Reviews/Commentaries/Position Statements CONSENSUS STATEMENT Peripheral Arterial Disease in People With Diabetes AMERICAN DIABETES ASSOCIATION lower-extremity amputation, especially in patients with diabetes. Moreover, even for the asymptomatic patient, PAD is a marker for systemic vascular disease in- eripheral arterial disease (PAD) is a 1) WHAT IS THE volving coronary, cerebral, and renal ves- condition characterized by athero- EPIDEMIOLOGY AND sels, leading to an elevated risk of events, P sclerotic occlusive disease of the IMPACT OF PERIPHERAL such as myocardial infarction (MI), lower extremities. While PAD is a major ARTERIAL DISEASE IN stroke, and death. risk factor for lower-extremity amputa- PEOPLE WITH DIABETES? Diabetes and smoking are the stron- tion, it is also accompanied by a high PAD is a manifestation of atherosclerosis gest risk factors for PAD. Other well- known risk factors are advanced age, likelihood for symptomatic cardiovas- characterized by atherosclerotic occlusive hypertension, and hyperlipidemia (3). cular and cerebrovascular disease. Al- disease of the lower extremities and is a Potential risk factors for PAD include though much is known regarding PAD in marker for atherothrombotic disease in other vascular beds. PAD affects ϳ12 mil- elevated levels of C-reactive protein the general population, the assessment (CRP), fibrinogen, homocysteine, apoli- and management of PAD in those with lion people in the U.S.; it is uncertain how many of those have diabetes. Data from poprotein B, lipoprotein(a), and plasma diabetes is less clear and poses some viscosity. An inverse relationship has special issues. At present, there are no the Framingham Heart Study (1) revealed that 20% of symptomatic patients with been suggested between PAD and alcohol established guidelines regarding the consumption. care of patients with both diabetes and PAD had diabetes, but this probably greatly underestimates the prevalence, In people with diabetes, the risk of PAD. given that many more people with PAD PAD is increased by age, duration of dia- On the 7–8 of May 2003, a Con- are asymptomatic rather than symptom- betes, and presence of peripheral neurop- sensus Development Conference was atic. As well, it has been reported that of athy. African Americans and Hispanics held to review the current knowledge those with PAD, over one-half are asymp- with diabetes have a higher prevalence of regarding PAD in diabetes. After a series tomatic or have atypical symptoms, about PAD than non-Hispanic whites, even after of lectures by experts in the field of one-third have claudication, and the re- adjustment for other known risk factors endocrinology, cardiology, vascular mainder have more severe forms of the and the excess prevalence of diabetes. It is surgery, orthopedic surgery, podia- disease (2). important to note that diabetes is most try, and nursing, a vascular medicine The most common symptom of PAD strongly associated with femoral- panel was asked to answer the following is intermittent claudication, defined as popliteal and tibial (below the knee) PAD, questions: pain, cramping, or aching in the calves, whereas other risk factors (e.g., smoking 1) What is the epidemiology and im- thighs, or buttocks that appears repro- and hypertension) are associated with pact of PAD in people with diabetes? ducibly with walking exercise and is more proximal disease in the aorto-ilio- 2) Is the biology of PAD different in relieved by rest. More extreme presenta- femoral vessels. people with diabetes? tions of PAD include rest pain, tissue loss, The true prevalence of PAD in people 3) How is PAD in diabetes best diag- or gangrene; these limb-threatening man- with diabetes has been difficult to deter- nosed and evaluated? ifestations of PAD are collectively termed mine, as most patients are asymptomatic, 4) What are the appropriate treat- critical limb ischemia (CLI). many do not report their symptoms, ments for PAD in people with diabetes? PAD is also a major risk factor for screening modalities have not been uni- formly agreed upon, and pain perception ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● may be blunted by the presence of periph- eral neuropathy. For these reasons, a pa- From the American Diabetes Association, Alexandria, Virginia. tient with diabetes and PAD may be more Address correspondence to Nathaniel Clark, MD, MS, RD, American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311. E-mail: [email protected]. likely to present with an ischemic ulcer or Received and accepted for publication 8 September 2003. gangrene than a patient without diabetes. This consensus statement has been reviewed and endorsed by the Vascular Disease Foundation. While amputation has been used by some