Abstract
Type 2 diabetes (T2D) and lower-extremity peripheral artery disease (PAD) are growing global health problems associated with considerable cardiovascular (CV) and limb-related morbidity and mortality, poor quality of life and high healthcare resource use and costs. Diabetes is a well-known risk factor for PAD, and the occurrence of PAD in people with T2D further increases the risk of long-term complications. As the available evidence is primarily focused on the overall PAD population, we undertook a systematic review to describe the burden of comorbid PAD in people with T2D. The MEDLINE, Embase and Cochrane Library databases were searched for studies including people with T2D and comorbid PAD published from 2012 to November 2021, with no restriction on PAD definition, study design or country. Hand searching of conference proceedings, reference lists of included publications and relevant identified reviews and global burden of disease reports complemented the searches. We identified 86 eligible studies, mostly observational and conducted in Asia and Europe, presenting data on the epidemiology (n = 62) and on the clinical (n = 29), humanistic (n = 12) and economic burden (n = 12) of PAD in people with T2D. The most common definition of PAD relied on ankle-brachial index values ≤ 0.9 (alone or with other parameters). Incidence and prevalence varied substantially across studies; nonetheless, four large multinational randomised controlled trials found that 12.5%–22% of people with T2D had comorbid PAD. The presence of PAD in people with T2D was a major cause of lower-limb and CV complications and of all-cause and CV mortality. Overall, PAD was associated with poor quality of life, and with substantial healthcare resource use and costs. To our knowledge, this systematic review provides the most comprehensive overview of the evidence on the burden of PAD in people with T2D to date. In this population, there is an urgent unmet need for disease-modifying agents to improve outcomes.
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This systematic review provides a comprehensive overview of the evidence available up to November 2021 on the epidemiology and burden of peripheral artery disease (PAD) in people with type 2 diabetes (T2D) |
Although incidence and prevalence data for PAD varied substantially across studies, four large multinational randomised controlled trials reported that approximately one to two people out of ten with T2D had comorbid PAD |
In people with T2D, comorbid PAD increased the risk of lower-limb complications (e.g. revascularisation procedures and amputations) and cardiovascular complications (e.g. major adverse cardiovascular events), as well as of mortality |
The presence of PAD (vs. absence) was associated with poorer quality of life and a considerable financial burden in terms of length of hospital stay, admissions, readmissions and direct costs |
The current study further highlights the urgent unmet need for disease-modifying agents to improve the outcomes of people with T2D and comorbid PAD |
Introduction
Lower-extremity peripheral artery disease (PAD) is characterised by a progressive obstruction in the peripheral arteries with impaired distal perfusion, primarily caused by atherosclerosis and resulting in poor functional capacity and considerable morbidity and mortality (usually due to cardiovascular [CV] causes such as sudden cardiac death) [1,2,3,4,5]. With more than 236 million people affected with PAD in 2015 [6], representing a 17.1% increase from 2010 [7], PAD is a growing public health concern worldwide [6,7,8]. Major risk factors, also common to coronary and cerebrovascular disease [9], include age, diabetes, smoking, microvascular disease and high levels of triglycerides [6, 7, 9, 10]. In addition, inflammation and thrombosis [11,12,13] have emerged as contributing to the development and progression of PAD.
Many patients with PAD and their treating clinicians do not recognise functional decline and/or leg discomfort as manifestations of vascular disease [14]; 30%–50% of patients have atypical exertional leg symptoms, and only a minority (up to 20%) suffer from intermittent claudication [15, 16]. Compared with the general population, people living with PAD have poorer limb function regardless of the types of symptoms [3, 17]. They may develop infections, acute occlusion, and ulcers [18]. The most severe forms of PAD, critical limb threatening ischaemia (CLTI) and acute limb ischaemia (ALI) [2], are associated with poor limb and CV outcomes, including major amputations (i.e. amputations at the level of or above the ankle [19, 20]), major adverse CV events (MACE) and mortality [19, 20]. In a large study of Medicare patients with PAD, those who required major amputation had significantly higher mortality rates overall and at 30 days, 1 year and 3 year post-procedure, compared with those who did not (p < 0.001); the risk of death was 30% higher for those who had above-the-knee vs. below-the-knee amputations (p < 0.001) [21].
People with diabetes are nearly twice as likely to develop PAD than those without diabetes [6, 7], and PAD has been reported to be the most common initial manifestation of CV disease (CVD) in type 2 diabetes (T2D) [22]. Comorbid PAD is associated with significant increases in the risk of limb and CV adverse events, including MACE, heart failure (HF) outcomes, kidney disease complications, adverse limb events, vascular hospitalisations and mortality [23,24,25,26,27,28]. A common serious complication in people with T2D and neuropathy is diabetic foot, which is associated with infections, ulcers (DFU), limb loss and premature death [29,30,31]. Neuropathy leads to foot deformity, loss of protective sensation and limited joint mobility, causing abnormal loading of the foot with subcutaneous haemorrhage and skin ulceration [29, 30]. The presence of PAD further raises the risk of foot ulcers [32], ulcer recurrence [33] and limb complications including CLTI, ALI, amputation and limb infections [24, 28].
Both T2D and PAD impose a high humanistic burden on patients and their caregivers [34,35,36,37]. Patients’ health-related quality of life (HRQoL) was found to be reduced in people with DFU, compared with those without [38], and to worsen further with DFU prognosis deterioration [39] and in patients who underwent amputation, compared with controls [40]. In this setting, the main determinant of HRQoL is the difficulty in walking with a prosthesis, which varies by the level of amputation (above or below the knee) [41]. T2D and PAD are also associated with a considerable economic burden, mainly driven by the direct costs for disease management [31, 42,43,44]. Nonetheless, data on HRQoL, healthcare resource use (HCRU) and direct and indirect costs in people with T2D and comorbid PAD are limited. Indeed, the available evidence is primarily focused on the overall PAD population, rather than being limited to the subgroup with coexisting T2D [7, 16].
To fill these gaps and provide an updated and comprehensive overview of the epidemiology of PAD in T2D, we systematically reviewed the evidence available up to November 2021.
Methods
Data Sources and Search Strategy
This systematic literature review (SLR) was conducted in accordance with the Cochrane Collaboration guidelines [45] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [46]. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Electronic databases (MEDLINE, Embase and Cochrane Library) were searched via the OVID platform up to 18 November 2021, using free text terms and Emtree/Medical Subject Heading (MeSH) terms. These searches were supplemented by hand searching of conference proceedings, reference lists of included publications and relevant identified reviews and global burden of disease reports. The complete search strategy is presented in Electronic Supplementary Material (ESM) Table 1.
Inclusion criteria for relevant publications were as follows: (1) any clinical study design; (2) adult patients with T2D and comorbid PAD; (3) all interventions/comparators; (4) epidemiology data, clinical, humanistic or economic burden data; and (5) studies published between January 2012 and November 2021, and conference abstracts published between 2019 and 2021. There were no restrictions with regards to the countries included. Studies conducted in patients with PAD alone, with PAD and diabetes other than T2D, patients without PAD and T2D, paediatric patients (aged < 18 years), in vitro studies, animal studies, epidemiological studies with < 1000 participants, SLRs and meta-analyses (included for reference checking purposes only), narrative reviews, editorial, letters, notes and communications and publications written in languages other than English were excluded. Details on eligibility criteria are provided in ESM Table 2.
Data Extraction and Quality Assessment
Two reviewers independently screened all abstracts, using the pre-defined eligibility criteria; if deemed relevant, the full-text articles were reviewed. Final inclusion and exclusion of citations was verified by the project lead, and disputes as to eligibility were referred to a senior expert. The reasons for exclusion following review were documented. Data extraction was conducted by a single analyst and quality checked for 100% of the data by a second analyst. Disputes were resolved by a senior lead.
Results
Studies Identified
Of 4445 potentially relevant publications, 195 were screened based on the full text and 87 were included in the final analysis. Of the studies included, 62 reported epidemiology data, 29 clinical outcome data, 12 humanistic outcome data and 12 economic outcome data (Fig. 1). Studies were mostly observational and primarily performed in Asia and Europe.
PRISMA flow diagram. aOf the 87 publications identified in the review, several studies reported multiple outcomes, resulting in an overlap in the count of the number of studies per type of burden. CA congress abstract, DM diabetes mellitus, PAD peripheral artery disease, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, T2D type 2 diabetes
PAD Definition
In brief, 22 studies did not provide a definition for PAD [26, 47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67], 32 relied on ankle-brachial index (ABI) values ≤ 0.9 (alone or in combination with other parameters [16, 68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98]) and 31 used the International Classification of Diseases codes or combinations of clinical and/or instrumental assessment [99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129].
Definitions are reported in ESM Table 3.
Epidemiology
Overall, 62 studies (63 publications) provided data on the epidemiology of PAD in people with T2D [16, 26, 47,48,49,50,51, 57, 58, 60,61,62, 64,65,66, 68,69,70,71,72,73,74,75, 77,78,79, 81,82,83,84,85,86,87, 89,90,91,92,93,94,95,96,97,98,99,100,101, 104,105,106, 108, 109, 111, 112, 114,115,116,117,118, 122, 124, 126,127,128]. The main characteristics of the included studies, mostly observational, are presented in Table 1.
Incidence
Fifteen studies (16 publications) reported the incidence rate (IR) of PAD and/or the proportion of people with T2D with incident PAD [47, 50, 61, 66, 70, 71, 73, 81, 96, 104, 105, 115, 116, 118, 124, 127]. One study included data from randomised controlled trials (RCTs) [71] and 14 from observational studies (Table 1).
Randomised Controlled Trial
The multinational RCT BARI-2D (N = 1479 from 49 clinical sites throughout North America, South America and Europe) reported 20.5% incident PAD cases among people with T2D and coronary artery disease (CAD) over an average follow-up of 4.6 years [71].
Observational Studies
Europe
Four observational studies were European [47, 61, 104, 124, 127]. In the 19-year follow-up study of the Danish Diabetes Care in General Practice RCT conducted in 1381 people with newly-diagnosed T2D, the incidence of PAD was 4.0 vs. 4.9 events per 1000 patient-year (PY) for people receiving 6 years of structured personal diabetes care vs. routine care, respectively [104]. In a Scottish study of 24,752 people with T2D, the overall IR of PAD was 2.72 per 1000 PY over 3 years of follow-up [124]. The overall proportion of incident cases was 1.6%–16.2% over 3 to 5.5 years [47, 61, 124, 127]. A large cohort study conducted in England in 1.9 million people with T2D aged ≥ 30 years without a prior history of CV events at baseline identified PAD as the most common first manifestation of CVD in people with T2D, with an incidence of 16.2% after a median follow-up of 5.5 years [61, 127]. In this study, the adjusted hazard ratio for PAD in people with vs. without T2D was 2.98 (95% confidence interval [CI]: 2.76, 3.22), p < 0.0001) [61, 127].
