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11 Articles in Volume 13, Issue #8
Ask the Expert: Intranasal Ketamine for Migraine Therapy
Assessment and Treatment of Neuropathic Pain
Diabetes & PAD: Diagnosis, Prevention, and Treatment Paradigms
Editor's Memo: Chronic Low Back Pain: Bringing Back A Forgotten Treatment
Evaluation and Treatment of Chemo- or Radiation-Induced Painful Complications
Guide to Implantable Devices for Intrathecal Therapy
Is Buprenorphine a ‘Partial Agonist’? Preclinical and Clinical Evidence
Letters to the Editor: Hormones and Genetic Testing
Pain Management in Kenya: A Team Experience
PROP versus PROMPT: FDA Speaks
Use of Ultrasound in Detection Of Rotator Cuff Tears

Diabetes & PAD: Diagnosis, Prevention, and Treatment Paradigms

Peripheral artery disease is common in patients with diabetes. Proper prevention and early diagnosis can help patients avoid painful neuropathies and lower-extremity amputations.

The epidemic of diabetes shows no signs of abating. It is estimated that 347 million people worldwide have diabetes. In 2008, the World Health Organization (WHO) projected that diabetes will be the 7th leading cause of death by the year 2030.1 The prevalence of diabetes in the United States may affect 10% to 14% of the population by 2025, with obesity likely the biggest risk factor. The prevalence of diabetes varies worldwide—it is greater in middle-aged people in developing countries and people >/65 years of age in developed countries, such as the US.2

As the population ages, the incidence of peripheral artery disease (PAD), a common comorbidity in patients with diabetes, also increases. Currently, the prevalence of PAD in persons aged >40 years is 4.3%,3 whereas this increases to as high as 29% in those aged >70 years (or 50-69 years with a history of diabetes or smoking).4

These two diseases do not just independently increase the risk for each other, but diabetes is synergistic with PAD. In the Framingham Study, there was a 3.5% to 8.6% increase in developing PAD if the patient has diabetes.5 As both diseases continue to increase in prevalence, clinicians on the front line will be faced with treating the combination of these two comorbidities. For example, the Hoorn study showed the prevalence rate of an ankle brachial index (ABI) of <0.9 in individuals with normal glucose tolerance was 7%, which increased to 20.9% in patients with diabetes.6 Recent research efforts show that these diseases do share a common pathological pathway—insulin resistance.7 Hence, it is essential that the characteristics of these combined epidemics be more closely evaluated.

Diabetes Type Affects Vascular Disease

It was once thought that the type of diabetes did not necessarily affect the prevalence of PAD, with essentially identical prevalences found in both diabetes mellitus type 1 (DM1) and diabetes mellitus type 2 (DM2).8 However, more recent studies have found a much higher prevalence of PAD (23.5%) in patients with DM1 than in those with DM2.9 The vascular disease that arises from diabetes is primarily microangio­pathy (abnormalities at the capillary level) and macroangiopathy (the result of arteriosclerosis). Microangiopathy is considered a vascular malfunction due to hyperglycemia, whereas macro­angiopathy is associated with conditions such as insulin resistance and metabolic syndrome.10 Compared with non-diabetic patients, patients with diabetes and PAD have an increased risk of lower-extremity amputations. Moreover, large population-based studies have shown that diabetic patients with PAD have a three- to four-fold increased mortality compared with healthy individuals.6

Is PAD Different in Diabetics?

In patients with diabetes, PAD may be asymptomatic until it reaches an advanced stage. It presents at an earlier age and progresses more rapidly than in non-diabetic patients. The vascular disease is usually more severe in extent and not all patients may be offered a revascularization procedure when needed. Outcomes after revascularization procedures are poorer in diabetic patients because of the extent of microangio­pathy, and many patients progress to major amputation. The presence of PAD is itself an independent risk factor for increased mortality due to associated cardiovascular and cerebrovascular diseases. However, early detection of PAD helps modify risk factors that in turn reduces its progression and improves outcomes.11

