; Caravaggi, C.; Chiavetta, A.; Cioni, R.; Da Ros, R.; De Feo, M.E.; Ferraresi, R.; Florio, F.; et al.
Treatment of peripheral arterial disease in diabetes: A consensus of the Italian Societies of Diabetes (SID, AMD), Radiology
(SIRM) and Vascular Endovascular Surgery (SICVE). Nutr. Metab. Cardiovasc. Dis. 2014, 24, 355–369. [CrossRef] [PubMed]
J. Clin. Med. 2025, 14, 1987 17 of 19

61. Butt, T.; Lilja, E.; Orneholm, H.; Gottsäter, A.; Eneroth, M.; Acosta, S. Amputation-Free Survival in Patients with Diabetes Mellitus
and Peripheral Arterial Disease with Heel Ulcer: Open Versus Endovascular Surgery. Vasc. Endovasc. Surg. 2019, 53, 118–125.
[CrossRef]
62. Butt, T.; Lilja, E.; Elgzyri, T.; Apelqvist, J.; Gottsäter, A.; Engström, G.; Acosta, S. Amputation-free Survival in Patients With
Diabetic Foot Ulcer and Peripheral Arterial Disease: Endovascular Versus Open Surgery in a Propensity Score Adjusted Analysis.
J. Diabetes Complicat. 2020, 34, 107551. [CrossRef]
63. Silvestro, M.; Palena, L.M.; Manzi, M.; Gómez-Jabalera, E.; Vishwanath, D.; Casini, A.; Ferraresi, R. Anterolateral RetrogradeAccess
to the Distal Popliteal Artery and to the Tibioperoneal Trunk for Recanalization of Femoropopliteal Chronic Total Occlusions. J.
Vasc. Surg. 2018, 68, 1824–1832. [CrossRef]
64. Gandini, R.; Del Giudice, C.; Merolla, S.; Morosetti, D.; Pampana, E.; Simonetti, G. Treatment of Chronic SFA In-Stent Occlusion
with Combined Laser Atherectomy and Drug-Eluting Balloon Angioplasty in Patients with Critical Limb Ischemia: A Single-
Center, Prospective, Randomized Study. J. Endovasc. Ther. 2013, 20, 805–814. [CrossRef] [PubMed]
65. Faglia, E.; Clerici, G.; Clerissi, J.; Mantero, M.; Caminiti, M.; Quarantiello, A.; Curci, V.; Lupattelli, T.; Morabito, A. When is a
technically successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical
limb ischaemia? Diabet. Med. 2007, 24, 823–829. [CrossRef] [PubMed]
66. Huizing, E.; Schreve, M.A.; de Vries, J.P.M.; Ferraresi, R.; Kum, S.; Ünlü, Ç. Below-the-Ankle Angioplasty in Patients With Critical
Limb Ischemia: A Systematic Review and Meta-Analysis. J. Vasc. Interv. Radiol. 2019, 30, 1361–1368.e2. [CrossRef]
67. Meloni, M.; Morosetti, D.; Giurato, L.; Stefanini, M.; Loreni, G.; Doddi, M.; Panunzi, A.; Bellia, A.; Gandini, R.; Brocco, E.; et al.
Foot Revascularization Avoids Major Amputation in Persons with Diabetes and Ischaemic Foot Ulcers. J. Clin. Med. 2021, 10,
3977. [CrossRef] [PubMed] [PubMed Central]
68. Gandini, R.; Uccioli, L.; Spinelli, A.; Del Giudice, C.; Da Ros, V.; Volpi, T.; Meloni, M.; Simonetti, G. Alternative techniques for
treatment of complex below-the knee arterial occlusions in diabetic patients with critical limb ischemia. Cardiovasc. Interv. Radiol.
2013, 36, 75–83. [CrossRef] [PubMed]
69. Nezzo, M.; Meloni, M.; Carini, A.; Carreri, B.; Nicita, F.; Garaci, F.; Morosetti, D. Efficacy of retrograde revascularization
in diabetic patients with chronic limb-threatening ischemia after a failed antegrade approach. Vascular, 2024; ahead of print.
