How to diagnose and manage lower extremity artery disease in patients with type 2 diabetes

Introduction

Among all peripheral arterial diseases, lower extremity arterial disease (LEAD) is a serious condition in subjects with type 2 diabetes mellitus (T2DM), associated with important disability, cardiovascular risk, and socio-economic burden. Patients with both conditions generally display poorer prognosis of affected limbs compared with non-diabetic subjects, leading to increased rates of adverse limb events including amputations.

Nonetheless, awareness on LEAD remains somehow suboptimal in the diabetic population, partly related to an atypical clinical presentation in several cases. A regular and appropriate screening for lower extremity arterial disease in patients suffering from T2DM is therefore recommended. Affected subjects should receive optimal medical treatment including careful management of the different cardiovascular (CV) risk factors through a healthy lifestyle, a regular and structured physical activity, the administration of lipid-lowering, antidiabetic drugs, and (when indicated) antihypertensive and antithrombotic drugs.

Lower extremity artery disease and type 2 diabetes: scale of the problem

 It is estimated that LEAD affects over 200 million people worldwide, including 40 million people living in European countries [1]. It is 2–4 times more frequent in subjects with T2DM as compared to general population. In the ADVANCE trial, the baseline prevalence of LEAD in the diabetic population was estimated at 4.6% when the disease was defined as chronic foot ulceration due to arterial insufficiency, need for peripheral revascularization procedure, or lower-limb amputation of at least one toe. Percentages rose up to > 20% when LEAD definition included abnormal ankle–brachial index (ABI) [2].

Almost all the population studies are concordant to present T2DM as a significant risk factor for LEAD even after multiple adjustments for potential confounders [3]. In a population study in the US, it was estimated that the proportional attributable fraction of T2DM for incident LEAD was 14% [4]. The risk of LEAD grows in parallel, with the severity of T2DM, the its duration, the poor level of glucose control and use insulin. It has been estimated that the risk of LEAD increases by 26% for every 1% increase in hemoglobin-A1c (HbA1c) level [5], while the UK Prospective Diabetes Study (UKPDS) showed a prevalence of LEAD of 1.2% and 12.5% at diagnosis of T2DM and after 18 years of its evolution, respectively [6].

Patients with LEAD and concomitant T2DM are at increased risk of chronic limb-threatening ischemia (CLTI) and major limb events (MALE), including major limb amputation and acute limb ischemia.

Furthermore, LEAD (with or without T2DM) is associated to an increased risk of coronary and cerebral artery disease, which may eventually result in the occurrence of major adverse cardiac events (MACE), such as myocardial infarction, stroke and CV death. This is particularly the case of symptomatic patients, in whom the rates of MACE were estimated at 4-5%/year [7].

How to screen patients with type 2 diabetes for lower extremity artery disease

Clinical LEAD is often preceded by a long phase of subclinical progression of the disease where patients are already at increased risk of CV events. Besides, the symptoms are more often atypical, and may suddenly express a severe form. For all the reasons, patients with T2DM should undergo annual clinical screening for LEAD [8]. An exhaustive interview should look for, any history of intermittent claudication (IC), ischemic rest pain, leg fatigue or decreased walking speed. Since sensory neuropathy may hide symptoms of LEAD, atypical pain has to be systematically investigated as well. The clinical presentation of LEAD may be assessed according to Lerich and Fontaine or Rutherford classifications [9]. Physical examination has to focus mainly on the inspection of the feet, the evaluation of skin temperature of the extremity, and the palpation of distal arteries (i.e. posterior tibial and dorsalis pedis pulses).

ABI is the first line diagnostic test in patients with symptoms or signs of LEAD. It should be considered also in asymptomatic patients at increased risk of LEAD, particularly in case of adjunctive CV risk factors (age > 50 years, smoking, hypertension and hyperlipidaemia), a history of other vascular territories, heart failure or chronic renal failure, as well as a duration of T2DM > 10 years [10]. It is defined as the ratio of systolic blood pressure (SBP) at the ankle over the SBP in the upper arm. It is considered as normal within the 1.0–1.4 range, borderline in the 0.90–0.99 range, and abnormal when <0.90. One specific presentation of artery disease at the distal level is medial arterial calcification (MAC), leading to incompressible arteries and abnormally increasing values of ABI over 1.40. In that case additional assessment is necessary to look for occlusive disease underneath, as MAC can be often associated with atherosclerosis. This can be identified by the analysis of waveforms by Doppler, or the measurement of the toe-brachial index (TBI) which is decreased <0.70 in case of occlusive disease.

A decreased ankle SBP > 30 mmHg, or a reduction of ABI >20% after the exercise are diagnostic for LEAD [11]. In case of CLTI, ABI (when measurable), TBI, and the transcutaneous pressure of oxygen (TcPO2) are indicated for the assessment of malperfusion severity (see below). TcPO2 may be used to estimate the likelihood of wound healing or a requirement of amputation in this setting. Treadmill test could be helpful when ischemic origin of limb pain is uncertain, such as in case of typical claudication and normal or borderline ABI at rest.

