The Link Between Diabetes and Peripheral Arterial Disease

Peripheral Arterial Disease (PAD) is a common condition in diabetes patients. PAD is caused by a buildup of fatty deposits in the walls of the arteries. The buildup causes the arteries to become blocked, therefore reducing blood flow to the feet and legs. High blood sugar weakens the arteries and makes diabetics more prone to fatty deposits building up in the arteries, which can result in the PAD advancing more rapidly than in non-diabetics. Common symptoms of PAD are pain and/or cramping in the feet and legs, especially when walking, and slower than normal healing of cuts in the feet and legs. In severe cases, PAD can lead to ulceration and possible amputation of limbs.

Diabetes is a condition that is characterized by problems with controlling the levels of sugar in the blood. This is due to a lack of the hormone insulin in the body or because the insulin that is there is not working properly. There are 2 different types of diabetes: Type 1 diabetes is usually diagnosed in children and young adults, and only accounts for 5-10% of diabetes patients; Type 2 diabetes is the most common form of diabetes and can develop at any age. It is a disease most often associated with adults and increasing rates of obesity in children. In type 2 diabetes, the body does not produce enough insulin or is unable to use the insulin properly. This results in a buildup of sugar in the blood. Over time, this high blood sugar can cause damage to the body and lead to many complications.

Definition of Diabetes

There are many definitions of diabetes, however, if we were to sum up the condition in one single definition, it would be that diabetes is a disorder with the body’s ability to process its main energy supply: glucose. The food we eat is broken down into glucose, which then enters the bloodstream, where it is used as energy to fuel the body. The hormone insulin, which is produced in the pancreas, is responsible for the regulation of glucose levels in the bloodstream. Insulin is the key that unlocks our body cells, allowing glucose to enter them and be converted into energy. Diabetes develops when the pancreas does not produce any or enough insulin, or when the body cells do not respond to insulin, which is known as insulin resistance. This results in a buildup of glucose in the bloodstream, which can cause damage to body organs and can lead to many other health problems. Diabetes can be described by its hyperglycemia (high blood sugar) and its disarrangement of metabolism. In layman’s terms, diabetes causes “the mess up of the body’s fuel and weeing system.” Because the blood glucose is not being converted into energy due to lack of insulin or insulin resistance, it then needs a way out of the bloodstream, so it is filtered out by the kidneys and passed into the urine. Due to excess glucose in the urine, fluids are absorbed from the body, causing the diabetic to often feel thirsty and experience a dry mouth. This then leads to an increase in urination as the body tries to replenish its fluid loss. The accompanying thirst and increase in urination are general symptoms of diabetes.

Definition of Peripheral Arterial Disease

The development of the concepts surrounding PAD is deeply rooted. Literature surrounding the disease tends to center around atherosclerosis, leaving large parts of the definition diagnostic. In 2000, the American Heart Association emphasized the importance of constructing a definition globally agreed upon to avoid variations, such as the disease possibly being defined as systemic atherosclerosis. The definition constructed was as follows: “Peripheral Artery Disease is a stenotic or occlusive arteriosclerotic disease resulting in decreased blood flow to the extremities.” This definition, although aiming to create a widespread understanding of the disease, in reality only describes patients suffering from intermittent claudication. Diabetes increases the severity of PAD, resulting in known limitations of the definition. Roughly only 35% of PAD patients will suffer from claudication, and the definition fails to describe the severe cases, patients with critical limb ischemia. The description does not take into account the multifocal nature of the arterial atherosclerotic lesions seen in diabetic patients. Luy outlines this, stating that in diabetes, the disease is often characterized by poorly localized events, suggesting involvement of small vessels not typical to atherosclerotic disease and leading to situations such as acute limb ischemia. He suggests that this should no longer be classified as “peripheral vascular disease,” but instead as “microvascular diabetic limb syndrome,” a condition that we should consider a separate entity to PAD in non-diabetic patients. This is still subject to further research and has yet no effect on current definitions and classification of PAD.

Understanding Diabetes and its Impact on Peripheral Arterial Disease

Several risk factors exist for developing PAD in those with diabetes. Smoking has been shown to significantly increase the risk of PAD in diabetes and is associated with more severe disease. Hypertension is another risk factor with studies showing a clear link between increased blood pressure and severity of PAD. The use of certain medications, for example insulin, has been linked to accelerated atherosclerosis and development of PAD. The duration of diabetes is also a significant risk factor with the prevalence of PAD increasing to 30% in those with diabetes of more than 15 years. Older age and the presence of other diabetic complications, such as retinopathy or neuropathy, are further risk factors for developing PAD in those with diabetes.