17085381241256022. [CrossRef] [PubMed]
70. Adami, D.; Marconi, M.; Piaggesi, A.; Mocellin, D.M.; Berchiolli, R.N.; Ferrari, M. Bifurcated bypass in severe chronic limb
threatening ischaemia. Vascular 2022, 30, 63–71. [CrossRef] [PubMed]
71. Troisi, N.; Adami, D.; Piaggesi, A.; Canovaro, F.; Pieruzzi, L.; Torri, L.; Ferrari, M.; Berchiolli, R. Non-reversed bifurcated vein
graft improves time to healing in ischemic patients undergoing lower limb distal bypass. Int. Angiol. 2023, 42, 1–8. [CrossRef]
[PubMed]
72. Rashid, H.; Slim, H.; Zayed, H.; Huang, D.Y.; Wilkins, C.J.; Evans, D.R.; Sidhu, P.S.; Edmonds, M. The impact of arterial pedal
arch quality and angiosome revascularization on foot tissue loss healing and infrapopliteal bypass outcome. J. Vasc. Surg. 2013,
57, 1219–1226. [CrossRef]
73. Nakama, T.; Watanabe, N.; Haraguchi, T.; Sakamoto, H.; Kamoi, D.; Tsubakimoto, Y.; Ogata, K.; Satoh, K.; Urasawa, K.; Andoh,
H.; et al. Clinical outcomes of pedal artery angioplasty for patients with ischemic wounds: Results from the multicenter
RENDEZVOUS registry. JACC Cardiovasc. Interv. 2017, 10, 79–90. [CrossRef]
74. Palena, L.M.; Brocco, E.; Manzi, M. The clinical utility of below-the-ankle angioplasty using “transmetatarsal artery access” in
complex cases of CLI. Catheter. Cardiovasc. Interv. 2014, 83, 123–129. [CrossRef] [PubMed]
75. Ucci, A.; Perini, P.; Freyrie, A.; Schreve, M.A.; Ünlü, Ç.; Huizing, E.; van den Heuvel, D.A.; Kum, S.; Shishehbor, M.H.; Ferraresi, R.
Endovascular and Surgical Venous Arterialization for No-Option Patients with Chronic Limb-Threatening Ischemia: A Systematic
Review and Meta-Analysis. J. Endovasc. Ther. 2023; ahead of print. 15266028231210220. [CrossRef] [PubMed]
76. Migliara, B.; Feriani, G.; Mirandola, M.; Griso, A.; Cappellari, T.F.; Nicoletti, C. Percutaneous Deep Venous Arterialization Using
an IVUS-Guided Technique in no-Option Patients with Chronic Limb-Threatening Ischemia: 24-Month Results. Cardiovasc. Interv.
Radiol. 2024, 47, 1727–1736. [CrossRef] [PubMed]
77. So, S.E.; Chan, Y.C.; Cheng, S.W. Efficacy and Durability of Percutaneous Deep Vein Arterialization: A Systematic Review. Ann.
Vasc. Surg. 2024, 105, 89–98. [CrossRef] [PubMed]
78. Acín, F.; Varela, C.; López de Maturana, I.; de Haro, J.; Bleda, S.; Rodriguez-Padilla, J. Results of infrapopliteal endovascular
procedures performed in diabetic patients with critical limb ischaemia and tissue loss from the perspective of an angiosome-
oriented revascularization strategy. Int. J. Vasc. Med. 2014, 2014, 270539.
79. Alexandrescu, V.A.; Brochier, S.; Limgba, A.; Balthazar, S.; Khelifa, H.; De Vreese, P.; Azdad, K.; Nodit, M.; Pottier, M.; Van Espen,
D.; et al. Healing of Diabetic Neuroischemic Foot Wounds with vs Without Wound-Targeted Revascularization: Preliminary
Observations From an 8-Year Prospective Dual-Center Registry. J. Endovasc. Ther. 2020, 27, 20–30. [CrossRef] [PubMed]
J. Clin. Med. 2025, 14, 1987 18 of 19

80. Bekeny, J.C.; Alfawaz, A.; Day, J.; Naz, I.; Attinger, C.E.; Fan, K.L.; Evans, K.K.; Akbari, C.M. Indirect Endovascular Revascular-
ization via Collaterals: A New Classification to Predict Wound Healing and Limb Salvage. Ann. Vasc. Surg. 2021, 73, 264–272.