USA
Three observational studies were conducted in the USA [105, 115, 116]. The overall crude IR of PAD was 0.1 events per 1000 PY in 377,205 people with T2D only and 1.1 events per 1000 PY in 130,132 people with T2D and prior CV events over 3 years [115], and 25.0 events per 1000 PY over a mean of 4.3 years in 3,293,983 people with T2D identified from nationally representative electronic medical records in 2017 [116]. This study demonstrated a consistent increase in PAD incidence from 2000, when the IR was 5 events per 1000 PY [116]. Another registry-based study reported an IR ranging from 1.68 to 5.67 events per 1000 PY in people subgrouped by duration of diabetes (< or ≥ 10 years) and by age (60–69, 70–79 and ≥ 80 years) [105].
Asia and Middle East
Incidence varied considerably across the studies conducted in Asia [50, 66, 70, 73, 81, 96, 118]. The overall IR was 3.53 events per 1000 PY in 30,932 people with T2D followed for 8.2 years [96] and 17.2 events per 1000 PY in 2512 people with incident T2D [81]. The lowest IR of 3 events per 1000 PY was found in the subgroup of people with T2D with irregular follow-up (i.e. < 2 visits and < 1 glycosylated haemoglobin [HbA1c] measurement per year) [73] and the highest IR was found in older people with T2D (44.7 events per 1000 PY in those aged > 60 years [81]). The proportion of incident PAD was 7.3% of all CVD events that occurred among 2039 people with T2D over 5.6 years in [70], 13.5% in 156,593 people with T2D followed for 7 years in [118] and 64.7% in 114,847 people with newly-diagnosed T2D during 7 years in [66]. Riandini et al. also reported the incidence of first diabetes-related lower extremity complications (DRLEC) (i.e. symptomatic PAD, ulceration, infection, gangrene), which was 25.34 events per 1000 PY overall [118].
Differences Among Subgroups
Significant differences in the incidence of PAD were observed across people with T2D subgrouped by age (higher in older vs. younger people [105]), sex (higher in women vs. men [81]) and treatment (higher with dipeptidyl peptidase 4 inhibitors [DPP4i] than with sodium-glucose cotransporter 2 inhibitors [SGLT2i] and glucagon-like peptide-1 receptor agonists [GLP-1RA] [116]). The incidence of first DRLEC was higher in Malay vs. Chinese, in men vs. women and in older vs. younger people with T2D [118]).
Prevalence
In total, 51 studies reported prevalence data for PAD in people with T2D [16, 26, 48, 49, 51, 57, 58, 60, 62, 64, 65, 68, 69, 72, 74, 75, 77,78,79, 81,82,83,84,85,86,87, 89,90,91,92,93,94,95, 97,98,99,100,101, 105, 106, 108, 109, 111, 112, 114, 116,117,118, 122, 126, 128]. Two studies were RCTs [68, 112], two were post-hoc analyses of RCT data [26, 60], and the remaining were observational studies.
Randomised Controlled Trials
In the two large multinational RCTs BARI-2D (N = 2249) and ADVANCE (N = 11,140 from 215 sites throughout Asia, Australasia, Europe and North America), the prevalence of PAD was 19% in people with T2D and documented stable CAD [68], and 22.0% in those with T2D who had at least one additional risk factor for CVD [112], respectively. In the post-hoc analysis of the US ELIXA trial of people with T2D and acute coronary syndrome (ACS; N = 6068), PAD prevalence was 6.5% [60]. Verma et al. [26] analysed data from the multinational LEADER and SUSTAIN trials conducted in people with T2D (N = 9340 and 3297, respectively) and reported a prevalence of PAD of 12.5% and 13.5%, respectively.
Observational Studies
Multinational
In the non-interventional prospective DISCOVER programme, conducted in 15,992 people with T2D initiating second-line therapy across 38 countries (in Africa, the Americas, South-East Asia, Europe, the Eastern Mediterranean region and the Western Pacific region), the crude prevalence of PAD was 1.2%, ranging from 0.1% in Southeast Asia to 3.1% in Europe [108].
Europe
Nine European studies described overall prevalence rates for PAD in people with T2D of 0.8%–32% [48, 51, 57, 64, 72, 91, 106, 122, 126]: one study found that PAD was present in 0.8%–3.0% of all patients within 10 years of T2D diagnosis; four studies reported overall rates between 5% and 6.3% [48, 51, 64, 106]; three studies reported overall rates between 12.9% and 18.7% [57, 72, 126]; and a Portuguese single-centre study of 100 people with T2D reported rates of 32% [91]. A Spanish study reported a prevalence of PAD of 14.7% among 34,689 people with T2D with no PAD symptoms and no CVD history [72].
One Dutch registry-based study of 2334 people with T2D described data by ethnicity only [75].
USA
In six US observational studies, the overall prevalence of PAD in people with T2D varied from 2.0% to 44% [58, 62, 65, 93, 116, 128]. Three studies reported rates between 2.0% and 10% (2 included people with newly-diagnosed T2D [58, 65] and one was a retrospective study of > 3 million people with T2D [116]); two large database-based studies described rates of 24.5% in people with T2D and atherosclerotic cardiovascular disease (N = 539,089) [128] and of 26.5% in people with T2D (N = 83,705) [62]; and one single-centre study of 13,561 people with diabetes (T2D or type 1 diabetes) reported a rate of 44% among those with T2D (and of 43% in those with type 1 diabetes) [93].
Latin America
Two single-centre cross-sectional studies reported a PAD prevalence of 13.7% and 14.5% in 73 Brazilian and 325 Ecuadorian people with T2D, respectively [79, 90].
Asia and Middle East
A total of 24 studies reporting prevalence data were conducted in Asia or the Middle East. Seven studies were conducted in China [16, 82, 85, 86, 97, 98, 111], six in India [49, 69, 81, 89, 92, 100], four in Taiwan [77, 84, 87, 101], two in Sri Lanka [74, 94] and one each in Singapore [114], Hong Kong [95] and Jordan [99]. One additional study from Singapore reported the prevalence of DRLEC [118]. All studies were observational and predominantly single-centre.
The overall prevalence of PAD ranged from 2% to 31.5% [16, 49, 69, 74, 77, 81, 82, 84,85,86,87, 89, 92, 94, 95, 97,98,99,100,101, 114]: 5.2%–31.5% in studies performed in China [16, 82, 85, 86, 97, 98]; 2%–29.2% in studies performed in India [49, 69, 81, 89, 92, 100]; and 3%–20.3% in those conducted in Taiwan [77, 84, 87, 101]. The highest values were reported in three single-centre studies: one Indian study of 11,157 people with T2D (28%) [69]; one performed in Jordan in 144 people with diabetes and DFU, of whom 92.4% had T2D (29.2%) [99]; and one Chinese study in 1476 people with T2D aged 60 years or older (31.5%) [16]. An Indian study reported a prevalence of 2% among 1500 people with newly-diagnosed young-onset diabetes [92]. In another Indian study of 1755 people with T2D, people with asymptomatic PAD accounted for 65.5% of those with PAD [89]. Among 2423 Sri Lankan people with T2D and no clinical evidence of CAD or CVD, 15.3% had asymptomatic PAD by ABI assessment [94].
One Chinese study described the prevalence of PAD in 2080 outpatients with T2D subgrouped by sex, age and HbA1c across ABI groups (range: 0%–58.2%, with significantly higher rates in people with ABI ≤ 0.9 compared with those with ABI 0.91–1.3 and > 1.3) [111]. A study conducted in Singapore and including data of 156,593 people with T2D found that the prevalence of PAD at T2D diagnosis was 5.3% in those with DRLEC, 3.2% in those without and 28.2% in those with DRLEC who had undergone limb amputation (p < 0.001) [118].
Australia
Four Australian studies described the prevalence of PAD in people with T2D [78, 83, 109, 117]. In a retrospective cohort study of 375 people with T2D, the estimated point prevalence of peripheral circulatory conditions was 11% [117]. Kurowski et al. selected all non-traumatic lower extremity amputations in adults from 2000 to 2010 and, in the subgroup with T2D (n = 3399), found a prevalence of PAD of 70.7% in those with initial amputations and of 90.6% in those with recurrent amputations [109]. Davis et al. analysed data from people with T2D included in the Freemantle Diabetes Study (FDS) subgrouped by enrolment period: cohort FDS1, 1993–1996 (n = 1291) and cohort FDS2, 2008–2011 (n = 1509); the prevalence rates were 29.3% and 22.6%, respectively (p < 0.001) [78]. In the same cohorts further subgrouped by incident hospitalisation for/with DFU, Hamilton et al. found similar results: 33.3% of those with incident hospitalisation and 24.9% of those without incident hospitalisation had PAD (p = 0.21) [83].
Differences Among Subgroups
The prevalence of PAD significantly increased with increasing age [81, 86, 89, 100, 111], duration of diabetes [100], and height [82] and in the presence (vs. absence) of either retinopathy or neuropathy [60] and non-alcoholic fatty liver disease [98], and in people with DRLEC and amputation versus DRLEC only and no DRLEC [118]. The impact of sex was inconsistent between studies [51, 74, 81, 86, 89, 95, 100].
Risk Factors for PAD in People with T2D
Risk Factors for Incident PAD
Risk factors for incident PAD in people with T2D included increasing age [81], female sex [81], the presence [61, 127] and duration of diabetes [81], high levels of fasting plasma glucose-coefficient of variation [96] and increased HbA1c [71, 96]. The use of DPP4i vs. non-use [50] and of SGLT2i vs. DPP4i and of GLP-1RA vs. SGLT2i was associated with a lower risk of PAD [116].