Diabetes is a metabolic disorder that is associated with many different co-morbid conditions. The most common association is with cardiovascular disease and peripheral arterial disease (PAD). Up to 10% of the general population has PAD, but this figure rises to 15-20% of those above the age of 70 and in diabetic patients. More than half of those with diabetes will have co-existing PAD. It has been estimated that the relative risk of developing PAD is 3.5 times higher in men with diabetes compared to men without diabetes. In women, the risk of PAD development is 6.3 times higher. The reason for this increased risk of PAD in diabetes is not fully understood. However, it is clear that diabetes is a potent and independent risk factor for PAD and is associated with a poor PAD prognosis.

Prevalence of Diabetes and Peripheral Arterial Disease

The prevalence of PAD in patients with diabetes has been examined in several prospective and retrospective studies. All studies demonstrate that diabetes is an independent risk factor for the development of PAD. Fowkes et al followed 5612 patients for a mean of 8.5 years and found that the age-adjusted relative risk for intermittent claudication in patients with diabetes compared to non-diabetic patients was 2.7 (95% CI 2.3-3.2). The Edinburgh Artery Study, a population-based study of 1592 patients followed for a mean of 12.8 years, found that diabetes carried a relative risk of 4.4 (95% CI 2.1-9.1) for developing intermittent claudication compared to non-diabetic patients. During the follow-up period, 8.45% of patients with diabetes developed IC compared to 1.6% in non-diabetic patients. There are several other studies demonstrating similar results. Our review of the Rhode Island Hospital database demonstrates similar findings in that 13.7% of vascular surgery patients with PAD have diabetes compared to 8.7% of patients with coronary artery disease and 4.7% in the general population. In a multivariate analysis study, patients with diabetes had a 1.8 odds ratio of developing critical limb ischemia compared to patients without diabetes. Reinecke et al conducted a single-center registry-based study in Germany of 656 unselected consecutive patients with peripheral arterial disease and found the prevalence of diabetes to be 36.5%. Further analysis of this patient subgroup using Cox regression modeling demonstrated a hazard risk of 2.2% for any first event of cardiovascular morbidity or mortality and 1.8 for amputation in patients with diabetes.

Risk Factors for Developing Peripheral Arterial Disease in Diabetic Patients

Age is a significant risk factor for both PAD and diabetes, so older diabetic individuals are at substantially higher risk of PAD than younger individuals. In the Framingham study, the age-specific prevalence rates of intermittent claudication in those aged 55-74 years was 10.3% for men and 7.8% for women, and in those aged 75-84 years it was 18.9% for men and 19.5% for women. Age was shown to have a synergistic effect with diabetes on the development of intermittent claudication, with claudication rates of 4.0% in the age group 45-54 years, 8.9% in the age group 55-64 years, and 12.6% in the age group 65-74 years. This compares to claudication rates of 1.5%, 2.8%, and 4.5% in the same age groups for non-diabetics. Diabetes was shown to double the risk of claudication in both men and women. These data indicate that older diabetic patients are at higher risk of PAD than younger diabetics, and it is likely that there will be a substantial increase in diabetic PAD patients over the coming decades, reflecting the increasing age of the population in developed countries and increased prevalence of diabetes. This has important implications for health resource utilization and provision of healthcare and treatment for PAD.

It is evident that the risk of developing PAD is increased in diabetic patients, but it is important to recognize and understand the specific risk factors that contribute to this. Knowledge of these risk factors can help to identify those diabetic patients who are at highest risk of PAD and who therefore would benefit from preventative therapy.

Mechanisms Linking Diabetes and Peripheral Arterial Disease

Another important mechanism is the effect of hyperglycemia on oxidative stress and antioxidant systems within the body. There is growing evidence showing that increased production and impaired detoxification of reactive oxygen species occurs in diabetes. Free radical oxidative stress has been suggested to play a crucial role in the cardiovascular complications of diabetes. Deleterious effects on the endothelium from increased oxidative stress, including decreased nitric oxide bioavailability, have adverse effects on vascular tone as well as promoting a pro-atherogenic environment. This is particularly relevant to PAD, as the lower limb vasculature is already predisposed to oxidative stress through its high level of mechanical stress and its reduced antioxidant defense compared to other vascular beds.

