peripheral arterial disease ( pad ) in people with type 2 diabetes mellitus ( t2 dm ) exhibits broad clinical characteristics and various consequences and is known as one of the major macrovascular complications of t2 dm , the prevalence of which is on the rise .
atherosclerosis is recognized as the most direct and important cause of pad , but acute or chronic limb ischemia may be induced by various risk factors . due to the increasing number of patients who undergo peripheral vascular procedures due to the aging of the overall population , the worldwide increase in t2 dm prevalence , and developments in medical technologies , the number of subjects who are exposed to the risks for pad and related complications is on the rise . in this review
, we will discuss the clinical and epidemiologic characteristics of pad , as well as the clinical significance of pad in t2 dm subjects .
pad is a general term for all vascular diseases that lead to abnormal function and structure of the aorta , its branches , and the lower - limb arteries secondary to atherosclerosis and thromboembolism - related pathophysiologies .
typically , atherosclerosis decreases the size of the vascular lumen , leading to deficiencies in arterial perfusion without noticeable symptoms .
however , depending on the degree of obstruction , various symptoms , including claudication , resting pain , ulceration , or gangrene , may occur during exercise .
the fontaine and rutherford classifications are the most well - known systems , under which increased stage describes severe symptoms ( table 1 ) .
depletion of effective vascular volume by thrombosis , embolism , dehydration , and shock may be a cause of acute exacerbation of pad .
this acute arterial occlusion is a fatal disease that requires emergent manipulations , such as amputation .
but , most studies on the prevalence of pad among general populations used a low ankle - brachial index ( abi , 0.9 ) as a surrogate for pad . from the analyses of national health and nutrition examination survey 1999 to 2004 in the united states , prevalence of low abi was 5.9% , corresponding 7.1 million adults with pad . excluding subjects with known cardiovascular disease , prevalence was 4.7% . similarly , a total of 5.8% of the united states population age 40 years had a low abi or history of lower - extremity revascularization , representing 6.8 million people .
prevalence of pad was known diverse by ethnicity , with black people having the highest age - adjusted prevalence of low abi .
prevalence of low abi is known to increase with age . in one study , prevalence of low abi
was 1.9% in the age group of 40 to 59 years , 8.1% in the group of 60 to 74 years , and 17.5% in the group of 75 years .
although pad is presumed to be more common in men , the prevalence of low abi does not estimated to vary significantly by gender .
the pad prevalence in t2 dm subjects is unclear , but in the framingham heart study , 20% of symptomatic pad subjects also exhibited diabetes . according to the the prevention of progression of arterial disease and diabetes ( popadad ) study , 20.1% of 40-year - old patients with diabetes were associated symptoms exhibited pad .
however , given that a large number of pad patients are asymptomatic , it is assumed that more subjects with diabetes exhibit pad . in the study conducted with 6,880 german people
whose age 65 years , the prevalence of pad by low abi in diabetes subjects was 26.3% ; whereas , prevalence of pad in non - diabetic subjects was 15.3% .
in korea , there has been no epidemiologic study on the prevalence of pad in the total population , although a study was conducted in 14 university hospitals with approximately 1,400 50-year - old t2 dm subjects exhibiting risk factors for pad . in this study , 11.9% of the subjects
, there were some epidemiologic evidences which have investigated mainly in the university hospitals in korea . in the previously diagnosed patients with coronary artery disease or cerebrovascular disease , prevalence of pad by low abi was estimated to be 7.8% . in the prospective study among subjects with acute ischemic stroke or transient
additionally , prevalence of pad by low abi was 12.8% in the patients with previous percutaneous coronary intervention .
dyslipidemia , smoking , hypertension , and diabetes are known risk factors of pad , similar to coronary artery disease .
these risks increase in patients who are 70-year - old ; in those who are 50- to 69-year - old with a history of diabetes or smoking ; and in patients 40- to 49-year - old with diabetes and one or more atherosclerosis - related risk factor(s ) , intermittent claudication , abnormalities in pulse palpation of the lower limb or atherosclerosis in non - peripheral arteries ( e.g. , coronary , carotid , and renal artery ) . when a symptom of claudication appears , the symptom becomes aggravated in approximately 10% to 20% of patients in 5 years and advances to critical limb ischemia ( cli ) in 1% to 2% of patients .
the clinical progression of pad patients with diabetes is worse than that of those who are not .
