Diabetes and Peripheral Vascular Diseases

Are You Sure the Patient Has Peripheral Vascular Disease?

Symptoms

Peripheral vascular disease results in limb ischemia. This can manifest as subcritical ischemia, with sufficient perfusion to support tissue metabolism at rest, but insufficient to support increased metabolism with exercise; or as critical ischemia, with tissue ischemia under all conditions. The classic symptom triad of pain, pallor, and pulselessness (3 Ps) reflects extreme disease, but is still commonly seen. Most often patients complain of pain on ambulation (claudication), in thigh or calf muscles.

In extreme ischemia they may have pain at rest. Cold feet are nonspecific symptoms, but may represent poor peripheral perfusion. Patients may complain of digital ulcerations, or poor wound healing including classic diabetic foot ulcerations. Dry skin on the feet may be present and predisposing to cracks or other wounds. Peripheral vascular disease is also commonly asymptomatic, and the American Diabetes Association recommends that all patients over 50 years of age with diabetes undergo routine screening.

Signs (in order of frequency)

Key Laboratory Findings

Diagnostic testing for peripheral arterial disease (PAD) in diabetes rests on imaging modalities rather than laboratory evaluation. Associated laboratory findings may include a leukocytosis and/or worsening glycemia in the setting of active foot infection; elevated C-reactive protein, and other markers of systemic inflammation. Because the existence of manifest atherosclerosis in peripheral circulation indicates likely atherosclerosis in other circulations including the coronaries, a routine evaluation of cardiovascular risk factors including blood lipid concentrations is indicated.

What Else Could the Patient Have?

Differential diagnosis

Peripheral diabetic neuropathy may be simultaneously present and contribute importantly to changes in the skin and microvascular regulation such that foot ulcers arise without other manifestations of peripheral vascular disease. Neuropathy is generally not associated with claudication, and if pain is associated, it tends to be peripheral in location and burning or dysesthetic in nature, not specifically associated with ambulation. Neurologic evaluation may be required concurrent with vascular evaluation to consider the relative contributions of vascular and neuropathic factors to the pathogenesis of diabetic foot ulcers.

Sciatica (radiculopathy) is on the list of alternate causes for pain with ambulation, and can be discerned from vascular disease on the basis of an unsupportive clinical and radiologic evaluation of the vasculature plus the presence of traditional signs and symptoms of nerve root disease (exacerbation with cough, straining at stool, and other nonambulating motions; positive straight leg raising test).

Diabetic amyotrophy is a variant form of diabetic neuropathy, and can present with significant muscular pain and disability that may mimic claudication. Vascular evaluation may reveal modest peripheral vascular disease, but generally inconsistent in severity with the degree of symptoms. Neurologic evaluation may be required to evaluate this possibility

Nonocclusive vascular disease may be present (peripheral arterial calcinosis) but not sufficiently occlusive to produce ischemic symptoms. Nevertheless, abnormalities will be revealed on imaging evaluation and do reflect the presence of vascular disease. Unlike documented occlusive disease, the connection between nonocclusive vascular disease and symptoms is less obvious and may not require intervention. On the other hand, the presence of significant vessel wall disease increases risk of occlusive disease and should prompt close monitoring including serial clinical and imaging evaluations.

Gout is prevalent among patients with diabetes, and can produce an inflamed and painful foot lesion. With modern medical care these almost never present as open wounds exuding gout crystals, but can sufficiently mimic a nonulcerating diabetic lesion that this diagnosis should be entertained if a foot wound is seen in the absence of obvious vascular or neuropathic disease.

Key Laboratory and Imaging Tests

Imaging modalities are the mainstay of the diagnosis of peripheral vascular disease.

A duplex ultrasound (B-mode plus Doppler evaluation) remains clinically useful and widely accessible, and carries little risk. The presence of arterial calcinosis can limit the utility of this modality, by altering the pressure waveforms and by calcified lesions impairing vessel wall evaluation. The sensitivity and specificity of this mode are perhaps less than what is possible with CT or MR approaches, but the broad availability and low cost, plus lack of need for contrast agents, makes this a routine first choice in subjects with diabetes in particular.

Arteriography using CT or MR approaches are highly sensitive and specific, and diagnostically useful (and will generally be required if a revascularization procedure is needed). Traditional radiograph methods require the use of iodinated contrast agents, which can be a concern in the setting of diabetes with renal disease. Methods for computer manipulation of the images, in particular digital subtraction angiography, can significantly augment the quality of these images and are increasingly used.