Mechanisms linking diabetes and peripheral arterial disease (PAD) may be classified into various processes, some of which overlap in nature. Hyperglycemia, the hallmark of diabetes, can instigate tissue damage through various metabolic pathways. One such pathway is the increased production of advanced glycation end products (AGEs), which are formed through a non-enzymatic reaction between glucose and proteins. AGEs result in protein cross-linking and damage to the extracellular matrix. This has several deleterious effects for the arterial wall; it increases arterial stiffness by affecting elastin function, and by reducing arterial compliance, it increases the systolic afterload on the left ventricle. Increased AGEs also stimulate inflammatory processes and trigger oxidative stress, further promoting atherosclerotic plaque formation.

Diagnostic and Treatment Approaches

Revascularization is a feasible option for many people with PAD, and it is seen by many as a way of restoring individuals to a pre-disabling state and improving quality of life. Unfortunately, with diabetics, there are higher short and long-term risks associated with surgical procedures, and they are often left to consider amputation as the best option. The decision for amputation cannot always be avoided in a diabetic with PAD; however, if there is clear evidence that an ulcer or gangrene in the lower limb is not likely to heal, amputation should be considered sooner as it has been shown that delay in this decision can lead to worse outcomes and higher level amputations.

The method of determining ankle systolic pressures and measurement of the toe brachial index are reliable non-invasive tests that are an excellent marker of PAD in a diabetic patient. Although angiography remains the gold standard diagnostic test, it is not recommended for routine screening in diabetics given that they are at a higher risk of developing kidney disease, which is a known complication of contrast media used in angiogram testing.

It is unfortunate that the leading cause of all amputations in the United States occurs on account of diabetes. Individuals with diabetes are at high risk of developing peripheral arterial disease and Buerger’s disease, often leading to amputation. They are also two to four times more likely to have a heart attack or a stroke. With already major complications in diabetes such as retinopathy, neuropathy, kidney failure, and the increased risk of cardiovascular disease, the mortality rate in individuals with diabetes and PAD is significantly higher than a normal individual with PAD. Therefore, it is crucial that these individuals are diagnosed and treated as soon as possible.

Screening and Diagnosis of Peripheral Arterial Disease in Diabetic Patients

The question that then arises is how to identify which diabetic patients are at higher risk for PAD and would benefit from aggressive risk factor modification in an effort to prevent the onset of intermittent claudication. Unfortunately, the American Diabetes Association has indicated that there is currently insufficient evidence to recommend for or against screening diabetic patients for PAD.

Screening and diagnosis are a crucial first step in the management of a disease. However, current physician practices indicate that diabetic patients are not being screened for PAD. As a result, most diabetic patients discover they have PAD only after they have developed intermittent claudication, which is a severe limitation of physical activity. This can lead to an impairment of quality of life. At this stage, aggressive risk factor modification and treatment may prevent the PAD from progressing to the point that revascularization or limb amputation is needed.

Management Strategies for Peripheral Arterial Disease in Diabetic Patients

Revascularization in patients with PAD has been proven to relieve symptoms of claudication and to increase walking distance. Several studies have demonstrated that in the general population of patients with PAD, those undergoing revascularization (surgical or percutaneous) have better outcomes than those treated with medical therapy alone, with the difference being more dramatic in patients with tissue loss. Unfortunately, the outcome of revascularization procedures in diabetics is not as successful. Patency rates of revascularization procedures in diabetics compared to non-diabetics are 30-60% less at one-year follow-up. Failure of revascularization procedures in diabetics has been linked to a more rapid progression of atherosclerosis and a higher incidence of microvascular disease affecting the vasa vasorum, the nutrient blood vessels of the peripheral arteries. This has led to a hypothesis that the removal of macrovascular and microvascular artery obstructions in diabetics may be necessary to increase the chances of a successful revascularization. A 5-year observational study of 458 patients with PAD targeting intervention to alter the natural history of atherosclerosis has produced interesting results in the subgroup of 285 diabetic patients. The study found that patients in the medical management group had a 47% incidence of acute coronary and cerebrovascular events before the endarterectomy or angioplasty era. These findings led to a consensus statement supporting endarterectomy and aggressive management of cardiovascular risk factors to prevent ischemic events in nascent patients.

Collaborative Care: The Role of Healthcare Professionals

These guidelines were informed by an extensive review of the scientific literature and are intended to serve as a conceptual framework to assist clinical decision-making and practice. As it is recognized that these are based on an interpretation of the evidence and expert consensus, they will require adaptation in the light of new evidence, changes in treatment options and resources. Finally, associated recommendations and practice points are summarized in Box 1. These are targeted toward health professionals involved in the care of diabetic patients with PAD. They are based on the lower extremity revascularization in diabetes, vascular nursing consensus guideline, comprehensive management of diabetic foot problems, the Society for Vascular Surgery practice guidelines and expert opinion. Evidence-based algorithms for diagnostic and treatment approaches were devised and graded in accordance with the level of evidence employed by the US Agency for Health Care Policy and Research. An overview of the evidence is provided in the text with additional information contained in the Web Only Data. This is intended for online use, it is recommended that the reader prints a hard copy for ease of reference.