Risk Factors for Prevalent PAD
Increasing age [16, 69, 77, 86, 89, 92, 111], high HbA1c levels [69, 84, 86, 89] and the presence [51] and duration of diabetes [69, 89, 111] were frequently reported to be risk factors for prevalent PAD in people with T2D. Other predictors included high blood pressure [16, 69], diabetic retinopathy [77, 86], diabetic neuropathy [16, 86], cerebrovascular disease [77, 86], nephropathy [86], smoking [16, 86], decreased estimated glomerular filtration rate [94], low levels of vitamin D [97], the presence of non-alcoholic fatty liver disease [98], intima-media thickness [89] and total cholesterol and uric acid levels [16, 86]. Older age, smoking, hypertension, diabetic neuropathy and hyperuricemia were risk factors for PAD in people aged ≥ 60 years with T2D [16, 86].
Clinical Burden of PAD in People with T2D
Overall, 29 studies provided data on PAD-related complications in people with T2D and comorbid PAD [26, 50, 53, 54, 56, 67, 68, 72, 77, 81, 87, 88, 102, 103, 107,108,109,110, 112, 116, 118,119,120, 122, 124, 125, 129,130,131]. Of these studies, six included data from multinational RCTs [26, 68, 88, 112, 130, 131] and one from the multinational prospective DISCOVER programme [108]. The remaining were observational studies conducted in Asia and the Middle East (n = 9) [50, 54, 67, 77, 81, 87, 107, 110, 118], Europe (n = 8) [72, 102, 103, 119, 120, 122, 124, 125], the USA (n = 3) [56, 116, 129] and Australia (n = 1) [109]; in one study (abstract only) the country was not specified [53]. Study characteristics and results are summarised in Table 2.
Limb-Related Complications
Lower-Limb Complications
Eight studies included data on limb-related events, including revascularisation procedures (n = 7) [88, 107, 108, 110, 125, 129,130,131] (Table 2).
Chronic limb ischaemia was reported at baseline for 5.9% of people with T2D and PAD participating in the EUCLID RCT [88]. In this trial, 15.6% of people presented no PAD symptoms, 53.2% presented mild or moderate claudication and 25.2% presented severe claudication at baseline; over a median of 30 months, 5.92 incident cases of lower extremity revascularisation per 1000 PY were reported [88].
A multinational observational study reported an overall crude prevalence of DF among 197 people with T2D and PAD of 44.2% [108]. A large US study reported a prevalence of 32.0% for CLTI, 17.7% for ulcers and 10.5% for complicated ulcers (ulcers plus 1 of gangrene, osteomyelitis and cellulitis), and 8.8% for all revascularisations (6.9% and 5.7% for endovascular and open revascularisation, respectively) [129]. In a large Taiwanese study of people with T2D and PAD, the use of a SGLT2i or DPP4i was associated with a reduced risk of lower limb ischaemia requiring revascularisation (IR: 9.7 vs. 13.2 per 1000 PY [0.97 vs. 1.32 events per 100 PY]; hazard ratio [HR]: 0.73 [95% CI: 0.54, 0.98], p < 0.0367) [110].
Two studies using data from the multinational ADVANCE RCT provided data for PAD complications in people with T2D. In Mohammedi et al. 2016a [131], among 10,624 people with T2D at high CV risk (i.e. with a history of major macrovascular or microvascular disease or at least 1 other risk factor for vascular disease [132]), during a median follow-up of 5 years, chronic ulceration and angioplasty procedures were reported for 3.0% and 0.08% of participants, respectively. In Mohammedi et al. 2016b [130], PAD complications included peripheral revascularisation procedures by angioplasty or surgery. Analysis of data from participants in the multinational ADVANCE RCT and in the ADVANCE-ON post-trial observational study (N = 11,140, median follow-up of 5 years) demonstrated that, at baseline, 1.7% of people with T2D had a history of peripheral revascularisation [130].
In the observational French study SURDIAGENE, which included 1468 people with T2D for at least 2 years, 5% of participants had a history of lower-limb revascularisation (angioplasty or surgery) at baseline [125]; among those without a history of revascularisation, 5.6% required a procedure during the follow-up (IR: 7.7 events per 1000 PY, respectively) [125].
Lower Limb Amputation
In total, 17 studies described data for limb amputation in people with T2D and PAD [50, 54, 67, 88, 102, 103, 108,109,110, 116, 118,119,120, 125, 129,130,131] (Table 2).
In the EUCLID RCT, the IR of major amputation in people with T2D and PAD was 9.4 events per 1000 PY (0.94 per 100 PY) [88]. Among the observational studies, the IR of amputations ranged from 0.76 to 5.2 events per 1000 PY over 3 to 7 years of follow-up [50, 54, 103, 125]. In a single-centre study including 94 people with T2D and PAD, the proportion of incident cases was 3.8% over 7.1 years; 50% and 75% of amputees experienced foot infection and peripheral diabetic neuropathy, respectively [103]. In a large observational study conducted in Singapore that included 20,744 people with incident T2D who developed a DRLEC, the crude IR of first amputation was 7.28 events per 1000 PY and the risk of amputation significantly increased in the presence of PAD (HR: 2.33, 95% CI: 1.65, 3.28, p < 0.001) [118].
A lower risk of amputation was observed in people treated with statins versus matched non-users (HR: 0.79 [95% CI: 0.65, 0.96], p = 0.016 for any lower extremity amputation) [54] and in those treated with a SGLT2i versus a DPP4i (5.4 vs. 12.3 events per 1000 PY [0.54 vs. 1.23 events per 100 PY]; HR: 0.43 [95% CI: 0.30, 0.62], p < 0.0001) [110]. The use of a DPP4i was associated with a significantly lower risk of amputation versus no use (IR: 0.662 vs. 1.015 events per 1000 PY, HR: 0.65 [95% CI: 0.54, 0.79], p < 0.0001) [50].
A multinational RCT conducted at 811 sites in 28 countries across Europe, Asia and the Americas [133] and including 5134 people with T2D and PAD reported a prevalence of major and minor amputations (i.e. below and above the ankle, respectively) of 3.8% and 8.4%, respectively [88]. These data fall within the range of prevalence from observational studies of 2.7%–17.9% [108, 116, 119, 125, 129]. Mohammedi et al. 2016b analysed data from the multinational ADVANCE RCT and the ADVANCE-ON post-trial observational study, assessing lower-extremity chronic ulceration (at least 6 weeks) or amputation below the knee (of at least 1 toe) secondary to vascular disease as one presentation of PAD (vs. revascularisation, see the previous paragraph) [130]. At baseline, lower extremity ulceration or amputation was established in 2.7% of people with T2D [130]. In a US study of 13,228,140 people with T2D and PAD, the prevalence of major amputations and of major/minor amputations was 5.2% and 10.5%, respectively [129]. Another US study (N = 3,293,983; T2D and PAD, n = 148,867) described a prevalence of any amputation of 2.7% in people with T2D and comorbid PAD (vs. 0.2% in those without PAD) [116]. In this study, the presence of PAD was associated with more than a fourfold increased risk of any amputation or lower-limb amputation [116]. In a German study of hospitalised patients with PAD and T2D, the rate of amputation-free people progressively decreased from 72.0% at year 1 to 64.9% at year 4 [119].
Microvascular and Macrovascular Complications
Eleven studies reported data on microvascular and macrovascular complications, including MACE [26, 53, 68, 72, 77, 88, 110, 116, 120, 124, 130]. Of these, four studies were RCTs [26, 68, 88, 130].
The IR of MACE was 56.8 events per 1000 PY (5.68 events per 100 PY, 15.9%) over 30 months of follow-up in EUCLID [88]. In the BARI-2D RCT, the 5-year rate of freedom from MACE was 68% in people with low ABI versus 80% in those with normal ABI (MACE-adjusted risk ratio [RR] 1.37 [95% CI: 1.10, 1.70], p = 0.004) [68]. In a pooled analysis of data from the LEADER and SUSTAIN trials of people with T2D, the presence of PAD at baseline was associated with a 1.35 and 1.31 increased risk of MACE, respectively, and a 1.27 and 1.72 increased risk of expanded MACE (i.e. MACE and hospitalisation for unstable angina or HF, or revascularisation) [26].
Cardiovascular events (CV death, myocardial infarction [MI] and stroke) occurred in 34.5% of people with T2D and PAD (n = 197) and in 18.0% of those with T2D without vascular disease (n = 65) over 6.9 years [53]. In people with asymptomatic PAD sub-grouped by ABI values, the risk of CVD (acute MI [AMI], ischaemic stroke, and AMI + ischaemic stroke) and microvascular complications (nephropathy, retinopathy, and neuropathy) increased as ABI values decreased [72].
A large retrospective study of people treated with SGLT2i or DPP4i demonstrated a significantly lower IR of chronic HF (CHF) in those treated with SGLT2i (9.6 vs. 14.3 events per 1000 PY [0.96 vs. 1.43 events per 100 PY], HR: 0.66 [95% CI: 0,49, 0.89), p = 0.0062) but similar rates of ischaemic stroke and AMI [110]. In people with lower-extremity chronic ulceration (at least 6 weeks) or amputation below the knee (of at least 1 toe) secondary to vascular disease, or a history of peripheral revascularisation procedure by angioplasty or surgery, the risk of MACE was approximately 50% higher versus those without those complications at baseline in the ADVANCE and ADVANCE-ON studies [130]. The risk of retinal photocoagulation or blindness was higher in those with lower-extremity ulceration or amputation versus those without. The rate of MACE was 29.6% in people in whom PAD complications manifested as peripheral revascularisation versus 26.0% in those with lower extremity ulceration or amputation at baseline and 19.1% in those without [130].
Risk of Cancer
In the international ADVANCE trial in T2D (N = 11,140), the cumulative incidence of cancers was higher in participants with a baseline history of PAD compared with those without (18.9 vs. 11.8 events per 1000 PY, respectively; 8.7% vs. 5.6%, with a HR of 1.20 [95% CI: 1.01, 1.43], p = 0.04) [112].
Mortality
Mortality data were described in 15 studies [54, 56, 68, 72, 81, 87, 88, 110, 112, 119, 122, 124, 129,130,131], five of which were based on data from multinational RCTs [68, 88, 112, 130, 131].
In the EUCLID trial, the IR of mortality was 42.1 events for all-cause death and 25.3 events per 1000 PY for CV death (4.21 and 2.53 events per 100 PY, respectively) [88]. Two studies included data from the ADVANCE trial [112, 131]. Mohammedi et al. 2021 found a 45% increase in the HR for all-cause death, a 51% increase for CV death and a 32% increase for cancer death in people with versus those without PAD during a median of 5 years [112]. In the BARI-2D RCT, people with ABI ≤ 0.90 had a 5-year survival rate of 82%, which was significantly lower (p < 0.0001) than the 91% survival rate in people with a normal ABI (0.91–1.3) (RR of death: 1.65, 95% CI: 1.25, 2.18; p = 0.0005) [68].
