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Overview of peripheral artery disease in patients with diabetes mellitus

Overview of peripheral artery disease in patients with diabetes mellitus
Literature review current through: Jan 2024.
This topic last updated: Aug 26, 2022.

INTRODUCTION — More than 170 million people worldwide have diabetes mellitus (DM), and this number is projected to increase to nearly 370 million people by 2030 [1]. DM is a major risk factor for all forms of cardiovascular disease, which is the most common cause of death for adults with DM [2]. DM is also a strong risk factor for peripheral artery disease (PAD), defined as atherosclerosis in lower extremity arteries [3-6]. Patients with DM and PAD have an increased risk of adverse cardiac and limb events and impaired quality of life [7]. Moreover, PAD causes significant long-term disability in patients with DM [8,9].

An overview of the clinical manifestations, diagnosis, and treatment of PAD in patients with DM will be reviewed here with the goal of providing a detailed summary of this important cardiovascular phenotype, who have a high risk for vascular complications.

The manifestations of PAD in the general population, treatment, and outcomes are discussed in separate topic reviews.

(See "Overview of lower extremity peripheral artery disease".)

(See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

(See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

(See "Management of claudication due to peripheral artery disease".)

(See "Management of chronic limb-threatening ischemia".)

(See "Endovascular techniques for lower extremity revascularization" and "Lower extremity surgical bypass techniques".)

EPIDEMIOLOGY AND RISK FACTORS — Peripheral artery disease (PAD) affects more than 8.5 million people in the United States, approximately one third of whom have comorbid diabetes mellitus (DM) [8-10]. The prevalence of PAD may be underestimated in the diabetic population due to the asymptomatic nature of less severe PAD and the often concomitant diabetic neuropathy [9,11-13]. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

Even before reaching a diagnostic threshold for DM, 20 percent of patients with dysglycemia alone have an abnormal ankle-brachial index (ABI) compared with only 7 percent of patients with normal glucose homeostasis [14]. The prevalence of DM increases with age, as does the prevalence of PAD in those with, as well as those without, DM. Among individuals with DM older than 70 years of age attending outpatient medical or vascular surgery clinics in Spain, PAD was detected by screening (ABI <0.90) in more than 70 percent [15]. Additionally, among patients with PAD undergoing lower extremity revascularization, approximately 50 percent have concomitant DM [16].

DM also increases the incidence of limb ischemia manifested as ischemic rest pain or ulceration among patients with PAD (figure 1) [17]. Among patients with DM who have chronic limb-threatening ischemia in one lower extremity, nearly one half will develop limb-threatening ischemia in the contralateral lower extremity within five years [18]. In addition to poor outcomes, patients with DM are more likely to have arterial disease distal to the knee compared with those without DM [19,20].

Risk factors — DM is a powerful risk factor for PAD and is second only to cigarette smoking in contributing to the magnitude of increased risk [21]. In a large, multinational meta-analysis, the presence of DM among participants in developed countries was associated with nearly a twofold increased odds for PAD (odds ratio [OR] 1.88, 95% CI 1.66-2.14) [21].

Advanced age, smoking, hypertension, dyslipidemia, and coronary heart disease are known risk factors for PAD. These traditional risk factors also confer significant risk for PAD among patients with DM and are discussed in detail separately. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

Diabetes-specific — A number of risk factors that specifically influence the occurrence of PAD in patients with DM, including diabetes duration, diabetes severity, sex, and race/ethnicity, are briefly reviewed below.

Duration – The duration of DM correlates with the incidence and extent of PAD [19,22]. This was shown clearly among 3834 participants in the United Kingdom Prospective Diabetes Study (UKPDS 59), which showed a higher prevalence of PAD among participants with longer durations of DM [23].

Diabetes severity – UKPDS 59 also showed that each 1 percent increase in HbA1c was associated with nearly a 30 percent increased risk of developing PAD during follow-up (OR 1.28, 95% CI 1.12-1.46) [23]. Other measures of DM severity, such as insulin use, may also be associated with prevalent PAD [4].

Diabetes and patient sex – On the basis of limited data, DM appears to be a more significant risk factor for females compared with males for the development of claudication [24]. In a review of the Framingham Study Cohort, DM in the presence of glycosuria increased the risk of claudication nearly ninefold in women compared with 3.5-fold in men [25]. No confidence interval or test for heterogeneity by sex was reported.

Diabetes and race/ethnicity – African American and Hispanic patients with DM have a higher prevalence of PAD compared with non-Hispanic White patients, even after adjustment for other known risk factors and the excess prevalence of DM [7,9]. Reasons for these potential racial/ethnic differences in the burden of PAD among patients with DM are unknown.

PAD risk is also associated with peripheral neuropathy [8]. Thus, individuals with DM may confuse PAD symptoms with a neuropathy, a common symptom of diabetes that manifests as a burning or painful discomfort of the feet or thighs.

Other risk factors — Other risk factors associated with PAD are discussed separately. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

Mechanisms of increased risk — The pathophysiology of PAD in the diabetic population is similar to that in the nondiabetic population [9] but is potentiated by the presence of concomitant DM. (See "Pathogenesis of atherosclerosis".)

