Macro Vascular Complications

Macrovascular complications Atherosclerotic disease accounts for most of the excess mortality in patients with diabetes.
In the UK prospective diabetes study, fatal cardiovascular events were 70 times more common than deaths from microvascular complications. The relation between glucose concentrations and macrovascular events is less powerful than for microvascular disease; smoking, blood pressure, proteinuria, and cholesterol concentration are more important risk factors for atheromatous large vessel disease in patients with diabetes. Hyperlipidaemia is no more common in patients with well Controlled type 1 diabetes than it is in the general population. In patients with type 2 diabetes, total and low density lipoprotein cholesterol concentrations are also similar to those found in non-diabetic people, but type 2 diabetes is associated with a more atherogenic lipid profile, in particular low concentrations of high density lipoprotein cholesterol and high concentrations of small, dense, low density lipoprotein particles. Hypertension affects at least half of patients with diabetes. In the UK prospective diabetes study fight blood pressure control (mean 144/82 mm Hg) achieved significant reductions in the risk of stroke (44%), heart failure (56%), and diabetes related deaths (32%), as well as reductions in microvascular complications (for example, 34% reduction in progression of retinopathy). One third of patients required three or more antihypertensive drugs to maintain a target blood pressure [is less than] 150/85 mm Hg. In another recent study (hypertension optimal treatment study) rates of cardiovascular events in patients with type 2 diabetes were reduced even further when combination treatment was used to aim for target diastolic blood pressures [is less than] 80 mm Hg. Peripheral vascular disease Atheromatous disease in the legs, as in the heart, tends to affect more distal vessels--for example, the tibial arteries--producing multiple, diffuse lesions that are less straightforward to bypass or dilate by angioplasty. Medial calcification of vessels (Monckeberg's sclerosis) is common and can result in falsely raised measurements of the ankle brachial pressure index. This index is therefore less reliable as a screening test in patients with diabetes and intermittent claudication.
Oxidative stress and diabetic vascular complications.

Giugliano D, Ceriello A, Paolisso G. Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported
by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelialdependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.
Discussion
The major cause of death and complications in patients with type 2 diabetes is cardiovascular disease. More than 60% of all patients with type 2 diabetes die of cardiovascular disease, and an even greater percentage have serious complications. The prevalence of vascular disease, hypertension, dyslipidemia, and other abnormalities is very high, and the consequences of these abnormalities are burdensome to patients, their families, and society.20 Interventions such as lifestyle changes, control of blood pressure and lipids, and antiplatelet therapy can reduce the development, progression, and complications associated with type 2 diabetes.21 Glucose control may reduce microvascular complications, but not cardiovascular complications. Even with microvascular complications, blood-pressure control has a greater effect than glucose control.22 In patients with advanced type 2 diabetes, the unanswered question is whether glucose control independently reduces cardiovascular complications. Population surveys, cross-sectional studies, and short-term intervention trials have produced mixed results in attempts to answer this question.3,4,5,6,7,8 The United Kingdom Prospective Diabetes Study (UKPDS) showed a nonsignificant trend toward improvement in the rate of myocardial infarction (P=0.052) in patients with newly diagnosed disease, but the trial was complicated by less-than-strict blood-pressure and lipid control, according to current standards.1,22 Nevertheless, the trend was accepted by many observers as evidence of the importance of glucose control for macrovascular complications. The Diabetes Control and Complications Trial (DCCT) did not show a significant reduction in cardiovascular events with intensive control in young patients with type 1 diabetes,2 but a follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, showed a delayed benefit.23 Ten years after both groups reached similar glycated hemoglobin levels, the patients in the previous intensive-therapy group had significantly fewer cardiovascular events than those in the standard-therapy group. Similar results were seen in the 10-year follow-up of the UKPDS.24 One year after the end of the trial, no significant difference in glycated hemoglobin levels was present. Despite this finding, in the original intensive-therapy group, there was a reduction in the risk of microvascular complications (15%, P=0.01), of any diabetes-related outcome (9%, P=0.04),