Higher IRs of all-cause mortality for people with low ABI values compared with those with normal ABI (27.2–62.7 vs. 15.4 events per 1000 PY, respectively) were also reported in a large cohort of people with T2D without symptomatic PAD and a history of CVD [72]. The IRs of in-hospital CV mortality were 6.24, 4.33 and 8.72 events per 1000 PY in people with T2D and PAD treated with statins, lipid-lowering agents and no drugs, respectively, with a lower risk of death in statin users vs. non-users (HR: 0.85, 95% CI: 0.76, 0.95; p = 0.005) [54]. In-hospital mortality rates were also reported in three large studies, with similar results of 1.8%, 3.1% and 3.5% [56, 119, 129]. Richter et al. demonstrated a progressive decrease in cumulative survival over 4 years from hospitalisation, from 81.4% to 56.4% [119].
Finally, the use of SGLT2i was associated with a 42% lower risk of all-cause mortality and a 33% lower risk of CV mortality compared with the use of a DPP4i (IR: 31.9 vs. 54.4 events per 1000 PY [3.19 vs. 5.44 events per 100 PY], HR: 0.58 [95% CI: 0.49, 0.67], p < 0.001; and 9.1 vs. 13.3 events per 1000 PY [0.91 vs. 1.33 events per 100 PY], HR: 0.67 [95% CI: 0.49, 0.90), p = 0.0089, respectively) [110].
The rate of death due to PAD complications was 0.02% during the follow-up in Mohammedi et al. 2016a [131]. The adjusted risk of all-cause mortality and of CV death was significantly higher in people with a history of lower-extremity ulceration or amputation below the knee, or of peripheral revascularisation at baseline versus those without [130]. Similar results for the same outcomes were observed by history (yes vs. no) of lower extremity ulceration or amputation and peripheral revascularisation at baseline [130].
Humanistic Burden
Twelve studies assessed HRQoL in people with T2D and PAD [49, 52, 55, 63, 64, 76, 79, 80, 90, 91, 99, 123]. One was an Italian single-centre RCT of 59 people with T2D and PAD [80], and 11 were observational studies: nine single-centre studies including between five and 150 people [49, 52, 55, 63, 76, 79, 90, 91, 99] and two database studies [64, 123]. Six studies were conducted in Asia or the Middle East [49, 52, 55, 76, 99, 123], four in Europe [63, 64, 80, 91] and two in Latin America [79, 90]. Study characteristics and results are presented in Table 3.
In the RCT conducted by Derosa et al. in people with T2D and PAD, the pain-free walking distance at baseline was 247.2 ± 20.3 vs. 249.2 ± 21.7 m in the treatment versus placebo arms, respectively [80].
The most commonly used instruments to assess the HRQoL in people with T2D and PAD were based on the EuroQoL-5 dimensions (EQ-5D) [55, 64, 90, 123] and the Short-Form (SF) Health Survey [63, 79, 91, 99] instruments. Zhang et al. measured HRQoL in newly-diagnosed T2D (N = 114,847; T2D and PAD, n = 1035) and found a significant decrease in those with versus those without PAD (0.74 ± 0.20 vs. 0.81 ± 0.18, p ≤ 0.05) [123]. Similarly, Sepulveda et al. recorded a significant decrease in the SF-36 domains of physical functioning, role-physical and general health in people with versus those without PAD (T2D, N = 100; T2D and PAD, n = 32; p ≤ 0.040) [91]. Tedeschi et al. reported low SF-12 scores (in both the mental and the physical component) in 25 people with T2D and pain due to PAD and poor sleep quality in all people (very disturbed in 32% and frequent awakenings in 68%) [63].
The Vascular Quality of Life Questionnaire-6 (VASCUQoL-6) was used in a study of 150 people with T2D and CLTI by Baram and Baban. Results showed a poor HRQoL before and 3 months after undergoing revascularisation, with a rise indicative of improvement at 36 months [76]. Alrub et al. used the DF scale to assess the impact of DF on the QoL of 42 people with T2D and comorbid PAD, together with the physical and mental component of the SF-8. These authors found significantly lower mean scores for DFS-SF and the physical component of SF-8 in people with versus those without PAD (p < 0.004 and p < 0.009, respectively) [99]. Cong et al. found that people with T2D and PAD (n = 85) were 2.48-fold more likely to have low QoL (as measured through the Diabetes-Specific Quality-of-Life Scale) than those with T2D only (p < 0.05) [52].
No other significant differences were observed across the studies included.
Economic Burden
Twelve studies provided information on the economic burden of PAD in people with T2D [48, 56, 59, 76, 106, 113, 114, 117, 119, 121, 124, 129]: eight assessed HCRU [48, 56, 76, 113, 114, 119, 121, 129], eight assessed costs [48, 56, 59, 106, 117, 119, 124, 129] and four assessed both HCRU and costs [48, 56, 119, 129]; only one study analysed indirect costs [106]. Four studies were performed in Europe [48, 106, 119, 124], three in the USA [56, 113, 129], three in Asia and the Middle East [59, 76, 114] and two in Australia [117, 121]. Study characteristics and results are provided in Table 4 [93].
Healthcare Resource Use
The healthcare resources described in the studies were length of hospital stay, admissions and readmissions. Three large database-based studies (2 conducted in the USA and 1 in Germany) and one Iraqi single-centre study reported a mean/median length of stay for people with T2D and PAD of 6.5–10 days [56, 76, 119, 129].
In a US study, people with T2D had a significantly increased chance of 30-day unplanned readmission after infrainguinal bypass surgery, compared with those without T2D (odds ratio: 1.21, p = 0.01); however, statistical significance was lost after adjustment on multivariate analysis [113]. A Spanish cost-effectiveness analysis estimated that people with T2D and PAD had a mean of 4.5 primary care visits per year [48]. A Singaporean study reported that 32.5% of people with T2D and PAD had at least one admission in 2010 [114]. In Australia and New Zealand, 10.8% of all unplanned admissions within 30 days of a PAD-related procedure readmissions were due to T2D [121].
Costs
Of eight studies reporting cost data for PAD in people with T2D, six assessed hospital costs [56, 59, 106, 117, 119, 129]. Two US studies used data from the Nationwide Inpatient Sample database and estimated the overall median PAD-related procedural hospitalisation costs at US$52,172 (data from 2005 to 2014) and US$45,242 (data from 2003 to 2014), respectively, for people with T2D [56, 129]. In a German study of people hospitalised with a primary or secondary diagnosis of PAD between 2009 and 2011, the median cost per patient was estimated at € (euro)4414 [119]. An Indonesian study assessing the cost-effectiveness of T2D treatments in people with PAD complications hospitalised during 2014–2017 reported that mean total annual direct costs were Indonesian Rupiah (IDR) 31,472,019, comprising of drug costs (IDR 10,279,236; 32.3% of the total cost), medical services (IDR 8,819,214; 28.3%), hospital stay (IDR 6,639,778; 20.8%), laboratory tests (IDR 3,617,972; 12.0%), consultation fees (IDR 1,246,926; 3.9%) and blood transfusions (IDR 868,893; 2.7%; US$1 = IDR 13,451) [59].
Two cross-sectional nationwide registry studies published in 2020 assessed the cost of PAD in people with T2D over a 3-year period and found that a substantial proportion of the costs occurred in the first year following a PAD event [106, 124]. McMeekin et al. reported an annual cost per patient of pound sterling (£)9200 in Scotland, the main driver being secondary care (£6500), followed by prescriptions (£1000), primary care (£700) and residential care (£280) [124]. Analysis of the costs following an incident case of PAD over a 3-year period revealed that a substantial proportion of the costs occurred in the first year post-event [124]. Similar results were obtained in a Danish study, where the mean total PAD attributable healthcare costs over 3 years following the first incident event for 7797 people with T2D and PAD in Denmark were €8309 (approximately 75% attributed to inpatient admissions), with most costs incurred in the first year [106].
Indirect costs were described only in the Danish study by Kjellberg et al. 2020, reporting the costs associated with a first incident PAD event over the period from 2007 to 2013 in people with T2D; the average total productivity loss per person over 3 years was €2869 [106].
Discussion
This SLR identified a large body of evidence (mostly from observational studies conducted in Asia and Europe) for the incidence and prevalence of PAD in people with T2D. Indirect comparisons reveal somewhat similar trends of incident and prevalent PAD in people with T2D across geographical regions [68, 112, 125, 131]. Comorbid PAD in people with T2D is associated with increased risk of lower-limb, CV complications and mortality, as well as a substantial humanistic and economic burden.
The symptomatology of PAD varies considerably from unrecognised symptoms to CLTI and ALI. According to the 2024 PAD guidelines, resting ABI should be performed to confirm a diagnosis of PAD (i.e. ≤ 0.90, vs. 1.00–1.40 considered as the normal range; > 1.40 is indicative of noncompressible arteries, in which case the toe-brachial index is used to make the diagnosis of PAD) [134]. Moreover, the 2024 American Diabetes Association Standards of Care recommend using ABI to screen people with T2D for PAD if they are asymptomatic, aged ≥ 50 years and have microvascular disease, foot complications or any end-organ damage from diabetes [135]. This criterion (ABI ≤ 0.90) was adopted by most of the identified studies that provided a definition for PAD.
In general, incidence and prevalence data for PAD varied substantially across studies. This heterogeneity may be at least partly attributable to the different characteristics (design, sample size, follow-up and PAD definition) of the studies included. Four large multinational RCTs reported that approximately one to two people out of ten with T2D had comorbid PAD [26, 68, 112]. One study conducted in India and one in Sri Lanka described the prevalence of asymptomatic PAD, which was 15.3% and 65.5% [89, 94]. Well-known risk factors for PAD were identified, including increasing age [16, 69, 77, 81, 86, 89, 92, 111] and a number of modifiable factors, including comorbidities such as diabetes [51, 61, 69, 81, 89, 111, 127], its complications (retinopathy [77, 86] and neuropathy [16, 86]) and hypertension [16, 69], as well as poor glucose [69, 71, 84, 86, 89, 96] and lipid control [86].