DM is characterized by hyperglycemia, dyslipidemia, and insulin resistance. The underlying metabolic abnormalities in DM enhance vascular inflammation, endothelial dysfunction, vasoconstriction, platelet activation, and thrombotic risk, processes important to the pathogenesis of PAD among patients with DM [26].

Increased inflammation — Inflammation as measured by elevated levels of C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) is an established risk factor for systemic cardiovascular disease, including PAD [27,28]. DM is a hyperinflammatory state, with elevated levels of CRP and other markers of systemic inflammation [29]. Some of these inflammatory markers may also be important in PAD pathogenesis. As an example, CRP has procoagulant effects related to its enhancement of tissue factor expression [30]. Hyperglycemia from DM also leads to overproduction of mitochondrial reactive oxygen species via the protein kinase C (PKC) pathway, which in turn serves as a causal link between elevated glucose and major adverse vascular outcomes [31]. Once activated, PKC leads to structural and functional changes in the vasculature, including changes in cellular permeability, inflammation, angiogenesis, cell growth, extracellular matrix expansion, and apoptosis [32].

Endothelial dysfunction — Endothelial dysfunction is extremely common among patients with comorbid DM and PAD. In healthy blood vessels, endothelial cells synthesize nitric oxide (NO), which is a potent vasodilator that inhibits platelet activation and vascular smooth muscle cell migration [9]. Diabetic hyperglycemia induces an imbalance between NO bioavailability and accumulation of reactive oxygen species (ROS), leading to impaired vascular health [31,33-35]. Endothelial dysfunction in diabetes is also a result of increased synthesis of vasoconstrictors and prostanoids [34]. Mitochondrial ROS production also enhances advanced glycation end product (AGE) and AGE receptor (RAGE) signaling [31,36], in turn activating ROS-sensitive biochemical pathways that further induce endothelial dysfunction and vascular homeostasis [36,37].

Enhanced vasoconstriction — Enhanced protein kinase C (PKC) activity also leads to increased production of endothelin-1 (ET-1), leading to enhanced vasoconstriction and platelet aggregation [32]. Notably, endogenous ET-1 has enhanced vascular activity among patients with type 2 DM [38]. In the setting of diabetic hyperglycemia, increased PKC activity alters NO signaling and enhances vasoconstriction [31], two processes important in the pathogenesis of PAD [39].

Enhanced thrombosis — Among patients with DM, insulin resistance and hyperglycemia contribute to a prothrombotic state, characterized by increased platelet activation and coagulation [40,41].

Insulin resistance increases levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Patients with DM and poor glycemic control have high levels of PAI-1, and some studies have suggested that treatment with glucose-lowering agents such as glipizide and metformin decrease levels of PAI-1 [42]. In addition, hyperinsulinemia and hyperglycemia can act synergistically to increase monocyte expression of tissue factor, increasing procoagulant activity and thrombin generation [43,44].

Microparticles, which are vesicles released in the circulation from various cell types in response to apoptosis or activation, are increased in patients with DM and independently predict cardiovascular events in patients with stable coronary heart disease [45]. Microparticles also increase coagulant activity in the endothelial cells of patients with DM and promote thrombus formation at sites of injury [46]. Increased platelet-derived microparticles are also associated with PAD and may represent a pathway of shared pathogenesis for PAD risk among patients with DM [47].

Finally, platelet hyperreactivity likely has major relevance for macrovascular disease and PAD in those with DM. A number of mechanisms contribute to platelet dysfunction and hyperreactivity in DM [31], many of which may also play a role in the pathogenesis of PAD [47]. Hyperglycemia alters platelet-calcium homeostasis and increases secretion of factors that increase platelet aggregability [48]. Upregulation of glycoproteins Ib and IIb/IIIa among patients with DM interacts with von Willebrand factor and fibrin to trigger thrombogenesis [31].

CLINICAL MANIFESTATIONS AND DIAGNOSIS — The clinical manifestations of lower extremity atherosclerotic vascular disease (ie, peripheral artery disease [PAD]), which include claudication, rest pain, ulceration, and gangrene, are predominantly due to progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque or material can also occur. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Thromboembolism from aortic plaque".)

Single-level disease (ie, aortoiliac, superficial femoral) often manifests initially as claudication. Multilevel disease can also manifest as claudication, provided that sufficient collateral circulation develops. Some [49], but not all [19], studies suggested that patients with diabetes mellitus (DM) and PAD are less likely to present with typical claudication symptoms. While it may be challenging to discern differences in PAD symptomatology in patients with versus without DM, patients with DM tend to present with more advanced disease and have a worse prognosis. As an example, the rates of foot ulcers and lower extremity amputations are higher in PAD patients with DM compared with those who do not have DM [49,50]. In addition to presenting with more advanced disease, there may be anatomic differences in the vascular distribution of PAD that contribute to a worse prognosis. DM may be associated with more severe below-the-knee PAD (eg, popliteal, anterior tibial, peroneal, and posterior tibial) [8,19]. By comparison, risk factors such as smoking are associated with more proximal PAD in the aortoiliofemoral vessels.