of myocardial infarction (15%, P=0.01), and of death from any cause (13%, P=0.007). This delayed effect may have been associated with the cumulative effects of hyperglycemia. Our study, along with the ADVANCE and ACCORD studies, examined different populations with different approaches and came to similar conclusions. Intensive glucose control did not reduce cardiovascular events in patients with previously diagnosed type 2 diabetes. The ACCORD study was terminated at 3.5 years because of increased mortality in the intensivetherapy group. The ADVANCE study showed a reduction in the progression of albuminuria, but there were no changes in the rates of severe nephropathy, retinopathy, or cardiovascular events. The mean age of patients in the ACCORD study was 62 years, and the duration of diabetes was 10 years, with 35% of patients receiving insulin at baseline. The mean age in our study was 60 years, with 52% of patients receiving insulin and the remainder receiving a maximal dose of an oral agent; diabetes had been diagnosed a mean of 11.5 years earlier. The ADVANCE study had an older population (mean, 66 years) with a shorter disease duration of 8 years and 1.5% of patients receiving insulin at baseline. In the three studies, baseline glycated hemoglobin levels were 7.2% in the ADVANCE study, 8.1% in the ACCORD study, and 9.4% in our study. After intensive therapy, glycated hemoglobin levels were 6.4% in the ACCORD and ADVANCE studies and 6.9% in our study; after standard therapy, the values were 7.5%, 7.0%, and 8.4%, respectively. None of these studies showed a decrease in cardiovascular events. The rates of hypoglycemia and weight gain were greater in the intensive-therapy group in all three trials. In our study, we followed a population of veterans for up to 7.5 years (median, 5.6 years). Cardiovascular risk factors were controlled, and the between-group difference in glycated hemoglobin levels was maintained.25,26 Microvascular complications were minimally affected by intensive glucose control. No significant differences in retinopathy, major nephropathy, or neuropathy were seen. A nominally significant reduction (P=0.05) in any worsening of albumin excretion was observed in the intensive-therapy group. Overall, the benefit of decreasing the glycated hemoglobin level from 8.4% to 6.9% appeared to be minimal. Our study had several limitations. Since we were studying veterans, the patients were predominantly men, and extrapolation of our findings to women must be done with caution. Changes in therapeutic agents have occurred since the design of our protocol. The protocol specified that any approved drug could be used, but the availability of new agents was limited. The study was designed to limit the effect of differences in agents used, but it remains possible that newer agents might have different effects. Since studies with intensive control of risk factors were not available at the time of the protocol development, the study may have been underpowered. This concern is lessened by the very similar results in the ACCORD and ADVANCE studies.9,10 Such factors as levels of HDL cholesterol, weight gain, systolic blood pressure, and pharmacologic agents could play a role in the observed lack of benefit of intensive glucose control and need to be examined in detail. Another possibility is a delayed benefit of intensive control, as seen at the 10-year follow-up in the DCCTEDIC and UKPDS studies. Nevertheless, the results of this and other studies do not indicate that intensive glucose control in this population decreased the rate of cardiovascular events. In addition, it appears that
intensive glucose control had minimal effects on microvascular complications during a period of 5 to 6 years. Intensive glycemic control earlier in the disease course may produce benefit, especially if severe hypoglycemia is avoided. For now, appropriate management of hypertension, dyslipidemia, and other cardiovascular risk factors appears to be the most effective approach to preventing cardiovascular morbidity and mortality.