Abbreviations: ABI, ankle-brachial index; CABG, coronary artery bypass graft; CAPRIE, Clopidogrel as a measure for PAD prevalence, medical versus Aspirin in Patients At Risk of Ischemic Events; CLI, critical limb ischemia; CRP, C-reactive protein; eNOS, endothelial cell nitric oxide synthase; FDA, Food and Drug Administration; FFA, free fatty acid; MI, care and local indications for amputation myocardial infarction; MRA, magnetic resonance angiogram; NF-␬B, nuclear factor-␬B; PAD, peripheral versus revascularization of the patient arterial disease; PAI-1, plasminogen activator inhibitor-1; PI, phosphatidylinositol; PKC, protein kinase C; with critical limb ischemia widely vary. PVR, pulse volume recording; RAGE, receptor for advanced glycation end products; UKPDS, U.K. Prospec- The nationwide age-adjusted amputation tive Diabetes Study; VSMC, vascular smooth muscle cell. rate in diabetes is ϳ8/1,000 patient years A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ϳ factors for many substances. with a prevalence of 3%. However, re- © 2003 by the American Diabetes Association. gional patterns differ—there is nearly a DIABETES CARE, VOLUME 26, NUMBER 12, DECEMBER 2003 3333 Peripheral arterial disease in people with diabetes ninefold variation of major amputations curring in ϳ4%. While the majority of have a slower walking speed (generally in people with diabetes across the U.S. patients remain stable in their lower-limb Ͻ2 mph) and a limited walking distance. Therefore, the incidence and prevalence symptomatology, there is a striking excess This may result in a “cycle of disability” of amputation may be an imprecise mea- cardiovascular event rate over the same with progressive deconditioning and loss sure of PAD. 5-year time period, with 20% sustaining of function. Finally, there are significant The reported prevalence of PAD is nonfatal events (MI and stroke) and a economic costs of health care, reduced also affected by the methods by which the 30% mortality rate (7). For those with productivity, and personal expenses asso- diagnosis is sought. Two commonly used CLI, the outcomes are worse: 30% will ciated with a chronic manifestation of ath- tests are the absence of peripheral pulses have amputations and 20% will die erosclerotic disease such as PAD. and the presence of claudication. Both, within 6 months (8). The natural history however, suffer from insensitivity. A more of PAD in patients with diabetes has not 2) IS THE BIOLOGY OF PAD accurate estimation of the prevalence of specifically been studied longitudinally, DIFFERENT IN PEOPLE PAD in diabetes should rely upon a vali- but it is known from prospective clinical WITH DIABETES? dated and reproducible test. Such a test is trials of risk interventions that the cardio- Diabetes affects nearly every vascular bed; the ankle-brachial index (ABI), which in- vascular event rates in patients with PAD however, the pervasive influence of dia- volves measuring the systolic blood pres- and diabetes are higher than those of their betes on the atherothrombotic milieu of sures in the ankles (dorsalis pedis and nondiabetic counterparts. the peripheral vasculature is unique. The posterior tibial arteries) and arms (bra- abnormal metabolic state accompanying chial artery) using a hand-held Doppler Diagnosis of PAD diabetes results in changes in the state of and then calculating a ratio. Simple to Diagnosing PAD is of clinical importance arterial structure and function. The onset perform, it is a noninvasive, quantitative for two reasons. The first is to identify a of these changes may even predate the measurement of the patency of the lower patient who has a high risk of subsequent clinical diagnosis of diabetes. Relatively extremity arterial system. Compared with MI or stroke regardless of whether symp- little is known about the biology of PAD an assessment of pulses or a medical his- toms of PAD are present. The second is to in individuals with diabetes in particular. tory, the ABI has been found to be more elicit and treat symptoms of PAD, which However, it is felt that the atherogenic accurate. It has been validated against an- may be associated with functional disabil- changes observed with other manifesta- giographically confirmed disease and ity and limb loss. PAD is often more subtle tions of atherosclerotic disease, such as found to be 95% sensitive and almost in its presentation in patients with diabe- coronary and carotid artery disease, are 100% specific (4). There are some limita- tes than in those without diabetes. In generally applicable to patients with both tions, however, in using the ABI. Calci- contrast to the focal and proximal athero- PAD and diabetes. fied, poorly compressible vessels in the sclerotic lesions of PAD found typically