It has also been reported that patients with PAD and comorbid DM experience worse lower extremity function compared with those with PAD alone [49]. Impaired lower extremity functioning is an important predictor of future disability, including mobility loss and nursing home placement. Thus, the patient with DM and PAD is a high-risk clinical phenotype who should be evaluated for comorbidities such as neuropathy, foot ulceration, or concomitant coronary heart disease that could contribute to disability [49].

Diagnosis — In patients with DM, a thorough history of physical activity will frequently identify patients with PAD risk factors or preexisting PAD. However, symptoms of leg pain, the development of ulcers, and functional impairments can be due to PAD or can be manifestations of diabetic neuropathy [8]. (See "Screening for diabetic polyneuropathy".)

For patients with an appropriate history and physical examination, the diagnosis of PAD is established with the measurement of the ankle-brachial index (ABI) [51]. The ABI is a comparison of the higher posterior tibial or dorsalis pedis systolic blood pressure in each leg divided by the higher of the right or left arm systolic blood pressure (SBP) [51]. An ABI ≤0.90 is sensitive and specific for arterial stenosis and is diagnostic for PAD [52], though additional testing may be warranted for patients with DM. For patients with appropriate symptoms and a normal ABI, an ABI following exercise testing may provide additional information. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Exercise testing' and "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Diagnosis of lower extremity PAD'.)

DM and other comorbid conditions such as chronic kidney disease may lead to calcification of the arterial wall, which can make the ankle artery incompressible and limit the measurement of systolic pressure at that location in spite of blood pressure cuff inflation even as high as 250 mmHg [51]. It is important to remember that vascular wall calcification does not imply that occlusive arterial disease is present, although these two conditions frequently coexist. However, when vascular calcification is present, stenotic vascular disease cannot be detected by ABI [53,54]. In this setting, other noninvasive tests such as measurement of the toe-brachial index (TBI) or Doppler waveform analysis may enable detection of occlusive disease despite a falsely elevated ABI [51]. Measurement of the TBI is useful in this setting because the digital vessels rarely develop calcification and can provide an accurate determination of vascular disease in the presence of vascular calcification [53,54]. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Toe-brachial index'.)

Screening — Many patients with DM and PAD have symptoms, which may be typical or atypical. In these situations, formal ABI testing is required to diagnose PAD [55]. Measuring an ABI among patients with DM and typical intermittent claudication or atypical lower extremity symptoms is endorsed in a white paper from the American Heart Association and a position statement from the American Diabetes Association [8,51]. There should be a very low threshold to obtain vascular studies in patients who develop any lower extremity symptoms that may be consistent with PAD, such as atypical leg pain or claudication, and it is mandatory in those with wounds that are slow to heal to determine whether arterial disease is a contributing factor (algorithm 1) [3,56]. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Diagnosis of lower extremity PAD'.)

The use of screening ABI among patients with DM without any symptoms or wound problems is controversial. There are no randomized trials comparing PAD screening versus no screening solely in DM [57]. The American Diabetes Association has recommended that a screening ABI should be performed in patients >50 years of age with DM and, if normal, should be repeated every five years [8]. The guideline further recommends consideration of screening ABI in patients with DM age <50 years with other PAD risk factors, such as smoking, hypertension, hyperlipidemia, or diabetes duration >10 years [8]. The American College of Cardiology/American Heart Association guidelines state that screening for PAD by ABI is reasonable among asymptomatic individuals over age 50 with DM, or less than age 50 with one additional cardiovascular disease risk factor, or who have known atherosclerosis in another vascular bed [3,58]. These broad screening criteria are considered justifiable given the noninvasive nature of ABI testing and the high prevalence of abnormal resting ABIs in asymptomatic high-risk patients, such as diabetes [58-61]. By contrast, the US Preventive Services Task Force Recommendation Statement suggested that since patients with DM or known risk factors or cardiovascular disease are already at high risk for cardiovascular disease (CVD) events, screening for PAD with an ABI is unlikely to alter effective management decisions and improve clinical outcomes [62].

MANAGEMENT — The management of patients with diabetes mellitus (DM) and peripheral artery disease (PAD) is similar to the management of patients with PAD without DM and is focused on relieving symptoms and lowering the risk of cardiovascular disease progression and complications. This will necessarily take into account managing comorbid DM and other medical comorbidities, compliance with pharmacologic treatments and follow-up care, along with the subjective values and goals of the individual patient.

Risk factor modification — PAD and DM are both regarded as risk equivalents for coronary heart disease. We agree with major cardiovascular practice guidelines for the management of both DM and PAD (asymptomatic or symptomatic) that recommend secondary prevention strategies to reduce the risk of future cardiovascular events for patients with either DM or PAD [58,63].