The studies included in this SLR demonstrated that PAD in people with T2D is a major cause of lower-limb and CV complications as well as of mortality. Some studies described the prevalence of various lower-limb outcomes, including CLTI, ulcers, and DF, which varied from 5.9% to 44.2% [88, 108, 129]. Up to one in five people experienced limb loss [119], and the risk of amputation significantly increased in people with vs. those without PAD [116]. The presence of PAD significantly increased the risk of MACE and of other microvascular and macrovascular events in people with T2D [26, 68, 130]. Comorbid PAD was associated with a higher occurrence of death (all-cause and CV) [68, 72, 112]. Similar results were observed in the placebo arm of an RCT of dapagliflozin, where people with T2D and PAD, compared with those without PAD, had a higher risk of limb adverse events (adjusted HR: 8.37 [95% CI: 6.45, 10.87], p < 0.001), MACE (adjusted HR: 1.23 [95% CI: 0.97, 1.56], p = 0.094), CV death/hospitalisation for HF (adjusted HR: 1.60 [95% CI: 1.21, 2.12], p = 0.001) and progression of kidney disease (adjusted HR: 1.51 [95% CI: 1.13, 2.03], p = 0.0058) [24]. A study conducted in 18,144 people with ACS enrolled in IMPROVE-IT, outside the scope of this SLR, demonstrated that the concomitant presence of polyvascular disease and T2D was associated with a significantly higher rate of the primary composite endpoint (CV, a major coronary event or stroke; 60.0%), compared with people with polyvascular disease (39.8%) or T2D (39.9%) and with those without these conditions (29.6%) [27].
In a retrospective cohort study of people with T2D treated with different glucose-lowering drugs in a real-world setting [116], the use of SGLT2i and of GLP-1RA in patients without a history of PAD at baseline was associated with lower PAD rates during the follow-up, compared with DPP4i and other drugs. Compared with patients receiving GLP-1RA, those on SGLT2i had a 20% higher adjusted risk of developing PAD (CI of HR: 1.14, 1.26) [116]. Two observational studies described outcomes in DPP4i users vs. non-users [50], and in people treated with SGLT2i vs. DPP4i [110]. While the use of DPP4i has not been associated with an increase or decrease in the risk of CV events [136], SGLT2is have provided clinical benefits for various CV and kidney outcomes [137,138,139]. The observational studies included in this SLR demonstrated that, in people with T2D and PAD, the use of DPP4i vs. no DPP4i and SGLT2i vs. DPP4i was associated with a 35% and 57% lower risk of amputation, respectively (p < 0.001 for both) [50, 110]. Moreover, in people treated with SGLT2i vs. DPP4i, the risk of lower-limb ischaemia requiring revascularisation decreased by 27% (p = 0.0367), of CHF occurrence by 34% (p = 0.0062) and of all-cause mortality and CV death by 42% (p < 0.001) and 33% (p = 0.0089), respectively [110]. Although these findings are from observational studies and, therefore, causality could not be shown, they are in line with the findings from the DECLARE-TIMI 58 RCT, where dapagliflozin provided consistent benefits for the endpoints of CV death/hospitalisation for HF and progression of kidney disease, with no increased risk of lower-limb events [24]. In a recent post-hoc analysis of the LEADER and SUSTAIN RCTs, both liraglutide and semaglutide consistently reduced the risk of MACE and other CV events in people with T2D with or without comorbid PAD vs. placebo [25, 26]. Moreover, both GLP-1RAs provided a greater reduction in HbA1c from baseline than placebo, the estimated treatment contrast being −0.34% and −1.08%, respectively, in people with PAD at baseline, and −0.40% and −0.81% in those without PAD (p = 0.047 for the comparison between people with and without PAD in SUSTAIN 6) [25].
Patient-reported outcomes (PROs) are tools to collect the experiences and perceptions of people with their disease and treatment. Inclusion of PROs among clinical trial endpoints has become increasingly important from both a clinical and regulatory standpoint [140, 141]. Disease-specific PROs are more sensitive and responsive than generic PROs and can help to capture relevant outcomes for a specific population. T2D and PAD are associated with a wide spectrum of complications impairing patient HRQoL [34,35,36,37,38,39]. A recent SLR identified 35 themes covering symptoms, impact on physical and social functioning, psychological and financial impact and process of care, all considered as determinants of the QoL of people living with PAD, and found that the VASCUQoL was the best disease-specific measure in this setting [142]. This tool, together with the EQ-5D and SF-12 tools, has been employed in recent RCTs conducted in patients with CTLI [143, 144]. Moreover, VASCUQoL-6 is included among the secondary endpoints of STRIDE, an ongoing multinational RCT comparing the effect of semaglutide vs. placebo on functional outcomes such as walking ability and QoL in 800 adults with T2D and PAD with intermittent claudication [145]. In this SLR, only one study used VASCUQoL-6: Baram and Baban reported a very poor HRQoL in people with T2D and CLTI before and 3 months after undergoing revascularisation, with improvement at 36 months [76]. In another study of 42 people with DFU, the use of the DF scale revealed a significantly poorer HRQoL for those with vs. without PAD [99]. In general, a variety of instruments were used to measure QoL, and most studies included in the SLR were single-centre and with a small sample size. Across those that described significant differences in the HRQoL of people with T2D and PAD vs. no PAD, the presence of PAD was associated with a poorer HRQoL [52, 91, 99, 123].
People and healthcare systems incur considerable costs for the management of T2D and PAD. In 2017, the medical expenditures for people diagnosed with diabetes were estimated to be approximately 2.3-fold higher than those for people without diabetes (US$16,752 vs. US$7151, respectively) [43]. Of US$327 billion spent on diabetes, US$237 billion were for direct medical costs [43]. Similarly, between 2011 and 2014, the average annual expenditure for people with PAD was significantly greater than for those without (US$11,553 vs. US$4219, respectively) [42]. Medication prescription, inpatient and outpatient care were the main cost drivers [43]. The data reported in this SLR support the financial burden imposed on people and healthcare systems in terms of HCRU (length of hospital stay, admissions and readmissions) and direct costs.
This SLR has some limitations. Firstly, most studies were observational and, especially for those covering the humanistic burden of T2D and comorbid PAD, the sample size was limited. Epidemiological studies with a sample size < 1000 were excluded based on the assumption that larger studies would provide more credible real-world evidence. Secondly, different definitions of PAD were provided, although most relied on ABI values, in line with current guidelines on the management of PAD [134]. Findings from the 2020 study by Li et al. [87] suggested that using percent of mean arterial pressure together with ABI may improve the prediction of all-cause mortality. However, further research is needed to validate these results. Thirdly, our SLR did not address treatment effects as this was beyond the scope of this review. Some observational studies reporting data in people with T2D and PAD treated with a number of drugs in clinical practice met the eligibility criteria and were included. However, we excluded RCTs specifically reporting the effects of treatment in this population because this was not the focus of the present work. Additional studies are needed to fill this gap. Finally, publications were restricted to 10 years prior to 18 November 2021.
To our knowledge, this SLR of evidence from RCTs and observational studies provides the most comprehensive overview of the epidemiology and of the clinical, humanistic, and economic burden of PAD in people with T2D to date. Indeed, two previous SLRs presented data for the overall PAD population, not limited to the subgroup with coexisting T2D [7, 16].
Conclusion
While treatment advances continue to improve outcomes for people with T2D and complications of PAD (DFU and amputation), efforts should be directed at prompt diagnosis and primary prevention with healthy lifestyle or timely medical or surgical interventions. In people with diabetes, pharmacotherapy should be tailored based on individual risk factors such as the presence of established atherosclerotic cardiovascular disease [135, 146]. Although, at present, no disease-modifying agent for PAD is approved for use in people with T2D and PAD, rivaroxaban and evolocumab have both been shown to reduce the risk of MACE and major adverse limb events (MALE) in people with CVD and PAD (and diabetes in > 40% of cases) [147,148,149,150]. Accordingly, the latest 2024 American College of Cardiology/American Heart Association/Multisociety PAD Guideline acknowledge the efficacy of low-dose rivaroxaban combined with low-dose aspirin to reduce the risk of MACE and MALE, and recommend the use of this combination in patients who underwent endovascular or surgical revascularisation for PAD [134]. Current medications for PAD are tailored on individual risk factors and include cilostazol, recommended to mitigate leg symptoms and increase walking distance in patients with claudication, antiplatelet therapy to reduce MACE/MALE, glucose-lowering agents to reduce the risk of MACE and renal events regardless of diabetes status, and anti-hypertensive and lipid-lowering agents [2, 14, 134, 151]. The presence of comorbidities can complicate patient management and impact on the choice of treatment: for instance, patients with ALI and severe comorbidities preferentially receive endovascular therapy, and those with LEAD and HF may receive beta-blockers [152]. In patients with CTLI and ALI revascularisation procedures are recommended to improve claudication symptoms and functional status; in case of a non-salvageable limb, amputation is performed [134], which, however, is associated with poor outcomes [21]. In people with T2D and PAD, recent guidelines recommend the use of SGLT2i and/or GLP-1RA to reduce CV risk [135, 151, 153]. Yet, evidence suggests that GLP-1RA may provide clinical benefits in terms of limb outcomes in people with T2D and comorbid PAD [154, 155]; in this setting, results from STRIDE will shed light on the potential of semaglutide to also improve functional capacity [156].
Data Availability
All data used to write this manuscript are presented in the text, tables or references.
References
Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008;300(2):197–208.
Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(12):e686–725.
McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA. 2001;286(13):1599–606.
Howard DP, Banerjee A, Fairhead JF, Hands L, Silver LE, Rothwell PM. Population-based study of incidence, risk factors, outcome, and prognosis of ischemic peripheral arterial events: implications for prevention. Circulation. 2015;132(19):1805–15.
Kochar A, Mulder H, Rockhold FW, et al. Cause of death among patients with peripheral artery disease. Circ Cardiovasc Qual Outcomes. 2020;13(11):e006550.
Song P, Rudan D, Zhu Y, et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health. 2019;7(8):e1020–30.
Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329–40.
Sampson UK, Fowkes FG, McDermott MM, et al. Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010. Glob Heart. 2014;9(1):145-58.e21.
Aday AW, Matsushita K. Epidemiology of peripheral artery disease and polyvascular disease. Circ Res. 2021;128(12):1818–32.