Clinical Features of PAD

The occlusive form of arterial disease is more widespread in patients with comorbid PAD and diabetes, and occlusion occurs more frequently than stenosis (Table 1). Arterial wall calcification is frequently more present and the anatomical localization is mainly distal (ie, lower in the leg).12 Intermittent claudication is the most common symptom of PAD, defined as the cessation of walking after a given distance due to pain that is only relieved at rest. This pain is often described as an aching or cramping in the hips, thighs, or calves. Based on the location of pain, one can often surmise the vasculature occluded—hip pain signifying aorto-iliac vessel, thigh pain as originating from iliac disease, and calf pain suggesting superficial femoral artery involvement. Since PAD in patients with diabetes frequently occurs more distally in the leg, the tibial and peroneal arteries are those most often affected. Because of their concomitant sensory neuropathy, patients with PAD and diabetes may not describe typical claudication pain symptoms. The majority of diabetic patients with PAD are asymptomatic (up to 75%) when an ABI of <0.9 is used for making the diagnosis. In fact, patients may describe foot pain rather than calf pain when walking.13

Peripheral neuropathy and PAD are known risk factors for foot ulceration: Moulik et al found that between 40% to 60% of diabetic patients with foot ulcers have PAD, which increased their risk of amputation and mortality.14 As the vascular disease progresses, tissue ulceration and ultimately gangrene can occur if reperfusion does not occur.

Risk factors for PAD In Diabetic Patients

There are several risk factors described for the development or progression of PAD in diabetic patients, the majority of which can be modifiable if aggressive screening, identification, and intervention are used (Table 2).

Increasing age has been shown to correlate strongly with PAD in diabetic patients. The Framingham Offspring Study found that for every 10 years of age, the odds ratio of developing PAD was 2.6.15

Tobacco use is the most important modifiable risk factor for the development of PAD.16

Hyperlipidemia, most importantly high total cholesterol (>200 mg/dL), has been shown to double the risk of intermittent claudication.17

The United Kingdom Prospective Diabetes Study (UKPDS) found that an elevated systolic blood pressure (SBP) was an independent risk factor for PAD. For every 10-mmHg increase in SBP, there was an associated 25% increased risk for the development of PAD at the end of 18 years.18

The same study also showed a strong correlation between PAD and hyperglycemia (defined as an HbA1c greater
than 6)—for every 1% increase in HbA1c there was an associated 28% increase in the risk of developing PAD.18 In a correlated report, UKPDS investigators noted that each 1% reduction in mean HbA1c was associated with reductions in risk of 37% for microvascular complications (P<0.0001).19

Duration of diabetic disease is another risk factor, especially in patients with DM1. In one study, the risk of developing PAD was 28.9% and 51.1% for patients with DM1 lasting 20–29 years and greater than 30 years, respectively. Patients with DM2 had a smaller risk, which also increased with time: 3.8% and 4.3% for a DM2 lasting 10-19 years and greater than 20 years, respectively.20

Diagnosis of PAD

A comprehensive history must be elicited to aid in a formal diagnosis of PAD. This includes identifying the common risk factors as previously noted, as well as obtaining a family history of diabetes. The history should review any ulcerations, chronic wounds, or previous vascular evaluations and treatments—including that of venous disease. Specifically, asking patients about foot pain, especially with walking, may help uncover hidden PAD.13 Clinicians must visually inspect the foot to evaluate any signs of vascular insufficiency, which may include dependent rubor (redness when legs are hanging down), absence of hair growth, dystrophic/brittle toenails, pallor on elevation of the foot, and cool, dry, cracked skin. The interdigital spaces of the toes need to be inspected for any underlying fissures or ulceration. Palpation of the peripheral pulses in the ankle is an essential element of the physical exam. Remember that the dorsalis pedis and posterior tibial pulses are reported to be absent in approximately 8% and 2% of healthy individuals, respectively.