Vascular disease risk markers in diabetes: Monitoring & intervention

Nurse Practitioner , Jun 2000 by Winters, Shelia, Jernigan, Verna

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ABSTRACT Identifying and treating risk markers for vascular disease in diabetes is significant in preventing long-term disabilities and containing health care costs. Current research recommends maintaining normal blood glucose levels in all diabetes patients. Blood glucose that is elevated for several years is a major factor in the development and progression of microvascular diabetes complications. Patients play a key role in monitoring vascular disease risk markers. This article provides information on the risk markers to monitor, microvascular and macrovascular complications, and current therapies to combat complication progression. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, which results from impaired insulin secretion, impaired insulin action, or both.1 Diabetes affects 16 million Americans and approximately S% to 20% of the population in Western societies.2 Chronic hyperglycemia that is associated with diabetes results in significant morbidity and mortality. Diabetes vascular complications are profound, causing blindness, end-stage renal disease, amputation, and fatality from myocardial infarction. National costs approximate $105 billion per year, and the bulk of this sum is spent on treating long-term complications.3 Vascular complications deplete health care resources and significantly impact the patient's quality of life. Lowering glucose and lipid levels, controlling hypertension, and intervening at the first sign of complication can prevent many of the complications or their progression. This article reviews the pathophysiology of vascular complications of diabetes, identifies risk markers that require monitoring and intervention, and discusses current therapies and patient education.4 Etiology Coronary artery disease (CAD), nephropathy, retinopathy, and neuropathy are considered diabetes complications. However, diabetes patients in less affluent societies have fewer cardiovascular complications than those in the United States. Other factors that may influence complications include diet, body weight, physical activity, and tobacco use.
Platelet function abnormalities and blood viscosity are known to influence micro- and macrovascular disease in diabetes. Some researchers believe that a connection exists between chronic hyperglycemia and decreased oxygen delivery (relative hypoxia), leading to the pathogenesis for several diabetes complications. The hypoxia is related to capillary and arteriole dysfunction in diabetes.5,6 Glycemic control has not been proven to be an independent factor in preventing macrovascular disease. Heparin sulfate may be a common factor between vascular disease and diabetes. Heparin sulfate has antiatherogenic properties and contributes to the structural integrity of large vessel walls and basal membrane cells. If heparin sulfate is elevated, there is less possibility of cholesterol plaque development in the vascular structures.7 If blood sugar is chronically elevated, the heparin sulfate level decreases. Another common factor of vascular disease and diabetes is thyroid function in the body. Hypothyroidism can lead to decreased insulin production, elevated glucose levels, decreased heparin sulfate production, elevated albumin, increased basement membrane thickening, and increased insulin resistance.8 As with decreased heparin sulfate, the process outcome in large blood vessels may result in atherosclerosis and CAD. In the kidneys, a decreased renal glomerular filtration rate and chronic renal insufficiency development may occur. In ocular blood vessels, this process may lead to retinopathy and cataracts. CAD risk factors that contribute to atherosclerotic plaque development include smoking, elevated cholesterol, hypertension, genetic predisposition, insulin resistance, and fibrin deposition on the surface of endothelial cells leading to platelet adhesion. Other pathophysiologic mechanisms that may influence vascular complications include protein glycosylation, disruption in the polyol pathway, decreased myoinositol, impaired glucose tolerance, and beta cell dysfunction in the pancreas.9 Pathophysiology Four theories emerge in the literature on the pathophysiology of diabetes and vascular disease. The common factor in all of the theories is hyperinsulinemia and/or increased insulin resistance. Insulin resistance is a state where tissues, such as skeletal muscle, have a reduced sensitivity to the effects of insulin-stimulated glucose uptake. This impairment leads to hyperinsulinemia, which sometimes evolves into overt Type 2 diabetes.10 Insulin resistance is expressed in the liver through overproduction of glucose and in peripheral tissues through impaired utilization of glucose by skeletal muscle and adipose tissue." Each theory has a different starting point