Yang C, Kwak L, Ballew SH, et al. Retinal microvascular findings and risk of incident peripheral artery disease: an analysis from the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2020;294:62–71.
McDermott MM, Greenland P, Green D, et al. D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease. Circulation. 2003;107(25):3191–8.
Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Markers of coagulation activation, endothelial stimulation and inflammation in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg. 2005;29(2):171–6.
Ding N, Yang C, Ballew SH, et al. Fibrosis and inflammatory markers and long-term risk of peripheral artery disease: The ARIC study. Arterioscler Thromb Vasc Biol. 2020;40(9):2322–31.
Criqui MH, Matsushita K, Aboyans V, et al. Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the american heart association. Circulation. 2021;144(9):e171–91.
McDermott MM. Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia. Circ Res. 2015;116(9):1540–50.
Shou Z, Zhao Y, Zhang Y, Li S. Risk factors for peripheral arterial disease in elderly patients with type-2 diabetes mellitus: a clinical study. Pak J Med Sci. 2020;36(6):1–5.
McDermott MM, Liu K, Greenland P, et al. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA. 2004;292(4):453–61.
Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015;116(9):1509–26.
Abu Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 2015;62(6):1642-51.e3.
Hess CN, Huang Z, Patel MR, et al. Acute limb ischemia in peripheral artery disease. Circulation. 2019;140(7):556–65.
Jones WS, Patel MR, Dai D, et al. High mortality risks after major lower extremity amputation in Medicare patients with peripheral artery disease. Am Heart J. 2013;165(5):809–15.
Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of a wide range of cardiovascular diseases: a cohort study in 1·9 million people. Lancet Diabetes Endocrinol. 2015;385(2):S86.
Verma S, Dhingra NK, Bonaca MP, et al. Presence of Peripheral artery disease is associated with increased risk of heart failure events: insights from EMPEROR-pooled. Arterioscler Thromb Vasc Biol. 2023;43(7):1334–7.
Bonaca MP, Wiviott SD, Zelniker TA,et al. Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58. Circulation. 2020;142(8):734–47.
Verma S, Al-Omran M, Leiter LA, et al. Cardiovascular efficacy of liraglutide and semaglutide in individuals with diabetes and peripheral artery disease. Diabetes Obes Metab. 2022;24(7):1288–99.
Rsshasrm VS. Liraglutide and semaglutide reduce cardiovascular events in patients with type 2 diabetes and peripheral arterial disease. Diabetologia. 2020;63(1):S283–4.
Bonaca MP, Gutierrez JA, Cannon C, et al. Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. Lancet Diabetes Endocrinol. 2018;6(12):934–43.
Hess CN, Fu JW, Gundrum J, et al. Diabetes mellitus and risk stratification after peripheral artery revascularization. J Am Coll Cardiol. 2021;77(22):2867–9.
Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367–75.
Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1): e3266.
Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16.
Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Predictive factors for diabetic foot ulceration: a systematic review. Diabetes Metab Res Rev. 2012;28(7):574–600.
Peters EJ, Armstrong DG, Lavery LA. Risk factors for recurrent diabetic foot ulcers: site matters. Diabetes Care. 2007;30(8):2077–9.
Grandy S, Fox KM. Change in health status (EQ-5D) over 5 years among individuals with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health Qual Life Outcomes. 2012;10:99.
Peyrot M, Rubin RR, Lauritzen T, Snoek FJ, Matthews DR, Skovlund SE. Psychosocial problems and barriers to improved diabetes management: results of the Cross-National Diabetes Attitudes, Wishes and Needs (DAWN) Study. Diabet Med. 2005;22(10):1379–85.
Wu A, Coresh J, Selvin E, Tanaka H, Heiss G, Hirsch AT, et al. Lower extremity peripheral artery disease and quality of life among older individuals in the community. J Am Heart Assoc. 2017;6(1):e004519. https://doi.org/10.1161/JAHA.116.004519.
Çamur S, Batıbay SG, Bayram S. Effect of lower extremity amputation on caregiving burden in caregivers of patients with diabetic foot: prospective cohort study. Int Wound J. 2020;17(4):890–6.
Ribu L, Hanestad BR, Moum T, Birkeland K, Rustoen T. A comparison of the health-related quality of life in patients with diabetic foot ulcers, with a diabetes group and a nondiabetes group from the general population. Qual Life Res. 2007;16(2):179–89.
Ribu L, Birkeland K, Hanestad BR, Moum T, Rustoen T. A longitudinal study of patients with diabetes and foot ulcers and their health-related quality of life: wound healing and quality-of-life changes. J Diabetes Complicat. 2008;22(6):400–7.
Remes L, Isoaho R, Vahlberg T, Viitanen M, Koskenvuo M, Rautava P. Quality of life three years after major lower extremity amputation due to peripheral arterial disease. Aging Clin Exp Res. 2010;22(5–6):395–405.
Davie-Smith F, Coulter E, Kennon B, Wyke S, Paul L. Factors influencing quality of life following lower limb amputation for peripheral arterial occlusive disease: a systematic review of the literature. Prosthet Orthot Int. 2017;41(6):537–47.
Scully RE, Arnaoutakis DJ, DeBord SA, Semel M, Nguyen LL. Estimated annual health care expenditures in individuals with peripheral arterial disease. J Vasc Surg. 2018;67(2):558–67.
American Diabetes Association. Economic costs of diabetes in the US in 2017. Diabetes Care. 2018;41(5):917–28.
Jaff MR, Cahill KE, Yu AP, Birnbaum HG, Engelhart LM. Clinical outcomes and medical care costs among medicare beneficiaries receiving therapy for peripheral arterial disease. Ann Vasc Surg. 2010;24(5):577–87.
Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019. www.training.cochrane.org/handbook. Accessed: 18 June 2020.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PRISMA statement http://www.prisma-statement.org/PRISMAStatement/PRISMAStatement.
Arrieta F, Pinera M, Iglesias P, et al. Metabolic control and chronic complications during a 3-year follow-up period in a cohort of type 2 diabetic patients attended in primary care in the Community of Madrid (Spain). Endocrinol y Nutr. 2014;61(1):11–7.
Arrieta F, Rubio-Terrés C, Rubio-Rodríguez D, et al. Estimation of the economic and health impact of complications of type 2 diabetes mellitus in the autonomous community of Madrid (Spain). Endocrinol Nutr. 2014;61(4):193–201.
Bahety P, Agarwal G, Khandelwal D,et al. Occurrence and predictors of depression and poor quality of life among patients with Type-2 diabetes: a Northern India perspective. Indian J Endocrinol Metab. 2017;21(4):564–9.
Chang CC, Chen YT, Hsu CY, et al. Dipeptidyl peptidase-4 inhibitors, peripheral arterial disease, and lower extremity amputation risk in diabetic patients. Am J Med. 2017;130(3):348–55.
Collier A, Ghosh S, Hair M, Waugh N. Gender differences and patterns of cardiovascular risk factors in type 1 and type 2 diabetes: a population-based analysis from a Scottish region. Diabet Med. 2015;32(1):42–6.
Cong JY, Zhao Y, Xu QY, Zhong CD, Xing QL. Health-related quality of life among Tianjin Chinese patients with type 2 diabetes: a cross-sectional survey. Nurs Health Sci. 2012;14(4):528–34.
Haeberli D, Saely C, Heinzle C, et al. The effects of peripheral and coronary artery disease as well as type 2 diabetes mellitus on the risk of cardiovascular events-a prospective cohort study. Vasa. 2019;(Suppl 103):9. https://doi.org/10.1024/0301-1526/a000836.
Hsu CY, Chen YT, Su YW, Chang CC, Huang PH, Lin SJ. Statin therapy reduces future risk of lower-limb amputation in patients with diabetes and peripheral artery disease. J Clin Endocrinol Metab. 2017;102(7):2373–81.
Ishii H, Takamura H, Nishioka Y, et al. Quality of life and utility values for cost-effectiveness modeling in Japanese patients with Type 2 diabetes. Diabetes Ther. 2020;11(12):2931–43.
Jain N, Agarwal M, Dokun AO. Differences in treatment of peripheral arterial disease procedures in hospitalized patients with type 1 or 2 diabetes. J Investig Med. 2019;67:350–652.
Lautsch D, Wang T, Yang L, Rajpathak SN. Prevalence of established cardiovascular disease in patients with type 2 diabetes mellitus in the UK. Diabetes Ther. 2019;10(6):2131–7.
Pantalone KM, Hobbs TM, Wells BJ, et al. Changes in characteristics and treatment patterns of patients with newly diagnosed type 2 diabetes in a large United States integrated health system between 2008 and 2013. Clin Med Insights Endocrinol Diabetes. 2016;9:23–30.
Priyadi A, Permana H, Muhtadi A, Sumiwi SA, Sinuraya RK, Suwantika AA. Cost-effectiveness analysis of type 2 diabetes mellitus (T2DM) treatment in patients with complications of kidney and peripheral vascular diseases in Indonesia. Healthcare (Basel). 2021;9(2):16.
Seferovic JP, Bentley-Lewis R, Claggett B, Diaz R, Gerstein HC, Kober LV, et al. Retinopathy, neuropathy, and subsequent cardiovascular events in patients with type 2 diabetes and acute coronary syndrome in the ELIXA: the importance of disease duration. J Diabetes Res. 2018;2018:1–9.
Shah DA, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of a wide range of cardiovascular diseases: a cohort study in 1.9 million people. Lancet. 20153(2):105-13. https://doi.org/10.1016/S0140-6736(15)60401-9.
Slabaugh SL, Curtis BH, Clore G, Fu H, Schuster DP. Factors associated with increased healthcare costs in Medicare Advantage patients with type 2 diabetes enrolled in a large representative health insurance plan in the US. J Med Econ. 2015;18(2):106–12.
Tedeschi A, De Bellis A, Francia P, et al. Tapentadol prolonged release reduces the severe chronic ischaemic pain and improves the quality of life in patients with type 2 diabetes. J Diabetes Res. 2018;2018:1–6.
Wasem J, Bramlage P, Gitt AK, et al. Co-morbidity but not dysglycaemia reduces quality of life in patients with type-2 diabetes treated with oral mono- or dual combination therapy–an analysis of the DiaRegis registry. Cardiovasc Diabetol. 2013;12:47.
Weng W, Liang Y, Kimball ES, et al. Longitudinal changes in medical services and related costs in a single cohort of patients newly diagnosed with type 2 diabetes, 2006 to 2012. Clin Ther. 2016;38(6):1314–26.