Doppler ultrasound (DUS) is an imaging test with a sensitivity of 85–90% and a specificity > 95% to detect arterial stenosis > 50% [12] and is thus indicated as a first line method to confirm the diagnosis of LEAD. DUS is a simple and non-invasive technique providing anatomical and hemodynamic assessments of the vessels, and is also capable of assessing vein quality for bypass procedures. Furthermore, it is the test of choice for routine follow-up after revascularization. Besides, the test largely depends on the operator experience and good training is mandatory. Moreover, DUS is not able to provide a precise topographic diagnosis compared to other techniques, such as computed tomography angiography, magnetic resonance angiography and digital subtraction angiography (which is still considered the gold standard for the diagnosis of LEAD). Such imaging tests explore the roadmap of the entire vasculature and are thus to be considered in the pre-operative work-up. Nonetheless, certain limitations exist with the former techniques, due to the potential for artefacts, particularly in the presence of calcified plaques, which are quite frequent in diabetic patients.

Chronic limb-threatening ischemia: new concept for old entities

The burden of T2DM is increasingly predominant in CLTI: T2DM is associated to CLTI in 50-70% of cases, and the neuro-ischemic diabetic foot ulcers represent a relatively common entity in this context. In contrast to the former term ‘critical limb ischemia’, CLTI encompasses clinical patterns presenting with a threatened limb viability related to several factors, not limited to severe ischemia and including neuropathy, the presence and extent of wounds, infection and inflammation (often in combination). According to recent European guidelines, ‘critical’ implies that all patients have to undergo revascularisation on urgently to avoid limb loss, while some patients with CLTI may actually receive a conservative treatment for long periods, even in the absence of revascularisation. Moreover, the risk of amputation does not depend exclusively on the severity of ischemia, but also on the presence of a wound and infection. In this setting, the wound ischaemia and foot infection (WIFI) classification may be a useful tool, providing a risk stratification based on the severity of the wound, ischaemia, and foot infection [13].

How to treat lower extremity arterial disease in patients with type 2 diabetes

The management of LEAD in patients with T2DM requires a multidisciplinary team including vascular physicians and surgeons, diabetologists, infectious disease specialist, cardiologist, radiologist, rehabilitation specialist and podiatrist. In the light of the high risk of MALE and MACE in affected subjects, a strict control of CV risk factors should be strongly encouraged. When indicated, subjects with T2DM and concomitant LEAD should undergo lifestyle modifications including smoking cessation, dietary changes (favouring the Mediterranean diet), and exercise training (ideally supervised). Optimization of the antidiabetic therapy is a cornerstone in CV prevention and has to be achieved in each patient. A lipid-lowering drug (statin) should be also considered in this setting, in order to reach an LDL-cholesterol target of < 1.4 mmol/L and a reduction of at least 50% of LDL-cholesterol from baseline levels [14]. When present, arterial hypertension has to be treated to reach a SBP of 130 mmHg, and lower if tolerated. In older patients (aged ≥65 years) the SBP target range should be 130–140 mmHg if tolerated. In light of the well-known U-shape relationship between BP and CV events in general population, excessive lowering of BP should be avoided [15].

Current guidelines recommend the use of an antiplatelet monotherapy in subjects with symptomatic LEAD. The CAPRIE trial, which included 20% of participants with T2DM, showed reduction of the risk of LEAD-related events in participants assigned to clopidogrel 75 mg compared with those assigned to aspirin 325 mg [16], and this drug should be thus preferred in this context. Conversely, antithrombotic treatment is not currently indicated in asymptomatic patients, unless concomitant coronary or cerebrovascular disease. This is related to the results of two randomized trials, one after LEAD screening in general population, another in diabetic patients free of any known CV disease, where aspirin showed no benefit over placebo to reduce CV events.
Of note, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial study, which included 7470 patients with LEAD plus coronary artery disease or clinically manifest cerebrovascular disease, showed that rivaroxaban 2.5 mg combined with aspirin significantly decreased the occurrence of MACEs, lower limb ischaemia and major amputations compared with aspirin alone [17]. This pharmacological association may be particularly beneficial in diabetic patients with LEAD.

To date, there revascularization indications for LEAD do not differ according the diabetes status, and neither do the strategies (i.e. bypass surgery vs. endovascular therapy). According the guidelines, revascularization is mandatory as far as possible in case of CLTI, while it can also be considered in case of disabling IC, particularly if not improving after medical and exercise therapy. Contrasting findings were reported concerning perioperative outcomes in patients with T2DM undergoing revascularization [18]. Recent studies have shown similar peri- and post-operative mortality in subjects with T2DM compared with those without the disease. Nonetheless, the former had higher risks of incomplete wound healing and major amputation, prolonged length of hospital stay, and more frequent readmission.

The different options of revascularization largely depend on several factors, such as anatomical location and extension of arterial lesions, patients’ general condition and comorbidities, as well as surgeon experience. Treating distal lesions (i.e. infra-popliteal) is particularly challenging, and such an anatomical location has been reported to be more frequent in patients with concomitant T2DM than in those without the disease. Current ESC and ESVS guidelines recommends endovascular therapy as first choice for infra-popliteal stenotic lesions and short occlusions, while bypass with an autologous vein gives may be discussed for long occlusions [10]. However, endovascular therapy can be tried in patients with long occlusions if the surgical risk is considered as high, or in the absence of autologous vein.