An aggressive approach to risk factor modification is warranted in patients with diabetes and PAD. A subgroup analysis of the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial evaluated outcomes in 5345 patients with diabetes (mostly type 2) and PAD compared with PAD alone [64,65]. Patients with PAD and diabetes had a higher composite risk of major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, and ischemic stroke), all-cause mortality, and adverse limb events in spite of risk reduction therapies, including statins, blood pressure–lowering medications, and antiplatelet therapy. The risk for major amputation was increased by 96 percent, the risk for lower extremity revascularization was increased by 25 percent, and the risk for carotid revascularization was increased by 35 percent. Each 1 percent increase in glycated hemoglobin (HbA1c) increased the risk for MACE by 14 percent. However, the association between HbA1c and major amputation was not statistically significant.

Domains of risk factor modification to improve PAD outcomes and reduce risk of incident cardiovascular disease risk include smoking cessation, antiplatelet therapy, lipid-lowering therapy, blood pressure control, diet and exercise, as well as care of the foot and lower extremity. These domains of risk factor modification are relevant for all patients with PAD. (See "Overview of lower extremity peripheral artery disease", section on 'Risk factor modification'.)

We will focus herein on data supporting practices to improve PAD and coronary heart disease outcomes for patients with comorbid DM and PAD.

Smoking cessation — We agree with consensus guidelines that recommend smoking cessation for all PAD patients [58] and believe these recommendations also apply to patients with both PAD and DM. Numerous epidemiological and observational studies have shown that smoking cessation reduces adverse cardiovascular events and the risk for limb loss in patients with PAD. Tobacco use is a strong risk factor for the development and progression of PAD [66]. There is also evidence that among patients with a recent myocardial infarction, the benefits of smoking cessation were similar for those with and without DM [67]. Data have also shown that weight gain associated with smoking cessation, even among patients with DM, does not significantly attenuate the reduction in cardiovascular risk observed with smoking cessation [68].

Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (varenicline, bupropion, and/or nicotine replacement) and/or referral to a smoking cessation program. In a trial of 124 probable smokers with PAD, participants randomly assigned to receive PAD-specific smoking cessation counseling were more likely to be confirmed abstinent at six months than participants assigned to usual care (21.3 versus 6.8 percent) [69]. Two meta-analyses of randomized trials of smoking cessation medications showed no evidence of increased cardiovascular event rates with nicotine replacement, bupropion, or varenicline [70,71]. (See "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults".)

Antithrombotic therapy — Based upon randomized trials demonstrating a reduction in incident cardiovascular events, we agree with major cardiovascular consensus guidelines recommending long-term antiplatelet therapy for patients with symptomatic lower extremity PAD [58]. Similarly, we also agree with recommendations for long-term antiplatelet therapy for patients with diabetes mellitus (DM) age ≥50 years with risk factors for cardiovascular disease (CVD) or younger DM patients with prior CVD [26,72]. We do not routinely recommend the use of dual antiplatelet therapy for patients with DM and PAD in the absence of other indications (eg, drug-eluting stent) given the increase in bleeding and the absence of proven benefit.

In a meta-analysis of 18 trials comprising nearly 5300 patients with PAD (symptomatic and asymptomatic), aspirin therapy alone or in combination with dipyridamole was associated with nonsignificant reduction in the primary endpoint (composite of nonfatal myocardial infarction [MI], nonfatal stroke, and cardiovascular death) but a significant reduction in the secondary outcome of nonfatal stroke (relative risk [RR] 0.66; 95% CI 0.47-0.94) [73]. There have been two randomized trials of aspirin that predominantly enrolled patients with PAD and DM: one was limited to patients with DM and asymptomatic PAD [74], and in the other (Critical Leg Ischemia Prevention Study [CLIPS]), a majority of trial participants (approximately 80 percent) had symptomatic PAD [75]. Aspirin treatment was not associated with a benefit in patients with DM and asymptomatic PAD [74]. The CLIPS trial demonstrated a benefit of aspirin (100 mg daily) compared with placebo for preventing vascular events, but the study was too small to derive meaningful conclusions [58,75]. The use of other antiplatelet agents (clopidogrel, ticagrelor, vorapaxar) for use in the general PAD population is reviewed elsewhere. (See "Overview of lower extremity peripheral artery disease", section on 'Antithrombotic therapy'.)

The evidence to support the use of these agents among patients with DM and PAD is summarized as follows:

In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg/day) had a modest but significant benefit over aspirin (325 mg/day) for reducing the risk of the combined outcome of ischemic stroke, myocardial infarction (MI), or vascular death among patients with a recent stroke, MI, or symptomatic PAD [76]. The benefit of clopidogrel was driven largely by the subgroup of patients with PAD [76]. Among the 19,185 patients in CAPRIE, there were 3866 patients with DM. Subgroup analyses suggested that patients with DM in CAPRIE, and particularly those DM receiving insulin, derived a greater benefit from clopidogrel than from aspirin for the trial composite outcome plus rehospitalization for ischemia or bleeding [77].