lesions occur over a wider range of vasculature ; the frequency of amputation was higher ; and there was a significant difference in mortality . in the results from multicenter study conducted by asian subjects with type 2 diabetes , obesity , smoking , duration of diabetes and previous cardiovascular disease were identified as independent risk factors of pad .
non - fatal myocardial infarction ( mi ) or stroke occurs in 20% of patients , and 15% to 30% of patients were died . in the results from domestic study , subjects with previous history of coronary artery disease or cardiovascular disease had significantly higher prevalence of diabetes , dyslipidemia , renal insufficiency , and pad with claudication .
cli occurs in both lower limbs in 50% of patients at 1-year follow - up .
cli is accompanied by lower limb amputation in 25% and by cardiovascular disease in 25% .
the abi is the standard for the diagnosis of pad in clinical treatment or epidemiologic studies and represents a useful resource for the salvage of the lower limb , wound healing and survival prediction of patients .
abi is calculated as the ratio of systolic blood pressure in the brachial artery to that in the posterior tibial artery after resting in a supine position , which is considered abnormal when it is below 0.90 . when the diagnostic threshold was set to 0.90 , the sensitivity of abi for the diagnosis of pad with > 50% stenosis was 95% , and its specificity was 100% .
an abi between 0.41 and 0.90 is evaluated as a mildly to moderately decreased blood flow , and an abi < 0.40 is evaluated as severely decreased blood flow . in the recent meta - analysis , the pooled sensitivity and specificity of abi 0.90 for pad diagnosis were 75% and 86% and the pooled platelet lymphocyte ratio and neutrophil lymphocyte ratio were 4.18 and 0.29 , respectively .
these results may means that abi is useful for identifying serious stenosis in clinical practice .
however , in patients with diabetes , patients with distal lesions in elderly patients , and patients with mild stenosis less than 75% , diagnostic value of abi was decreased .
angiography is the most accurate test to examine vascular anatomy and pathology   and is , considered an essential evaluation tool prior to surgical management .
however , because angiography is an invasive procedure , risks such as bleeding , infection , and rupture as well as side effects associated with contrast media , such as hypersensitivity reaction and nephrotoxicity , may occur . in recent years , non - invasive imaging technologies have been developed , and ultrasound , multidetector computed tomography ( mdct ) and magnetic resonance ( mr ) angiography have been widely used .
such non - invasive imaging modalities had reported comparable diagnostic and prognostic accuracy to conventional angiography . in meta - analyses ,
sensitivity for detecting more than 50% stenosis or occlusion in mdct was estimated 95% , and its specificity was 96% , and sensitivity for diagnosing segmental steno - occlusions for mr angiography was estimated 94.7% and specificity was 95.6% . however , several limitations were also reported .
we could observe decreased accuracy by intestinal gas , and decreased sensitivity in multivessel lesion in ultrasound imaging . in mdct images , the risk of contrast media induced nephrotoxicity is well known in the subjects with chronic kidney disease .
moreover , utility of mr angiography is limited for detection of in - stent restenosis , and risk of gadolinium induced nephrogenic systemic fibrosis is also concerned in the subjects with chronic kidney disease .
the diagnosis of pad necessitates the regulation of associated risk factors , medical treatment , and intervention of lesions in the lower limb .
the management of risk factors of pad is similar to the regulation of risk factors of disease in the coronary artery .
exercise is known to be effective for the improvement of symptoms of claudication , the extension of walking distance to the aggravation of pain and the promotion of maximum oxygen consumption . walking exercise
is typically recommended , and patients are asked to partake in this exercise at least three times a week for 30 to 45 minutes for 12 weeks or more .
a systematic review identified that compared exercise with usual care or placebo , exercise improved walking ability from 50% to 200% , and significantly improved maximal walking time , pain - free walking distance , and maximum walking distance .
the cumulative proportions with mis after 10 years were 11% and 53% ; the cumulative rates of cardiac deaths 6% and 43% ; and the 10-year survival 82% and 46% among non - smokers and smokers , respectively . for patients who have difficulty in stopping smoking on their own , varenicline , bupropion , and nicotine replacement therapy
the management of associated diseases , such as diabetes , high blood pressure , and dyslipidemia , has an important impact on the clinical progress of pad .
in particular , meticulous foot care to prevent aggravation , crucial for clinical progress in diabetic patients , is recommended . in diabetic patients ,
the general goal of blood glucose regulation is to achieve glycosylated hemoglobin < 7% , but the goal of treatment is individualized for each patient 's characteristics .
no controlled trials have directly evaluated the effects of glucose lowering on the natural history of pad .
