Diabetes & PAD: Diagnosis, Prevention, and Treatment Paradigms
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