Emerging alternative methods include magnetic resonance angiography (MRA), and other experimental approaches. Recent concerns regarding adverse effects of MRI contrast (systemic fibrosis with gadolinium-based contrast agents) in the setting of renal dysfunction may sway the investigative team away from MRA in the patient with diabetes.

Laboratory testing is not a meaningful component of the diagnostic evaluation, but renal functionshould be evaluated before and after contrast exposure if such methods are applied.

Other Tests That May Prove Helpful Diagnostically

Peripheral oximetry can be applied to the toe, and provide a vessel-independent measure of the adequacy of peripheral perfusion. These measures are not well standardized but may be useful, and carry prognostic value.

Management and Treatment of the Disease

Peripheral vascular disease rarely presents as an emergent condition, but this can happen with critical limb ischemia. Treatment in these circumstances necessarily focuses on assessing the vasculature to determine the location(s) of critical occlusions with an eye to a subsequent bypass or possibly endovascular procedure to restore peripheral perfusion.

Poorly healing diabetic foot ulcers may also require a revascularization procedure, but this is not generally an emergent decision.

In general, management falls into categories of medical management and revascularization.

Medical management

Medical management consists of

Aggressive treatment of underlying risk factors including optimizing glycemic control, using HMG CoA reductase inhibitors to reduce LDL cholesterol, tobacco cessation, and blood pressure control. The data specifically demonstrating benefit in the peripheral vasculature from each of these measures is modest at best, and in general consists of retrospective sub-group analyses in clinical trials evaluating stroke or cardiac benefits. Glucose control has not been definitively shown to reduce occurrence or severity of peripheral vascular disease but remains a goal by virtue of demonstrated benefits in traditionally vulnerable microvascular beds. Statins provide benefit for claudication symptoms and walking distance, in addition to the demonstrated benefits in cerebrovascular and coronary vascular beds. Smoking cessation reduces overall CVD risk as well as progression of peripheral vascular disease specifically but has not been shown to reduce symptomatic claudication. There is evidence that blood pressure control with angiotensin-converting enzyme (ACE) inhibitors reduces peripheral arterial disease in trials that included significant diabetic subgroups. Despite historical concerns that beta blockers might worsen claudication symptoms, meta-analyses failed to support this observation. The cholesterol and blood pressure targets for patients with diabetes are not modified by the presence of peripheral vascular disease.
Antiplatelet therapy is an important component of medical therapy of peripheral vascular disease in patients with and without diabetes. The benefits of aspirin in the context of coronary and cerebrovascular disease are well demonstrated but these benefits have not been specifically demonstrated in the peripheral vasculature. Clopidogrel showed a superior reduction compared to aspirin in non-limb vascular events in the large subgroup of patients with peripheral vascular disease in CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), but no specific differential benefit was seen for the limb ischemia. Combined therapy has not been shown to be superior to either agent alone. Anticoagulation with warfarin is not indicated in the absence of a separate reason for the use of this agent (e.g., atrial fibrillation, DVT, prosthetic valves).
Therapy directed at improving limb perfusion includes exercise (with superior effects from supervised treadmill exercise programs compared to leg resistance training, suggesting that the systemic effects of whole-body exercise may contribute importantly to the benefit) and weight loss. Pharmacologic choices include the traditionally used methylxanthine derivative pentoxifyllene, and the phosphodiesteratse 3 inhibitor cilostazole. The clinical trial data with pentoxifyllene are at best inconsistent, and arguably do not support objective clinical benefit. However, the perception of benefit persists and this agent is recommend as second-line treatment. Cilostazole has demonstrated effects on claudication and walking distance, including superiority to pentoxifyllene. Cilostazole is structurally similar to milrinone, which increased mortality in patients with congestive heart failure, and on this basis the use of cilostazole is contraindicated in CHF. An increase in mortality has not been demonstrated in long-term follow-up of cilostazole-treated patients, but overall the data are insufficient to negate this concern at present. Other medical therapies include the 5-hydroxytryptamine type 2 antagonist naftidrofuryl, not currently approved for use in the US but with reasonable data supporting efficacy, and intravenous prostaglandins which are perhaps best used as adjunct therapy in the setting of foot ulcers or rest pain.
Therapy directed at vascular neogenesis. Proangiogenesis treatments are being actively investigated for use in limb ischemia (not specific to diabetic patients) but remain experimental. Proof of principle experiments in animal models have demonstrated the promise of vascular endothelial growth factors and fibroblast growth factors, but the small clinical trials undertaken to date have failed to show benefits. Other therapies under active investigation in this realm include bone marrow–derived stem cell treatments, and directed gene therapy treatments. These remain far from clinical application at present.