the goal hypertension therapy is to achieve blood pressure below 140/90 mm hg , and the use of angiotensin - converting enzyme inhibitor is preferentially considered .
there are no data evaluating whether treatment of hypertension alters aggravation in patients with pad .
nevertheless , hypertension should be controlled in such patients to reduce morbidity from cardiovascular disease .
the use of statins for dyslipidemia regulation is preferentially considered , which may be combined with fibric acid derivatives . in a systemic review , specifically evaluated patients with lower limb pad concluded that lipid - lowering therapy reduced disease progression , helped alleviate symptoms , and improved total walking times and pain - free walking distance .
there is an insufficient evidence to suggest a direct relationship between the use of antiplatelet agents and increases in pain or walking distance , but such agent have been proven to be significantly effective in decreasing the incidence of mi , stroke , or cardiovascular death ; thus , low - dose aspirin ( 75 to 325 mg / day ) is typically recommended .
a systematic review found a similar reduction in mortality for patients with claudication treated with antiplatelet therapy compared with placebo .
clopidogrel is a secondary drug recommended if aspirin can not be used ; 75 mg / day is recommended .
the clopidogrel versus aspirin in patients at risk of ischaemic events ( caprie ) trial found that clopidogrel 75 mg / day had a modest , but significant advantage over aspirin 325 mg / day for the prevention of stroke , mi , and pad in subjects with a recent stroke , mi , or pad .
cilostazol is a phosphodiesterase inhibitor that impedes platelet aggregation and exhibits vasodilatory effect and improves dyslipidemia .
treatment with cilostazol for 24 weeks reportedly improved walking distance without claudication by approximately 54% on average compared with a placebo group or a group to which pentoxifylline was administered . in a meta - analysis ,
the administration of 200 mg / day cilostazol for 12 to 24 weeks increased the maximum walking distance without claudication by up to 50% or 67% .
if patient symptoms do not improve despite proper drug treatment and rehabilitation , invasive procedures should be considered .
if normal activities are not possible due to claudication and if the lesions exhibit minimal surgery - related risks and the intervention exhibits a high probability of success , re - perfusion should be attempted through a transcutaneous procedure or operation .
early intervention is recommended when resting pain , ischemic ulceration , or necrosis is present .
balloon angioplasty and stent insertion are known to be effective in the alleviation of symptoms in many pad patients . in the past
, the transcutaneous vascular procedure was used restrictively to cause stenosis of short lesions or occlusive lesions , but with advances in technology , transcutaneous vascular intervention has been widely applied prior to the surgical procedure and widely attempted in patients in whom it is difficult to perform the surgical treatment .
for the long - term success of transcutaneous vascular intervention , the position and length of the lesions are important , and surgical treatment is preferred if the lesions are long , if there is stenosis in multiple areas , if the lesion is occlusive and if the lesion is calcified and stenotic .
experimental or investigational agents for pad include prostaglandins , naftidrofuryl , propionyl levocarnitine , defibrotide , ginkgo biloba , hyperbaric oxygen , and angiogenic growth factors .
naftidrofuryl can be used for treatment of claudication , and it has known to have fewer side effects than cilostazol
. however , there had not been any large scale , randomized trial for relevant treatment , and more clear evidences are required for extensive clinical application .
as pad becomes an increasingly important complication in t2 dm subjects , a deeper understanding of the related diseases and the establishment of a standardized method of treatment is particularly important .
indeed , pad confers poorer prognosis in t2 dm patients compared with nondiabetic patients , and early diagnosis , management and positive treatment are necessary .
however , with the exception of a few epidemiological studies , there is a lack of data concerning korean type 2 diabetes patients , and more strategies for the diagnosis and treatment of pad based on empirical evidence are needed .
 peripheral arterial disease ( pad ) in patients with type 2 diabetes mellitus ( t2 dm ) exhibits broad clinical characteristics and various consequences and is known as one of the major macrovascular complications of t2 dm . 
 atherosclerosis is recognized as the most direct and important cause of pad , but acute or chronic limb ischemia may be the result of various risk factors . in light of 
 the increasing number of patients who undergo peripheral vascular procedures , the number of subjects who are exposed to the risks for pad and related complications is increasing . in this review 
 , we will discuss the clinical and epidemiological characteristics of pad , as well as the clinical significance of pad in t2 dm subjects . 
INTRODUCTION
DEFINITION AND CLASSIFICATION
EPIDEMIOLOGY
CLINICAL CHARACTERISTICS
DIAGNOSIS
TREATMENT
CONCLUSIONS