Prevention and Future Directions

Lifestyle modifications are often effective in preventing or slowing the progression of peripheral arterial disease (PAD) in diabetics. Smoking cessation is one of the most important aspects of preventing PAD. Patients who smoke should be strongly encouraged to quit, and all diabetic patients should be advised to avoid exposure to second-hand smoke. Structured exercise programs increase walking distance in claudicants with or without diabetes. Patients with intermittent claudication should be offered a supervised exercise program. A program of 3 months with a combination of supervised walking exercise and behavioral intervention has been shown to be cost-effective in improving walking performance in patients with PAD. Those with limited mobility can benefit from increasing routine activities, such as walking for exercise or just moving around the house, interspersed with rest, and some have found success with partial treadmill training. The benefits of exercise appear to be long-lasting, and it can reduce cardiovascular mortality in diabetics with PAD. High cardiovascular risk patients should have their blood pressure and cholesterol aggressively managed, and antiplatelet therapy has been shown to reduce the risk of myocardial infarction, stroke, and vascular death in diabetics with PAD. All these measures are also of benefit to the patient’s general health and cardiovascular risk, and should thus be part of comprehensive preventative care for diabetics, whether or not they have PAD. In addition to managing cardiovascular risk factors, it is important for diabetics to protect their feet from trauma and maintain good foot hygiene. The majority of amputations in diabetics occur in individuals with foot ulcers, and patients in high-risk categories who have no history of foot ulcers can reduce the incidence of ulcers by 50% with preventative education and regular podiatric care. This can improve quality of life, reduce the personal and societal costs of ulceration, and limit the need for costly surgical procedures to save limbs.

Lifestyle Modifications to Reduce the Risk of Peripheral Arterial Disease in Diabetic Patients

Non-diabetic patients can reduce their risk of developing PAD by implementing certain lifestyle changes. Patients with type I diabetes should aim to achieve tightly controlled blood sugar levels to avoid the early onset of PAD. Studies have shown that for every 1% reduction in HbA1c, there is an associated 25% decrease in the risk of microvascular complications. There is not as much evidence to show the effects of tight blood sugar control in type II diabetics on the prevention of PAD, but it is still considered to be an important factor. The benefits of smoking cessation have already been discussed, but it is worth mentioning again. Hypertension and abnormal lipid levels are also significant risk factors for PAD, so their control and treatment are also advised. It is important to treat pre-existing CVD with anti-platelet agents and ACE inhibitors. All these are general preventive measures for CVD in diabetics, but will also help to prevent the onset or progression of PAD. Regular physical activity has been shown to improve general cardiovascular health and also aid in symptomatic relief for those already suffering from PAD. In both diabetic and non-diabetic populations, one study proved that every extra 30 minutes of lower intensity physical activity per day reduced the risk of PAD by 10%. This study also suggested that there was an inverse relationship between the physical activity levels and the risk of PAD, giving more reason for patients to maintain active lifestyles. High-intensity exercise can be beneficial for some patients as it can improve functional status and symptomatic relief, but a supervised exercise program is advised due to the potential for worsening the condition.

Advancements in Research and Emerging Therapies

A major reason for concern is the diagnosis of P.A.D. in patients diagnosed with diabetes. The fear is that they may be further disabled by amputation. Earlier detection of P.A.D. can lead to appropriate intervention to decrease the incidence of limb loss. A cost-effective intervention that can be performed in the office setting is the measurement of the ankle-brachial index. This has now been recommended by several expert panels. Invasive angiography is sometimes required to truly define the anatomy of the disease state, however, with advancements in non-invasive testing it is likely that non-invasive testing will soon become the standard. Imaging tests such as MRI and CT are being used more frequently to gain information about the disease state and more information is being obtained on the role of diabetes in the progression of disease. The translation of research into medications to treat P.A.D. has been relatively slow. PAD is currently treated with statins and anti-platelet therapy for the most part with the goal being to decrease progression of CAD. There are currently several drugs being tested in clinical trials to evaluate their effect on the progression of P.A.D. Some factors that have slowed drug development for P.A.D. in the past include the heterogeneity of the disease state and the relatively slow progression of P.A.D compared to CAD. With future advancements in drug therapy for P.A.D. the hope is that there can be a decrease in amputation and an improvement in functional status in diabetic patients who suffer from this debilitating disease.

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