in the cascade of factors leading to vascular complications in diabetes (see Figure 1). Risk Markers The significance of monitoring and treating risk factors for vascular disease is not only to prevent end-stage renal disease and death, but also to improve quality of life and increase life expectancy. Microalbuminuria is a significant factor in a complex chain of events that can lead to premature atherosclerosis, increased basement membrane thickening, and increased insulin resistance. Precipitating factors for microalbuminuria are decreased heparin sulfate, chronically elevated blood glucose, and increased low-density lipoprotein (LDL) cholesterol. Precipitating factors for insulin resistance are hypothyroidism (increased thyroid-stimulating hormone), microalbuminuria, and elevated LDL cholesterol. Clinicians should closely
monitor the laboratory values of thyroid levels and cholesterol. These tests should be performed every 5 years if normal and every 6 months if abnormal or if the patient is receiving therapy. Elevated blood glucose and elevated insulin levels are precipitating factors for decreased heparin sulfate. Monitoring insulin levels is not recommended. Monitoring blood glucose levels and HbAlc are the primary means for monitoring diabetes. HbA1c reflects blood glucose control over the previous 3 months. Other risk markers to monitor are blood pressure, weight, activity level, diet, and smoking history (see Table 1). Microvascular Diabetes Complications Retinopathy, nephropathy, and neuropathy are primary microvascular complications. These complications are present in Type 1 immune-mediated diabetes and Type 2 diabetes. Retinopathy Retinopathy can lead to vision changes and blindness. Diabetic retinopathy causes 24,000 new cases of adult blindness each year.'z The pathogenesis of diabetic retinopathy is not well understood. One theory holds that elevated blood glucose may lead to basement membrane thickening, causing retina edema. Decreased oxygen autoregulation can result in local ischemia in retinal blood vessels, causing microaneurysms and excessive vascular permeability (background diabetic retinopathy). Edema in the macula is the principal mechanism of vision loss. As retinopathy progresses, vascular occlusion may occur with proliferation of new blood vessels and fibrous tissue on the surface of the retina (proliferative diabetic retinopathy). Other causes of retinopathy include increased platelet adhesiveness, erythrocyte aggregation, and increased blood viscosity. Patients with these signs and symptoms are at an increased risk for vitreous hemorrhage and retinal detachment. Retinopathy can be reversed or prevented prior to onset with adequate glucose control. The extent and rate of progression correlate strongly with the duration and magnitude of elevated blood glucose. In Type 1 diabetes, there is a 2 % incidence of proliferative diabetic retinopathy after 5 to 10 years; a 50% incidence exists after 20 years for those diagnosed with diabetes before age 30. If diagnosed with Type 1 or Type 2 diabetes after age 30, 25% will have proliferatve diabetic retinopathy after 20 years if insulin dependent, and 5% of Type 2 diabetes patients using insulin will develop proliferatve diabetic retinopathy. In Type 1 and Type 2 diabetes, 12% to 20% will develop macular edema after 15 years, with probable vision loss.ze Retinopathy treatment includes laser therapy to decrease new vessel formation and macular edema. Aspirin, aminoguanides, or ticlopidine are used to decrease microaneurysm formation. Vitrectomy is only proposed if extensive vitreous hemorrhages or retinal detachment involving the macula exists. Cataracts appear earlier and progress more rapidly in patients with diabetes. Elevated glucose in the eye lens and increased polyol within the cells lead to osmotic edema and cell architecture disruption. An associated abnormality in electrolyte transport leads to an influx of sodium ions that cause edema and accelerated lens opacification.
Patients with diabetes should receive regular ophthalmologist-performed eye examinations. Type 1 diabetes patients should have their first eye examination S years after diagnosis and yearly thereafter. Type 2 diabetes patients should begin annual eye examinations at the time of diagnosis. Diabetes patients who are pregnant should have an eye examination each trimester. Disease control is instrumental in preventing retinopathy development rather than influencing progression once it is diagnosed. Thrombolytic drugs are contraindicated if there has been a recent vitreous or preretinal hemorrhage. l3 Diabetes may cause other ocular problems including refractive changes, glaucoma, and reversible cranial nerve palsies. Smoking cessation, hypertension control, and lipid control help prevent diabetic retinopathy. Neuropathy Neuropathy is the most common diabetes complication, afflicting 50% to 60% of diabetes patients. 