Zhang Y, He X, Wu J. Pdb31 direct medical costs of incident complications in patients with newly-diagnosed type 2 diabetes in China: findings from a medical claims database. Value Health. 2020;23(Suppl 1):S113.
Naqvi IH, Talib A, Naqvi SH, Yasin L, Rizvi NZ. The neuro-vascular consequence of diabetes: Foot amputation and evaluation of its risk factors and health-related economic impact. Curr Vasc Pharmacol. 2020;19(1):102–9.
Abbott JD, Lombardero MS, Barsness GW, Pena-Sing I, Buitron LV, Singh P, et al. Ankle-brachial index and cardiovascular outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Am Heart J. 2012;164(4):585-90.e4.
Agrawal RP, Ola V, Bishnoi P, Gothwal S, Sirohi P, Agrawal R. Prevalence of micro and macrovascular complications and their risk factors in type-2 diabetes mellitus. J Assoc Phys India. 2014;62(6):504–8.
Al Rawahi AH, Lee P, Al Anqoudi ZAM, Al Busaidi A, Al Rabaani M, Al Mahrouqi F, et al. Cardiovascular disease incidence and risk factor patterns among omanis with type 2 diabetes: a retrospective cohort study. Oman Med J. 2017;32(2):106–14.
Althouse AD, Abbott JD, Forker AD, et al. Risk factors for incident peripheral arterial disease in type 2 diabetes: results from the bypass angioplasty revascularization investigation in type 2 diabetes (BARI 2D) trial. Diabetes Care. 2014;37(5):1346–52.
Alves-Cabratosa L, Comas-Cufi M, Ponjoan A, et al. Levels of ankle-brachial index and the risk of diabetes mellitus complications. BMJ Open Diab Res Care. 2020;8(1):e000977.
Anjana RM, Shanthirani CS, Unnikrishnan R, et al. Regularity of follow-up, glycemic burden, and risk of microvascular complications in patients with type 2 diabetes: a 9-year follow-up study. Acta Diabetol. 2015;52(3):601–9.
Arambewela MH, Somasundaram NP, Jayasekara HBPR, et al. Prevalence of chronic complications, their risk factors, and the cardiovascular risk factors among patients with type 2 diabetes attending the diabetic clinic at a tertiary care hospital in Sri Lanka. J Diab Res. 2018;2018:1–10.
Armengol GD, Hayfron-Benjamin CF, van den Born BJH, Galenkamp H, Agyemang C. Microvascular and macrovascular complications in type 2 diabetes in a multi-ethnic population based in Amsterdam. the HELIUS study primary. Care Diab. 2021;15(3):528–34.
Baram A, Baban ZT. Short and long-term outcomes of the peripheral arterial indirect bypass in diabetic patients with chronic limb-threatening ischemia: Single-center case series. Int J Surg Open. 2020;27:72–8.
Chen SC, Hsiao PJ, Huang JC, et al. Abnormally low or high ankle-brachial index is associated with proliferative diabetic retinopathy in type 2 diabetic mellitus patients. PLoS ONE. 2015;10(7):e0134718.
Davis WA, Gregg EW, Davis TME. Temporal trends in cardiovascular complications in people with or without type 2 diabetes: the Fremantle Diabetes Study. J Clin Endocrinol Metab. 2020;105(7):e2471.
Sales ATDN, Fregonezi GAF, Silva AGCB, et al. Identification of peripheral arterial disease in diabetic patients and its association with quality of life, physical activity and body composition. J Vasc Bras. 2015;14(1):46–54.
Giuseppe D. Evaluation of the effects of mesoglycan on some markers of endothelial damage and walking distance in diabetic patients with peripheral arterial disease. Int J Mol Sci. 2017;18(3):572.
Eshcol J, Jebarani S, Anjana RM, Mohan V, Pradeepa R. Prevalence, incidence and progression of peripheral arterial disease in Asian Indian type 2 diabetic patients. J Diab Complic. 2014;28(5):627–31.
Fu X, Zhao S, Mao H, Wang Z, Zhou L. Association of height with peripheral arterial disease in type 2 diabetes. J Endocrinol Invest. 2015;38(1):57–63.
Hamilton EJ, Davis WA, Siru R, Baba M, Norman PE, Davis TME. Temporal trends in incident hospitalization for diabetes-related foot ulcer in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. 2021;44(3):722–30.
Lee IT. Mean and variability of annual haemoglobin A1c are associated with high-risk peripheral artery disease. Diabetes Vasc Dis Res. 2020;17(3):147916412090903.
Li DM, Zhang Y, Li Q, Xu XH, Ding B, Ma JH. Low 25-hydroxyvitamin D level is associated with peripheral arterial disease in type 2 diabetes patients. Arch Med Res. 2016;47(1):49–54.
Li X, Wang YZ, Yang XP, Xu ZR. Prevalence of and risk factors for abnormal ankle-brachial index in patients with type 2 diabetes. J Diabetes. 2012;4(2):140–6.
Li YH, Sheu WHH, Lee IT. Use of the ankle-brachial index combined with the percentage of mean arterial pressure at the ankle to improve prediction of all-cause mortality in type 2 diabetes mellitus: an observational study. Cardiovasc Diabetol. 2020;19(1):173. https://doi.org/10.1186/s12933-020-01149-7.
Low Wang CC, Blomster JI, Heizer G, et al. Cardiovascular and limb outcomes in patients with diabetes and peripheral artery disease: the EUCLID trial. J Am Coll Cardiol. 2018;72(25):3274–84.
Pradeepa R, Chella S, Surendar J, Indulekha K, Anjana RM, Mohan V. Prevalence of peripheral vascular disease and its association with carotid intima-media thickness and arterial stiffness in type 2 diabetes: The Chennai Urban Rural Epidemiology Study (CURES 111). Diab Vasc Dis Res. 2014;11(3):190–200.
Romero-Naranjo F, Espinosa-Uquillas C, Gordillo-Altamirano F, Barrera-Guarderas F. Which factors may reduce the health-related quality of life of ecuadorian patients with diabetes? P R Health Sci J. 2019;38(2):102–8.
Sepulveda E, Poinhos R, Constante M, Pais-Ribeiro J, Freitas P, Carvalho D. Relationship between chronic complications, hypertension, and health-related quality of life in Portuguese patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2015;8:535–42.
Sosale B, Sosale AR, Mohan AR, Kumar PM, Saboo B, Kandula S. Cardiovascular risk factors, micro and macrovascular complications at diagnosis in patients with young onset type 2 diabetes in India: CINDI 2. Indian J Endocrinol Metab. 2016;20(1):114–8.
Tseng AS, Girardo M, Atwal D, Liedl D, Wennberg PW, Shamoun F. Abstract 10406: differences in cardiovascular outcomes in patients with type 1 versus type 2 diabetes and peripheral arterial disease. Circulation. 2019;140(1):A10406-A.
Weerarathna TP, Herath M, Liyanage G, Weerarathna MK, Senadheera V. Prevalence and associations of subclinical peripheral artery disease among patients with type 2 diabetes without clinical macrovascular disease. Int J Prev Med. 2019;10(1):106.
Yan BP, Zhang Y, Kong APS, et al. Borderline ankle-brachial index is associated with increased prevalence of micro- and macrovascular complications in type 2 diabetes: a cross-sectional analysis of 12,772 patients from the Joint Asia Diabetes Evaluation Program. Diab Vasc Dis Res. 2015;12(5):334–41.
Yang CP, Lin CC, Li CI, et al. Fasting plasma glucose variability and HbA1c are associated with peripheral artery disease risk in type 2 diabetes. Cardiovasc Diabetol. 2020;19(1):4. https://doi.org/10.1186/s12933-019-0978-y.
Yuan J, Jia P, Hua L, Xin Z, Yang JK. Vitamin D deficiency is associated with risk of developing peripheral arterial disease in type 2 diabetic patients. BMC Cardiovasc Disord. 2019;19(1):145. https://doi.org/10.1186/s12872-019-1125-0.
Zou Y, Li X, Wang C, et al. Association between non-alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes. Intern Med J. 2017;47(10):1147–53.
Alrub AA, Hyassat D, Khader YS, Bani-Mustafa R, Younes N, Ajlouni K. Factors associated with health-related quality of life among jordanian patients with diabetic foot ulcer. J Diabetes Res. 2019;2019:4706720.
Ankush DA, Gomes E, Dessai A. Complications in advanced diabetics in a tertiary care centre: a retrospective registry-based study. J Clin Diagn Res. 2016;10(4):OC15–9.
Chang PY, Wang IT, Chiang CE, et al. Vascular complications of diabetes: natural history and corresponding risks of dementia in a national cohort of adults with diabetes. Acta Diabetol. 2021;58(7):859–67.
Davis TME, Coleman RL, Holman RR. Ethnicity and long-term vascular outcomes in type 2 diabetes: a prospective observational study (UKPDS 83). Diabet Med. 2014;31(2):200–7.
Foussard N, Saulnier PJ, Potier L, et al. Relationship between diabetic retinopathy stages and risk of major lower-extremity arterial disease in patients with Type 2 diabetes. Diabetes Care. 2020;43(11):2751–9.
Hansen LJ, Siersma V, Beck-Nielsen H, De Fine ON. Structured personal care of type 2 diabetes: A 19 year follow-up of the study Diabetes Care in General Practice (DCGP). Diabetologia. 2013;56(6):1243–53.
Huang ES, Laiteerapong N, Liu JY, John PM, Moffet HH, Karter AJ. Rates of complications and mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med. 2014;174(2):251–8.
Kjellberg J, Tikkanen CK, Bagger M, Gaede P. Short-term societal economic burden of first-incident type 2 diabetes-related complications-a nationwide cohort study. Expert Rev Pharmacoecon Outcomes Res. 2020;20(6):577–86.
Koo BK, Lee CH, Yang BR, Hwang SS, Choi NK. The incidence and prevalence of diabetes mellitus and related atherosclerotic complications in Korea: A National Health Insurance database study. PLoS ONE. 2014;9(10):e110650.
Kosiborod M, Gomes MB, Nicolucci A, et al. Vascular complications in patients with type 2 diabetes: Prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabeto. 2018;17(1):150. https://doi.org/10.1186/s12933-018-0787-8.