In the PEGASUS-TIMI 54 trial, 21,162 patients with an MI one to three years prior to enrollment were randomly assigned to ticagrelor 60 or 90 mg twice daily or placebo, all on a background of low-dose aspirin [78]. Among PAD patients with prior MI (1142 patients, 5 percent of total), ticagrelor significantly reduced the absolute rate of major adverse cardiovascular events (MACE) by 4.1 percent. The 90 mg dose of ticagrelor also significantly reduced the risk of peripheral revascularization (hazard ratio [HR] 0.63, 95% CI 0.43-0.93). However, a 0.12 percent absolute excess of major bleeding with ticagrelor was also observed [79]. Subgroup analyses of patients with DM in PEGASUS also demonstrated reductions in the primary endpoint with the use of ticagrelor. As patients with DM were at higher risk of MACE compared with participants without DM, the absolute risk reduction with ticagrelor tended to be greater in patients with DM (absolute risk reduction of 1.9, 1.5, and 1.1 percent for patients with DM requiring medication, all DM patients, and patients without DM, respectively) [80]. The benefits of ticagrelor on major adverse limb events (MALE) was observed in the Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS trial) which examined DAPT (dual antiplatelet therapy) with ticagrelor in patients with diabetes and coronary disease [81]. In THEMIS, 1687 participants had concomitant CAD and PAD. Dual antiplatelet therapy with aspirin and ticagrelor had a consistent reduction in MACE for participants with DM and CAD, with and without concomitant PAD, and showed an approximately 50 percent reduction in MALE for the overall study population (HR 0.45, 95% CI 0.23-0.86).

Vorapaxar is a novel antagonist of protease-activated receptor (PAR-1), which is located on platelets, vascular endothelium, and smooth muscle and is the primary receptor for thrombin on human platelets [82]. In the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50), among patients with symptomatic PAD, vorapaxar reduced the rate of first acute limb ischemia events, particular among those with prior revascularization [83-85]. There was also limited evidence that patients with DM and a prior MI were more likely to benefit from PAR-1 antagonism than MI patients without DM [86]. Data are lacking on prespecified comparisons of vorapaxar use among PAD patients with versus without DM. However, since DM is associated with a fourfold increase in limb-threatening ischemia [17], and vorapaxar may reduce the rate of first acute limb ischemia [83], PAR-1 antagonism may be a useful therapeutic option for patients with DM and PAD.

Whether there is a benefit for other anticoagulant formulations versus antiplatelet therapy for patients with DM and PAD has not been established [87,88]. For the overall PAD population, routine anticoagulation using warfarin in addition to aspirin does not reduce cardiovascular events including mortality and is associated with an increase in life-threatening bleeding [89]. There is a paucity of data on the use of warfarin in addition to aspirin for patients with DM and PAD.

Data suggest a benefit for combined aspirin and low-dose rivaroxaban (a direct oral anticoagulant) for individuals with PAD, including those with DM, although with an increased risk for bleeding. A multicenter international trial randomly assigned over 27,000 patients with stable coronary heart disease or PAD to a low dose of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily), rivaroxaban (5 mg twice daily) plus placebo, or aspirin (100 mg daily) plus placebo [87]. At a mean follow-up of 23 months, rivaroxaban plus aspirin significantly reduced cardiovascular mortality and ischemic stroke compared with aspirin alone. In a prespecified subgroup analysis among nearly 7500 participants with PAD, rivaroxaban plus aspirin reduced the composite of cardiovascular death, myocardial infarction, or stroke compared with aspirin alone (HR 0.72, 95% CI 0.57-0.90) along with major adverse limb events (1 versus 2 percent; HR 0.54, 95% CI 0.35-0.82) [88]. This benefit was similar for PAD patients with DM (HR 0.69, 95% CI 0.53-0.91) compared with those without DM (HR 0.69, 95% CI 0.50-0.94).

In another large international trial, 6564 patients with symptomatic PAD who underwent successful lower extremity revascularization within the preceding 10 days were randomly assigned to rivaroxaban 2.5 mg twice daily plus aspirin or placebo plus aspirin (VOYAGER-PAD) [90]. Approximately 40 percent of patients in VOYAGER-PAD trial had DM. Clopidogrel could be administered for up to six months after revascularization at the discretion of the investigator and was used in 51 percent of participants at baseline. At a median of 28 months of follow-up (interquartile range 22 to 34), use of rivaroxaban plus aspirin significantly reduced the primary efficacy outcome (composite outcome of acute limb ischemia, major amputation for vascular causes, stroke, myocardial infarction or cardiovascular death) compared with placebo plus aspirin (17.3 versus 19.9 percent; HR 0.85, 95% CI 0.79-0.96). There was no observed heterogeneity of treatment effect with rivaroxaban for participants with compared to without diabetes mellitus. While the incidence of thrombolysis in myocardial infarction major bleeding did not differ between groups, the incidence of International Society on Thrombosis and Haemostasis bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone (6 versus 4 percent; HR 1.42, 95% CI 1.10-1.84).