14 Signs and symptoms include diminished pain and a burning sensation in the feet and, less commonly, in the hands. The pathogenesis of diabetic neuropathy is not clear, but recent research implicates hyperglycemia, hypertension, and smoking, which lead to relative hypoxia and elevated LDL cholesterol.s Diabetic neuropathy is a precursor to foot ulcerations and is present in 80% of patients with foot lesions.14 More than half of all lower limb amputations in the United States are performed on diabetes patients.9 A study performed at the Deaconess Joslin Foot Center in Boston concluded that improved oxygenation of lower extremity nerves halted the progression of diabetic neuropathy. The Diabetes Control and Complications Trial (DCCT) study showed a 60% lower incidence of clinically detected neuropathy in the study group using intensive blood sugar control. These are important implications for preventing diabetic neuropathy.'s Clinical diagnosis of polyneuropathy is based on symptoms, sensory filament tests, and nerve conduction studies. Other neuropathies include autonomic neuropathy, focal limb neuropathy, and mixed forms. Microvascular abnormalities, particularly basement membrane thickening and endothelial cell hyperplasia, relate to neuropathic severity; differences in these abnormalities do not exist between Type 1 and Type 2 diabetics.16 Nephropathy Diabetic nephropathy is a major cause of end-stage renal disease in the United States, accounting for 30% of the 4,000 new cases each year." Nephropathy, even in the early stages, is associated with increased death rates, especially from cardiovascular disease. The early stages of nephropathy are asymptomatic; the first clinical sign, microalbuminuria, appears after significant renal damage has occurred. Microalbuminuria occurrence is related to endothelial dysfunction. Albuminuria in Type 1 diabetes is associated with a fortyfold increased risk of early death compared with those without albuminuria. Some SO% of patients with albuminuria die from cardiovascular disease before progressing to end-stage renal disease.' Microalbuminuria is a risk marker for renal disease. It occurs 7 to 10 years after Type 1 diabetes onset and may be present at the time of Type 2 diabetes diagnosis. Microalbuminuria
can exist for up to 10 years, without a change in glomerular filtration rate, before progressing to proteinuria and chronic renal insufficiency. In the DCCT study, each 10% increase in the HbA^sub 1C^ level was accompanied by a 20% increase in the microalbuminuria development rate. `g Elevated microalbuminuria correlates with elevated blood pressure, elevated LDL cholesterol, and heparin sulfate decreased density, which affects the blood vessel walls. Many factors cause increased albuminuria including hematuria, heart failure, recent exercise, excessive dietary protein intake, fever, uncontrolled hypertension, urinary tract infection, contaminated urine specimen, and elevated blood glucose.l9 Initial kidney changes resulting from diabetes include increased kidney size caused by cellular hypertrophy/proliferation and an increased glomerular filtration rate.2 Characteristic renal changes include glomerular basement membrane thickening and mesangial proliferation, which correlate with the onset of proteinuria and hypertension. Basement membrane thickening over many years causes progressive occlusion of glomerular capillaries, leading to chronic renal insufficiency. Some 30% to 50% of Type 1 diabetes patients and 6% to 9% of Type 2 diabetes patients eventually develop renal failure.7,20 Secondary to genetic predisposition, patients at high risk for diabetes and end-stage renal disease are African-Americans, Mexican Americans, and Pima Indians. The ability of the kidneys to retain plasma proteins is essential for life. Large molecules such as proteins and red blood cells are not normally excreted in the urine. The kidneys reabsorb protein in the renal tubules. Proteinuria can result from an intrinsic inability of the proximal tubule to reabsorb filtered proteins. Because synthesis of lipids and lipoproteins by the liver is increased, chronic proteinuria may lead to increased interstitial damage in the kidneys, muscle wasting, edema, decreased albumin, and hyperlipidemia. An interesting feature in the pathogenesis of diabetic renal disease is loss of negatively charged heparin sulfate; this occurs in the kidney and in the general body vasculature. Early results from two recent studies using heparin replacement to modulate negative charges of the vascular membrane are positive, but more work is needed. In these studies, exogenously administered heparin reduced albumin levels and prevented an increase in glomerular basement membrane thickness in diabetic rats.21 Advanced glycosylation end products also affect renal disease. Advanced glycosylation end products are products of a nonenzymatic reaction between glucose and various extracellular and intracellular macromolecules.22 Advanced glycosylation end products cause vascular tissue damage, thickening and narrowing of vascular lumen, increased endothelial cell permeability, thrombosis formation, and diabetic kidney disease. Proteins with a half life of more than a few weeks are most susceptible to advanced glycosylation, especially in basement membrane, connective tissue, lipids, and nucleic acids. This process accelerates atherosclerosis and is enhanced by chronically elevated blood glucose. Advanced glycosylation end products also interfere with nitric oxide function in the vascular wall, which can decrease the ability of blood vessels to dilate, precipitating hypertension.20