Kurowski JR, Nedkoff L, Schoen DE, Knuiman M, Norman PE, Briffa TG. Temporal trends in initial and recurrent lower extremity amputations in people with and without diabetes in Western Australia from 2000 to 2010. Diabetes Res Clin Pract. 2015;108(2):280–7.
Lee HF, Chen SW, Liu JR, et al. Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor. Cardiovasc Diabetol. 2020. https://doi.org/10.1186/s12933-020-01118-0.
Li Q, Zeng H, Liu F, et al. High ankle-brachial index indicates cardiovascular and peripheral arterial disease in patients with type 2 diabetes. Angiology. 2015;66(10):918–24.
Mohammedi K, Harrap S, Mancia G, et al. History of lower-limb complications and risk of cancer death in people with type 2 diabetes. Cardiovasc Diabetol. 2021;20:31. https://doi.org/10.1186/s12933-020-01198-y.
Najafian A, Selvarajah S, Schneider EB, et al. Thirty-day readmission after lower extremity bypass in diabetic patients. J Surg Res. 2016;200(1):356–64.
Ng C, Toh MPHS, Ko Y, Lee JU-C. Direct medical cost of type 2 diabetes in Singapore. PLoS ONE. 2015;10(3):e0122795.
Nguyen C, Luthra R, Kuti E, Willey VJ. Assessing risk of future cardiovascular events, healthcare resource utilization and costs in patients with type 2 diabetes, prior cardiovascular disease and both. Curr Med Res Opin. 2020;36(12):1927–38.
Paul SK, Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study. Eur Heart J. 2021;42(18):1728–38.
Rasekaba TM, Lim WK, Hutchinson AF. Effect of a chronic disease management service for patients with diabetes on hospitalisation and acute care costs. Aust Health Rev. 2012;36(2):205–12.
Riandini T, Pang D, Toh MPHS, et al. Diabetes-related lower extremity complications in a multi-ethnic Asian population: a 10 year observational study in Singapore. Diabetologia. 2021;64(7):1538–49.
Richter L, Freisinger E, Luders F, Gebauer K, Meyborg M, Malyar NM. Impact of diabetes type on treatment and outcome of patients with peripheral artery disease. Diab Vasc Dis Res. 2018;15(6):504–10.
Rodionov RN, Peters F, Marschall U, L’Hoest H, Jarzebska N, Behrendt CA. Initiation of SGLT2 inhibitors and the risk of lower extremity minor and major amputation in patients with Type 2 diabetes and peripheral arterial disease: a health claims data analysis. Eur J Vasc Endovasc Surg. 2021;12:12.
Woelk V, Speck P, Kaambwa B, Fitridge RA, Ranasinghe I. Incidence and causes of early unplanned readmission after hospitalisation with peripheral arterial disease in Australia and New Zealand. Med J Aust. 2021;216(2):80-6. https://doi.org/10.5694/mja2.51329.
Zareini B, Blanche P, D’Souza M, et al. Type 2 diabetes mellitus and impact of heart failure on prognosis compared to other cardiovascular diseases: A Nationwide Study. Circ Cardiovasc Qual Outcomes. 2020;13(7):386–94.
Zhang P, Brown MB, Bilik D, Ackermann RT, Li R, Herman WH. Health utility scores for people with type 2 diabetes in U.S. managed care health plans: Results from translating research into action for diabetes (TRIAD). Diabetes Care. 2012;35(11):2250–6.
McMeekin P, Geue C, Mocevic E, et al. The cost of prevalent and incident cardiovascular disease in people with type 2 diabetes in Scotland: data from the Scottish Care Information-Diabetes Collaboration. Diabet Med. 2020;37(11):1927–34.
Bertrand C, Saulnier PJ, Potier L, et al. Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study. Diabetologia. 2021;64(3):668–80.
Holzmann MJ, Rathsman B, Eliasson B, et al. Long-term prognosis in patients with type 1 and 2 diabetes mellitus after coronary artery bypass grafting. J Am Coll Cardiol. 2015;65(16):1644–52.
Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105–13.
Weng W, Kong SX, Ganguly R, et al. The prevalence of cardiovascular disease by vascular bed and impact on healthcare costs in a large, real-world population with type 2 diabetes. Endocrinol Diabetes Metabol. 2020;3(2):e00106. https://doi.org/10.1002/edm2.106.
Jain N, Agarwal MA, Jalal D, Dokun AO. Individuals with peripheral artery disease (PAD) and type 1 diabetes are more likely to undergo limb amputation than those with PAD and type 2 diabetes. J Clin Med. 2020;9(9):1–10.
Mohammedi K, Woodward M, Hirakawa Y, Zoungas S, Colagiuri S, Hamet P, et al. Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study. Cardiovasc Diabetol. 2016;15(1):129. https://doi.org/10.1186/s12933-016-0446-x.
Mohammedi K, Woodward M, Hirakawa Y, et al. Microvascular and macrovascular disease and risk for major peripheral arterial disease in patients with type 2 diabetes. Diabetes Care. 2016;39(10):1796–803.
ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.
Hiatt WR, Fowkes FGR, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2016;376(1):32–40.
Gornik HL, Aronow HD, Goodney PP, et al. ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines. Circulation. 2024;149(24):e1313–410. https://doi.org/10.1161/CIR.0000000000001251.
American Diabetes Association Professional Practice Committee 10. Cardiovascular disease and risk management: standards of care in diabetes-2024. Diabetes Care. 2024;47:S179–218.
Mannucci E, Nreu B, Montereggi C, et al. Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2021;31(10):2745–55.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018;9:353–67.
US Food and Drug Administration. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. 2009. https://www.fda.gov/media/77832/download. Accessed 23 Aug 2023.
Aber A, Lumley E, Phillips P, Woods HB, Jones G, Michaels J. Themes that determine quality of life in patients with peripheral arterial disease: a systematic review. Patient. 2018;11(5):489–502.
Menard MT, Farber A, Assmann SF, et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) Trial. J Am Heart Assoc. 2016;5(7):e003219.
Bradbury AW, Moakes CA, Popplewell M, et al. A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial. Lancet. 2023;401(10390):1798–809.
clinicaltrials.gov. A research study to compare a medicine called semaglutide against placebo in people with peripheral arterial disease and type 2 diabetes (STRIDE). https://classic.clinicaltrials.gov/ct2/show/NCT04560998 Accessed 23 August 2023.
Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: Developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC). Eur Heart J. 2023;44(39):4043–140.
Kaplovitch E, Eikelboom JW, Dyal L, et al. Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial. JAMA Cardiol. 2021;6(1):21–9.
Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (further cardiovascular outcomes research with pcsk9 inhibition in subjects with elevated risk). Circulation. 2018;137(4):338–50.
Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994–2004.
Anand SS, Hiatt W, Dyal L, et al. Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials. Eur J Prev Cardiol. 2021;29(5):e181–9.
Nordanstig J, Behrendt CA, Baumgartner I, et al. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2024 clinical practice guidelines on the management of asymptomatic lower limb peripheral arterial disease and intermittent claudication. Eur J Vasc Endovasc Surg. 2024;67(1):9–96.
Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018;39(9):763–816.
Abramson BL, Al-Omran M, Anand SS, et al. Canadian cardiovascular society 2022 guidelines for peripheral arterial disease. Can J Cardiol. 2022;38(5):560–87.
Dhatariya K, Bain SC, Buse JB, et al. The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: results from the LEADER Trial. Diabetes Care. 2018;41(10):2229–35.
Werkman NCC, Driessen JHM, Stehouwer CDA, et al. The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations: a nation-wide cohort study. Cardiovasc Diabetol. 2023;22(1):160.
Sillesen H, Debus ES, Enggaard RBB, et al. Effects of semaglutide on functional capacity in patients with type 2 diabetes and peripheral arterial disease: rationale and design of the STRIDE trial. Eur Heart J. 2021;2(1):ehab724.2027. https://doi.org/10.1093/eurheartj/ehab724.2027.
Ji L, Bonnet F, Charbonnel B, et al. Towards an improved global understanding of treatment and outcomes in people with type 2 diabetes: Rationale and methods of the DISCOVER observational study program. J Diabetes Complicat. 2017;31(7):1188–96.
Conte MS, Pomposelli FB, Clair DG, et al. Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication. J Vasc Surg. 2015;61(3 Suppl):2s–41s.
Acknowledgements
Medical Writing/Editorial Assistance
Palvi Gupta, Sunita Nair, and Roberto Bonemei (Clarivate) have supported the literature review and manuscript development, and Clara Ricci (Clarivate) has provided medical writing support and editorial assistance, all of which was funded by Novo Nordisk.
Funding
This study and the Rapid Service Fee were funded by Novo Nordisk.
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Subodh Verma, Lawrence A. Leiter, Kamal K. Mangla, Nick F. Nielsen, Yasemin Hansen and Marc P. Bonaca made substantial contributions to the conception of the work. Subodh Verma supported the development of the manuscript, and all authors contributed substantially. All authors read and approved the final manuscript.
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Subodh Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Lawrence A. Leiter has received research funding from, has provided CME on behalf of and/or has acted as an adviser to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS, Kowa, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi and Servier. Kamal K. Mangla, Nick F. Nielsen and Yasemin Hansen are employees and shareholders of Novo Nordisk A/S. Kamal K. Mangla has changed his affiliation from ‘Novo Nordisk A/S, Soborg, Denmark’ to ‘Novo Nordisk Service Center India Pvt. Ltd., Bengaluru, India’. Marc P. Bonaca is the Executive Director of CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between August 2021 and the present from: Abbott Laboratories, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., Anthos Therapeutics, ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cleerly Inc., Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd., EPG Communication Holdings Ltd., Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd., Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd., Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., Janssen and Affiliates, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharmaceuticals, Inc., Medimmune Ltd., Medpace, Merck & Affiliates, Nectero Medical Inc., Novartis Pharmaceuticals Corp., Novo Nordisk, Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Saint Luke’s Hospital of Kansas City, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stanford Center for Clinical Research, Stealth BioTherapeutics Inc., State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group. MB reported receiving support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). He also reported modest stock holdings in Medtronic and Pfizer, and receiving consulting fees from Audentes.
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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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Verma, S., Leiter, L.A., Mangla, K.K. et al. Epidemiology and Burden of Peripheral Artery Disease in People With Type 2 Diabetes: A Systematic Literature Review. Diabetes Ther (2024). https://doi.org/10.1007/s13300-024-01606-6
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DOI: https://doi.org/10.1007/s13300-024-01606-6