[CrossRef]
81. Zheng, X.T.; Zeng, R.C.; Huang, J.Y.; Pan, L.M.; Su, X.; Wu, Z.H.; Yu, G.F. The Use of the Angiosome Concept for Treating
Infrapopliteal Critical Limb Ischemia through Interventional Therapy and Determining the Clinical Significance of Collateral
Vessels. Ann. Vasc. Surg. 2016, 32, 41–49. [CrossRef]
82. Špillerová, K.; Settembre, N.; Biancari, F.; Albäck, A.; Venermo, M. Angiosome Targeted PTA Is More Important in Endovascular
Revascularisation than in Surgical Revascularisation: Analysis of 545 Patients with Ischaemic Tissue Lesions. Eur. J. Vasc.
Endovasc. Surg. 2017, 53, 567–575. [CrossRef]
83. Meloni, M.; Izzo, V.; Da Ros, V.; Morosetti, D.; Stefanini, M.; Brocco, E.; Giurato, L.; Gandini, R.; Uccioli, L. Characteristics and
Outcome for Persons with Diabetic Foot Ulcer and No-Option Critical Limb Ischemia. J. Clin. Med. 2020, 9, 3745. [CrossRef]
[PubMed] [PubMed Central]
84. Sojakova, D.; Husakova, J.; Fejfarova, V.; Nemcova, A.; Jarosikova, R.; Kopp, S.; Lovasova, V.; Jude, E.B.; Dubsky, M. The Use
of Autologous Cell Therapy in Diabetic Patients with Chronic Limb-Threatening Ischemia. Int. J. Mol. Sci. 2024, 25, 10184.
[CrossRef] [PubMed] [PubMed Central]
85. Dubský, M.; Husáková, J.; Bem, R.; Jirkovská, A.; Němcová, A.; Fejfarová, V.; Sutoris, K.; Kahle, M.; Jude, E.B. Comparison of the
impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in
patients with chronic limb-threatening ischemia: A randomized controlled trial. Front. Endocrinol. 2022, 13, 888809. [CrossRef]
[PubMed] [PubMed Central]
86. Dubský, M.; Jirkovská, A.; Bem, R.; Nemcová, A.; Fejfarová, V.; Jude, E.B. Cell therapy of critical limb ischemia in diabetic
patients—State of art. Diabetes Res. Clin. Pract. 2017, 126, 263–271. [CrossRef] [PubMed]
87. Scatena, A.; Apicella, M.; Mantuano, M.; Ragghianti, B.; Silverii, A.; Miranda, C.; Monge, L.; Uccioli, L.; Scevola, G.; Stabile, E.;
et al. Autologous cell therapy for ischemic diabetic foot: A meta-analysis of randomized controlled trials for the development of
the Italian guidelines for the treatment of diabetic foot syndrome. Acta Diabetol. 2024; ahead of print. [CrossRef] [PubMed]
88. Scatena, A.; Petruzzi, P.; Maioli, F.; Lucaroni, F.; Ambrosone, C.; Ventoruzzo, G.; Liistro, F.; Tacconi, D.; Di Filippi, M.; Attempati,
N.; et al. Autologous Peripheral Blood Mononuclear Cells for Limb Salvage in Diabetic Foot Patients with No-Option Critical
Limb Ischemia. J. Clin. Med. 2021, 10, 2213. [CrossRef] [PubMed] [PubMed Central]
89. Panunzi, A.; Madotto, F.; Sangalli, E.; Riccio, F.; Sganzaroli, A.B.; Galenda, P.; Bertulessi, A.; Barmina, M.F.; Ludovico, O.;
Fortunato, O.; et al. Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy
for no-option critical limb-threatening ischemia and severe diabetic foot ulcers. Cardiovasc. Diabetol. 2022, 21, 196. [CrossRef]
[PubMed] [PubMed Central]
90. Meloni, M.; Giurato, L.; Andreadi, A.; Bellizzi, E.; Bellia, A.; Lauro, D.; Uccioli, L. Peripheral Blood Mononuclear Cells: A New
Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia. J. Clin. Med. 2023, 12, 6123.