Lipid-lowering therapy — Lipid-lowering therapy with at least a moderate dose of high-intensity statin, regardless of baseline low-density lipoprotein (LDL) cholesterol, is recommended for all patients with atherosclerotic cardiovascular disease [91]. The evidence for benefit and the appropriate goals for cholesterol lowering in patients with all forms of cardiovascular disease are discussed in more detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Examples of a reduction in cardiovascular outcomes with the use of statin therapy among patients with PAD include the following:

Among nearly 6800 participants in the Heart Protection Study with PAD, there was a 22 percent relative risk reduction in a first major vascular event for those randomized to simvastatin 40 mg compared with placebo [92]. The absolute reduction in first major vascular event was 63 (standard error [SE] 11) per 1000 patients with PAD and 50 (SE 7) per 1000 without preexisting PAD.

Despite guidelines recommending high-intensity statin use for all adults with apparent atherosclerotic cardiovascular disease [91], evidence was lacking to support the use of high-intensity statins for patients with PAD. An observational cohort analysis from the Veterans Health Administration found that high-intensity statin use at the time of PAD diagnosis is associated with significant reduction in limb loss and mortality in comparison with low-to-moderate-intensity statin users [93]. In this population, the benefit associated with high-intensity statin use was similar for patients with PAD with and without DM [93].

Similar findings for a reduction in limb loss and mortality with high-intensity statin use were observed in a study of patients with chronic limb-threatening ischemia [94]. In this retrospective study of 931 patients (1019 affected limbs) undergoing first-time revascularization (endovascular or surgical), high-intensity statin therapy was associated with lower mortality (HR 0.73, 95% CI 0.60-0.99) and lower rate of major adverse limb events (HR 0.71, 95% CI 0.51-0.97) compared with PAD patients receiving lower-intensity dose statins.

There is also robust evidence for cardiovascular risk reduction with statins, including high-intensity dosing, for patients with DM with and without preexisting cardiovascular disease [95-97]. Thus, we suggest that all patients with PAD and DM should be treated with the maximum tolerated dose of a high-intensity statin (eg, rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg daily) [91]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Lipid management'.)

Finally, there are emerging data that lipid lowering with evolocumab, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, may be highly beneficial for patients with PAD [98]. FOURIER was a randomized trial of evolocumab versus placebo in 27,564 patients with established atherosclerotic disease on statin therapy that demonstrated a significant reduction in a composite cardiovascular outcomes compared with placebo over 2.2 years [99]. A prespecified secondary analysis of the 3642 patients with PAD at baseline (1505 with no prior myocardial infarction or stroke) demonstrated consistent reductions in the primary composite outcome (cardiovascular death, myocardial infarction, stroke, admission for unstable angina, or coronary revascularization) associated with the use of evolocumab among patients with PAD (HR 0.79, 95% CI 0.66-0.94) and without PAD (HR 0.86, 95% CI 0.80-0.93) [98]. In addition to significant reductions in the key secondary endpoint of cardiovascular death, myocardial infarction, or stroke, evolocumab reduced the risk of major adverse limb events in all patients (HR 0.58, 95% CI 0.38-0.88) with consistent effects in those with and without known PAD [98]. This analysis from FOURIER demonstrated that the addition of a non-statin low-density lipoprotein cholesterol (LDL-C) lowering to statin therapy reduces major adverse limb events in patients with symptomatic PAD, along with patients with symptomatic coronary or cerebrovascular disease, and that the benefits on lower extremity vasculature extend to very low achieved LDL-C [98].

In one other study of non-statin lipid-lowering treatment with fenofibrate versus placebo among individuals with type 2 DM and PAD, prior amputation or neuropathy demonstrated a significant 36 percent reduction in amputations over five years, likely via non-LDL-C mechanisms [100].

Glycemic control — Although it is unknown whether aggressive serum glucose control decreases the likelihood of adverse cardiovascular events among patients with PAD and DM, treatment of DM can be effective for reducing complications. We agree with recommendations for control of blood glucose levels with an HbA1c goal <7.0 percent [101]. Less stringent goals may be appropriate for some patients (eg, older patients, and those with multiple comorbid medical conditions). (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Cardiovascular outcomes trials with two new classes of agents, the sodium-glucose co-transporter 2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), have demonstrated reductions in cardiovascular events, including mortality, primarily for patients with DM and cardiovascular disease. In preclinical models, GLP1-RAs lowered vascular expression of proinflammatory pathways, improved endothelial function, and inhibited platelet aggregation and atherosclerosis [102-104]. GLP1-RAs lower glucose through a different mechanism. Cardiovascular outcomes trials for both SGLT2-i [105,106] and GLP1-RA [107,108] have included DM patients with PAD. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)

Cardiovascular outcomes and the safety of SGT2-i use among DM patients with PAD has proven to be of particular interest.

The CANagliflozin cardioVascular Assessment Study (CANVAS) Program identified safety concerns for amputations, collected as an adverse event of special interest (HR 1.97, 95% CI 1.41-2.75), and fractures (any fracture HR 1.26, 95% CI 1.04-1.52) [106,109]. The amputations in the CANVAS program were primarily below the ankle (ie, toe, transmetatarsal amputation) and occurred more often in those with a prior history of PAD or prior amputation. Similar findings were observed in a population-based cohort study involving over 25,000 patients with type 2 DM from the United States Department of Defense Military Health System [110]. The authors observed a consistent twofold risk of below-the-knee amputation, with the greatest absolute risk occurring among patients with established PAD [111,112]. Canagliflozin was used in 58.1 percent of patients in this study, with 26.4 and 15.5 percent on empagliflozin and dapagliflozin, respectively [110]. As this study was not powered to make comparisons among individual treatments, it could not evaluate whether below-the-knee amputation risk extended across the SGLT2-i medication class.