Revascularization

Revascularization approaches include traditional bypass surgery and endovascular approaches including stenting and angioplasty. Despite higher risk of limb loss on the basis of epidemiology, patients with diabetes do at least as well in terms of limb salvage with bypass procedures. The available data suggest that, as in the coronary arteries, patients with diabetes have higher rates of restenosis following angioplasty or stenting. This appears to be particularly true for the popliteal artery, and perhaps less so for the tibial artery. The medical literature contains multiple reports of cohort outcomes but no studies have pursued a systematic approach to comparing approaches or techniques.

What’s the Evidence?/References

Hirsch, AT, Haskal, ZJ, Hertzer, NR. “Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; Transatlantic Inter-Society Consensus; and Vascular Disease Foundation”. Circulation. vol. 113. 2006. pp. e463-e654. (This is the latest summary of recommendations for management from the main governing bodies in vascular medicine.)

Gandhi, S, Weinberg, I, Margey, R, Jaff, MR. “Comprehensive medical management of peripheral arterial disease”. Prog Cardiovasc Dis. vol. 54. 2011. pp. 2(A useful and broad summary of medical approaches to the management of peripheral vascular disease. Not specific to diabetes, but often highlights where diabetic patients were particularly well represented.)

Jude, EB, Eleftheriadou, I, Tentolouris, N. “Peripheral arterial disease in diabetes–A review”. Diab Med. vol. 27. 2010. pp. 4(A diabetes-specific review of the epidemiology, diagnostic approach, and management of PAD in diabetes.)

Ihnat, D, Mills, JL. “Current assessment of endovascular therapy for infrainguinal arterial occlusive disease in patients with diabetes”. J Vasc Surg. vol. 52. 2010. pp. 92S(An overview of revascularization approaches as they are currently applied in patients with diabetes and peripheral vascular disease.)

Owen, AR, Roditi, GH. “Peripheral arterial disease: The evolving role of non-invasive imaging”. Postgrad Med J. vol. 87. 2011. pp. 189(An up-to-date review of imaging approaches to peripheral vascular disease, with recommendations for selection among approaches.)

Ruiter, MS, Golde, JM, Schaper, MC, Stehouwer, CD, Huijberts, MS. “Diabetes impairs arteriogenesis in the peripheral circulation: Review of molecular mechanisms”. Clin Sci. vol. 119. 2010. pp. 225(The molecular details of how diabetes makes specific contributions to vascular pathogenesis were not addressed in the text above. This manuscript provides a thorough and updated summary of the current knowledge on this topic.)

Chapman, TM, Goa, KL. “Cilostazol: A review of its use in intermittent claudication”. Am J Cardiovasc Drugs. vol. 3. 2003. pp. 117(A summary of the data supporting the effectiveness of cilostazol in claudication.)

Reiter, M, Bucek, RA, Sumpflen, A. “Prostanoids for intermittent claudication”. Cochrane Database Syst Rev. 2004. pp. CD000986(A systematic review of the data supporting the use of prostanoids in intermittent claudication.)

Sneider, EB, Nowicki, PT, Messina, LM. “Regenerative medicine in the treatment of peripheral arterial disease”. J Cell Biochem. vol. 108. 2009. pp. 753(An overview of current advances and approaches to the treatment of PVD with experimental approaches to regeneration, including soluble, vector-delivered and cell-based methods under investigation.)

The following sources are representative of the clinical trial data that underlie current treatment recommendations as discussed earlier:

Belch, J, MacCuish, A, Campbell, I. “The Prevention of Progression of Arterial Disease And Diabetes (POPADAD) trial: Factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease”. BMJ. vol. 337. 2008. pp. a1840

“A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)”. Lancet. vol. 348. 1996. pp. 1329

Belch, JJ, Cormandy, J. “Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial”. J Vasc Surg. vol. 25. 2010. pp. 825

Murphy, TP, Hirsch, AT, Ricotta, JJ. “The Claudication:Exercise vs Endoluminal Revascularization (CLEVER) study: Rationale and Methods”. J Vasc Surg. vol. 47. 2008. pp. 1356

McDermott, MM, Ades, P, Guralnik, JM. “Treadmill exercise and resistance training in patients with peripheral arterial disease with and without intermittent claudication: A randomized controlled trial”. JAMA. vol. 301. 2009. pp. 165

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