In 2003, the American Diabetes Association (ADA) issued a consensus statement that recommended performing a screening ABI in all diabetic patients older than 50 years of age and, if normal, the screen should be repeated every 5 years.21 The ABI is defined as the ratio between the highest SBP of the ankle (either posterior tibial or dorsalis pedis arteries) and higher SBP of the arm (brachial or radial arteries). It is measured by using a 5-MHz Doppler probe over the popliteal and femoral arteries, an 8-MHz Doppler probe over the pedal arteries, a 10-MHz Doppler probe over the digital arteries, and the common sphygmomanometer.22 Any ABI value less than 0.91 signifies a high probability of the presence of PAD. Importantly, peripheral arteries in patients with diabetes frequently have intimal and medial calcification, resulting in higher segmental and ankle pressures and a falsely elevated ABI. Therefore, in patients with diabetes, ABI values greater than 1.30 signify a high probability of the presence of these calcification deposits, and thus the arteries are poorly compressible.12 Table 3 shows the values for PAD severity based on ADA guidelines.

A treadmill test may help diagnose PAD in patients with atypical symptoms or in those with a normal ABI but with typical symptoms of claudication. If claudication is present, patients will typically exhibit a >20 mmHg drop in ankle pressure after exercise. Imaging studies such as duplex ultrasound or magnetic resonance angiography (MRA) are noninvasive tests that also may be valuable in anatomical localization.

Treatment Options

Treatments for PAD in patients with diabetes include targeting and mitigating risk factors. Smoking cessation is the single greatest factor in reducing or even halting the progression of vascular disease. In addition to helping the effects of diabetes overall, physical exercise has also been shown to improve patients’ ability to walk without pain, with most of the studies reporting at least a doubling in walking distance.23

There is no conclusive evidence to suggest that optimal glycemic control lowers the risk of developing PAD, although it would be sensible in patients with PAD. Medications that improve insulin resistance may have advantages over other hypoglycemic agents, since insulin resistance is a risk factor for PAD. However, in clinical trials metformin was not superior to sulphonylureas or insulin in the prevention of PAD in patients with diabetes. In the PROACTIVE study, only patients without PAD at baseline benefited from treatment with pioglitazone.11

Aggressive management of dyslipidemia in patients with diabetes and PAD is necessary and the primary goal is an LDL-cholesterol of <100 mg/dL or even lower (<70 mg/dL) using primarily statins.24 Tight blood pressure control with a goal of <120/80 mmHg is shown to reduce stroke and death rates and was associated with a 50% lower risk for PAD in UKPDS.18 Currently, beta-blockers are recommended when indicated, except in patients with critical limb ischemia. Antiplatelet therapy in the form of aspirin with extended-
release dipyridamole (Aggrenox) resulted in the least progression of PAD compared with aspirin alone or placebo. A dose of 325 mg did not show any additional benefit over a dose of 75 mg.25

For symptomatic PAD, there are two agents available specifically for the treatment of intermittent claudication (Table 4). Pentoxifylline (Trental) reduces blood viscosity, has antiplatelet action, and reduces serum fibrinogen levels. Cilostazol (Pletal) induces vasodilation by inhibiting calcium-­induced contractions of smooth muscle cells. Cilostazol is contraindicated in patients with congestive heart failure and severe hepatic or renal impairment. These drugs are recommended if lifestyle modifications fail (Figure 1).

The number of revascularization procedures for PAD is 8 to 16 times higher in patients with diabetes compared with non-diabetic patients. The choice of a procedure depends on factors such as the site and severity of the disease and surgical risk due to associated cardiovascular disease.11 A review of surgical procedures is beyond the scope of this article.


Both diabetes and PAD are growing global problems, and PAD is heavily influenced by the presence of diabetes. Because of diabetic neuropathy, PAD is more commonly asymptomatic, even though it progresses more rapidly and is more severe. In the presence of diabetes, PAD is more widespread and occlusive, affecting the distal arteries of the lower extremities. Lifestyle modifications have shown benefit, and claudication medications such as pen-
toxifylline and cilostazol may be useful in patients who do not respond to lifestyle modifications. A heightened awareness of the subtleties and complications of these diseases can allow for earlier detection and more aggressive treatment, allowing for better patient outcomes.

Last updated on: November 4, 2013
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