Data from other SGLT2 inhibitor cardiovascular outcome trials have not indicated an increased risk of amputation [113-116].

Results from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, also evaluating canagliflozin versus placebo, did not show an increased risk of amputation among 4401 participants with DM and albuminuric chronic kidney disease with an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m2 [113]. Approximately 24 percent of participants in CREDENCE had a clinical diagnosis of PAD at baseline.

In addition, among the 1461 participants with PAD at baseline in EMPA-REG, empagliflozin had consistent, significant reductions in cardiovascular and all-cause mortality, along with composites of major adverse cardiovascular outcomes [114]. There was no significant difference in any or major amputations for patients receiving empagliflozin compared with placebo among patients with or without PAD at baseline. There was also no increase in the risk of amputation observed with dapagliflozin compared to placebo in The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction (DECLARE-TIMI) 58 [115].

Similar findings were observed when the use of dapagliflozin was examined among patients with and without PAD in DECLARE-TIMI 58 [116]. Among the 17,160 patients with DM and cerebrovascular disease included in DECLARE-TIMI 58, 1025 (6 percent) had PAD. Compared with those without PAD, participants with PAD were at higher risk for adverse events including cardiovascular death, heart failure, and progression of kidney disease. Participants with versus without PAD were at higher risk for major adverse limb events, there were no significant differences in any ischemic limb adverse events with dapagliflozin versus placebo with no significant interaction by history of PAD.

The observed effects on vascular function and platelet aggregation from preclinical studies may translate into the benefits for ischemic outcomes for GLP1-RA [107,108]. Ongoing studies are evaluating whether the vascular effects of GLP1-RA translate into improved functional outcomes for patients with PAD and diabetes (NCT04560998).

Post-hoc subgroup analysis from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER trial) showed that liraglutide significantly reduces the risk of amputation by approximately 35 percent (HR 0.65, 95% CI 0.45-0.95) [117]. Further outcomes come from an analysis of patients with DM and PAD receiving placebo or either liraglutide or semaglutide, respectively, from LEADER and Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6). Overall, 1184/9340 (12.7 percent) patients in LEADER and 460/3297 (14 percent) in SUSTAIN 6 had DM and comorbid PAD at baseline. The effects of both therapies on MACE appeared beneficial in patients with PAD. The absolute risk reduction for MACE was higher for patients with DM with compared to without comorbid PAD [118].

In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL trial [119]), there were 2800/14,752 (18.9 percent) with PAD at baseline. Patients with DM and comorbid PAD in EXSCEL had a higher adjusted hazard ratio ([aHR] 1.13, 95% CI 1.00-1.27) for MACE compared with patients without PAD. Patients with DM and PAD in EXSCEL more frequently underwent lower extremity amputation (aHR 5.48, 95% CI 4.16-7.22). However, patients treated with exenatide or placebo had similar rates of MACE and lower extremity amputation, regardless of PAD status [120].

Antihypertensive therapy — Hypertension is a major risk factor for PAD. We agree with current PAD guidelines that target blood pressure, and selection of antihypertensive therapy should be consistent with current published guidelines for hypertension management [58,121].

Concerns have been raised that antihypertensive therapy may worsen limb perfusion. However, a number of studies have demonstrated that blood pressure treatment, including the use of beta blockers, does not appear to worsen claudication or impair functional status for patients with PAD [122,123].

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET) trial was a study that compared telmisartan, ramipril, and combination therapy in patients with cardiovascular disease, including PAD and/or DM. The efficacy of telmisartan was similar in the 3468 patients with PAD and for patients with and without DM [124].

Diet and exercise — Healthy diets are associated with lower cardiovascular disease events. Guidelines from the American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Cardiology (ESC) on lifestyle management are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Lifestyle management is also crucial for reducing vascular risk among patients with DM. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "Management of claudication due to peripheral artery disease", section on 'Exercise therapy'.)

Evaluation and care of the diabetic foot — Foot problems are an important cause of morbidity and mortality in patients with DM. Evaluation of the diabetic foot may also reveal underlying PAD and prompt earlier diagnosis and management. These issues are discussed separately.

(See "Evaluation of the diabetic foot".)

(See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)

(See "Management of diabetic foot ulcers".)

REVASCULARIZATION — Revascularization, either via a surgical or endovascular approach, is an important therapeutic option for treatment of symptomatic peripheral artery disease (PAD) in patients with diabetes mellitus (DM) [9]. The overall volume of endovascular procedures has increased significantly among patients with DM and foot ulcer, while open surgical bypass has decreased [125]. Among patients undergoing lower extremity revascularization, prevalent DM is an independent risk factor for major limb amputation and six-month hospital readmission [16].