[CrossRef] [PubMed] [PubMed Central]
91. Stoberock, K.; Kaschwich, M.; Nicolay, S.S.; Mahmoud, N.; Heidemann, F.; Rieß, H.C.; Debus, E.S.; Behrendt, C.A. The
interrelationship between diabetes mellitus and peripheral arterial disease. Vasa 2021, 50, 323–330. [CrossRef]
92. UK Prospective Diabetes Study (UKPDS). Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837–853.
[CrossRef]
93. Dormandy, J.A.; Charbonnel, B.; Eckland, D.J.A.; Erdmann, E.; Massi-Benedetti, M.; Moules, I.K.; Skene, A.M.; Tan, M.H.;
Lefèbvre, P.J.; Murray, G.D. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study
(PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005, 366, 1279–1289.
[CrossRef]
94. American Diabetes Association Professional Practice Committee. 2. Diagnosis and Classification of Diabetes: Standards of Care
in Diabetes-2024. Diabetes Care 2024, 47 (Suppl. 1), S20–S42. [CrossRef] [PubMed] [PubMed Central]
95. Willigendael, M.; Teijink, J.A.; Bartelink, M.L.; Peters, R.J.; Buller, H.R.; Prins, M.H. Smoking and the patency of lower extremity
bypass grafts: A meta-analysis. J. Vasc. Surg. 2005, 42, 67–74. [CrossRef]
96. Armstrong, E.J.; Wu, J.; Singh, G.D.; Dawson, D.L.; Pevec, W.C.; Amsterdam, E.A.; Laird, J.R. Smoking cessation is associated
with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J.
Vasc. Surg. 2014, 60, 1565–1571. [CrossRef] [PubMed]
97. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in
20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002, 360, 7–22. [CrossRef] [PubMed]
98. Cosentino, F.; Grant, P.J.; Aboyans, V.; Bailey, C.J.; Ceriello, A.; Delgado, V.; Federici, M.; Filippatos, G.; Grobbee, D.E.; Hansen,
T.B.; et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
Eur Heart J. 2020, 41, 255–323, Erratum in Eur. Heart J. 2020, 41, 4317. [PubMed]
J. Clin. Med. 2025, 14, 1987 19 of 19

99. Williams, B.; Mancia, G.; Spiering, W.; Agabiti Rosei, E.; Azizi, M.; Burnier, M.; Clement, D.; Coca, A.; De Simone, G.; Dominiczak,
A.; et al. 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and
the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension. J. Hypertens. 2018, 36,
2284–2309, Erratum in J. Hypertens. 2019, 37, 456.
100. Faglia, E.; Clerici, G.; Scatena, A.; Caminiti, M.; Curci, V.; Morabito, A.; Prisco, V.; Greco, R.; Edmonds, M. Effectiveness of
combined therapy with angiotensin-converting enzyme inhibitors and statins in reducing mortality in diabetic patients with
critical limb ischemia: An observational study. Diabetes Res. Clin. Pract. 2014, 103, 292–297. [CrossRef] [PubMed]
101. Meloni, M.; Giurato, L.; Monge, L.; Miranda, C.; Scatena, A.; Ragghianti, B.; Silverii, G.A.; Vermigli, C.; De Cassai, A.; Volpe, A.;
et al. Effect of a multidisciplinary team approach in patients with diabetic foot ulcers on major adverse limb events (MALEs):
Systematic review and meta-analysis for the development of the Italian guidelines for the treatment of diabetic foot syndrome.
Acta Diabetol. 2024, 61, 543–553. [CrossRef] [PubMed]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.