Overall strategies for revascularization in patients with PAD are discussed in detail separately. Based upon the available data comparing outcomes in patients with and without DM, there does not appear to be any obvious subset of patients with DM for whom revascularization strategies should differ. Medical optimization including control of cardiovascular risk factors and glycemic control is important prior to revascularization. (See "Overview of lower extremity peripheral artery disease", section on 'Revascularization'.)

(See "Management of claudication due to peripheral artery disease" and "Approach to revascularization for claudication due to peripheral artery disease".)

(See "Management of chronic limb-threatening ischemia".)

(See "Endovascular techniques for lower extremity revascularization" and "Lower extremity surgical bypass techniques".)

Patency — Most data for surgical bypass (vein conduit) show no difference in patency between those with and without diabetes; however, for endovascular therapy, DM has an adverse impact on patency [126-131].

Reduced patency rates may, in part, be due to the more distal distribution disease in patients with DM and PAD, which tends to be more severe in arterial vessels below the knee, and which can be difficult to access from an endovascular approach. This finding may also be due to the quality of runoff. In a review of 127 iliac and femoropopliteal angioplasties, among patients with good runoff, patency rates were comparable to those without DM [132].

The relationship between glycemic control and lower extremity patency after revascularization has been evaluated, but data remain limited. A single-center, retrospective study divided patients with DM undergoing infrapopliteal balloon angioplasty into two groups based on median preprocedure fasting blood glucose (FBG) [133]. At one year of follow-up, freedom from restenosis or reintervention was significantly lower for those with FBG above versus below median FBG values (16 versus 46 percent) [133]. Amputation rates also trended higher among patients with high preprocedure FBG compared with low FBG.

The prevalence of DM among patients with limb-threatening ischemia is extremely high, with some estimating a prevalence over 75 percent, and it will usually require revascularization [9]. Data suggest that surgical and endovascular approaches with percutaneous transluminal angioplasty (PTA), with or without stenting, are associated with similar outcomes with regard to amputation-free survival or repeated target extremity revascularization [134]. Additional studies have shown that patients with DM and chronic limb-threatening ischemia treated with an aggressive multidisciplinary approach have limb salvage outcomes similar to the patients without DM [135].

Amputation — A program of preventive foot care and intervention when needed (eg, infection drainage, podiatric surgery, revascularization) can help prevent many major amputations. However, for some, amputation may represent an acceptable option for patients with a prolonged course of treatment and prognosis for a poor vascular and functional outcome after the procedure. Amputation is also indicated in the presence of severe infection threatening the life of the patient, or when the extent of ischemic tissue necrosis of the lower extremity is such that a functional foot is no longer salvageable [9]. (See "Lower extremity amputation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease" and "Society guideline links: Diabetes mellitus in adults".)

SUMMARY AND RECOMMENDATIONS

Peripheral artery disease (PAD) is more prevalent among patients with diabetes mellitus (DM) than in the general population. The clinical manifestations of PAD are largely similar in patients with and without DM. Limited data suggest that patients with DM may be more likely to be asymptomatic or have atypical symptoms leading to more severe disease at initial clinical presentation. Patients with DM also have an increased risk for limb loss. (See 'Epidemiology and risk factors' above and 'Clinical manifestations and diagnosis' above.)

Our recommendations align with American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommending screening ankle-brachial index (ABI) in subjects with diabetes age 50 to 64 years or <50 years and with at least one additional risk factor for atherosclerosis. Since patients with DM have an increased risk for cardiac and PAD morbidity and mortality, screening patients with DM for PAD may be considered, if therapy will be modified based on the results of the screening test. When symptoms do occur, there should be a low threshold to obtain vascular studies to evaluate for ischemia. (See 'Screening' above and "Screening for lower extremity peripheral artery disease".)

DM is an established risk factor for cardiovascular disease. As such, cardiovascular risk reduction strategies (smoking cessation, lipid-lowering therapy, antihypertensive therapy, glycemic control, diet and exercise) are recommended to reduce the risk for future cardiovascular events, including limb-related events. (See 'Risk factor modification' above and "Overview of established risk factors for cardiovascular disease".)

Long term antithrombotic therapy using aspirin (75 to 100 mg/day) or clopidogrel (75 mg daily) is recommended for all patients with PAD, including those with DM, to reduce the risk of overall cardiovascular events and death unless contraindications exist. We do not routinely recommended dual antiplatelet therapy (DAPT) for patients with DM and PAD, unless there is a clear indication such as coronary or peripheral arterial intervention. (See 'Antithrombotic therapy' above.)

Indications for revascularization (ie, angioplasty/stenting, surgical bypass) for patients with DM and PAD are no different compared with the general population. The nature of the intervention may differ since the distribution of lower extremity atherosclerosis differs with patients with DM tending to have severe occlusive disease in arterial vessels below the knee. In addition, patients with DM and chronic limb-threatening ischemia may require multiple revascularization procedures to achieve outcomes comparable to patients without DM. (See 'Revascularization' above.)

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Topic 17035 Version 13.0

References

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