Protein modification by advanced glycosylation end products also predicts the development of early changes in diabetic nephropathy Over 30 years, nephropathy in Type 1 diabetes patients progresses slowly. In Type 2 diabetes patients, nephropathy signs are frequently present at diagnosis, because the long-standing, elevated blood glucose has not been treated. Risk factors for nephropathy include genetic predisposition, hypertension, increased protein in the diet, and elevated blood glucose. In Type 1 diabetes, elevated blood glucose predates hypertension by several years, but in Type 2 diabetes they are both present at diagnosis in many patients. More men than women develop nephropathy Approximately, 100,000 end-stage renal disease diabetes patients are on dialysis nationwide.19 Most researchers now recommend maintaining blood glucose levels at almost normal levels in all diabetes patients.18 Chronically sustained elevated glucose levels are a major cause of microvascular complication development and progression in diabetes. In the DCCT study, intensive treatment with insulin reduced the incidence of microalbuminuria by 39% and of proteinuria by 54% in Type 1 diabetes patients. The risk of microalbuminuria development increased substantially when the HbA^sub 1c^ was above 8.8%. These results are similar to those found in previous studies.23 Several studies have documented that antihypertensive therapy, typically with angiotensinconverting enzyme inhibitors, stabilizes or reduces microalbuminuria in diabetic patients and may also preserve the glomerular filtration rate (see Figure 2).19 Proteinuria is also associated with increased plasma fibrinogen, increased platelet adhesiveness, increased vascular permeability, and increased lipoprotein (a). A precursor to proteinuria is microalbuminuria. Strict glucose control can decrease mild proteinuria in Type 1 diabetes patients without chronic renal insufficiency. If proteinuria is greater than 500 mg/day, tight glucose control does not slow renal impairment progression.24 Elevated serum creatinine, blood urea nitrogen, and gross proteinuria indicate advanced renal disease. High triglyceride levels have been shown to be a risk factor for more rapid progression of nephropathy in Type 2 diabetes patients with overt proteinuria. The combination of elevated triglycerides and increased LDL cholesterol correlates strongly with microalbuminuria progression and insulin resistance severity. Urine protein concentration is secreted by the renal tubular cells, not from plasma, and is usually 50 mg/day. If urine protein concentration is over 8 gram/day, nephrotic syndrome is present.2 Normal levels of albumin in urine are 15 mcg/minute; if over 20 mcg/minute, microalbuminuria is present; above 30 mcg/minute predicts subsequent renal failure. The 24hour urine test is considered to be more sensitive in evaluating microalbuminuria than the dipstick test. Recent studies suggest that the gene encoding aldose reductase (ALR2), the enzyme that converts glucose to sorbital, may confer susceptibility to microvascular disease. A significant decrease in the frequency of the Z+2 allele and Z/Z+2 genotype was found in patients with nephropathy compared with those with no complications after a 20-year duration of diabetes. This was accompanied by an increase in the Z-2 allele and ZZ-25= ALR2 genotype in the nephropathy group. Individuals with the Z+2 allele are more than seven times less likely to develop renal disease than those without this marker. The Z-2 allele confers susceptibility to
microvascular disease in patients with Type 1 or Type 2 diabetes. This may aid in future research to identify genetic risk markers for diabetic renal disease.zs Macrovascular Diabetes Complications Diabetes patients frequently suffer from microvascular diseases, but they more commonly die from macrovascular disease. Macrovascular diseases are characterized by atherosclerosis and involve vessels of the heart, cerebrum, and peripheral arteries. Atherosclerosis is accelerated by a two- to fivefold increase in the prevalence of cardiovascular, cerebrovascular, and peripheral vascular disease in diabetes patients.6,11 The cause of this acceleration is not known, but nonenzymatic glycosolation of lipoproteins may be involved. The atherosclerotic lesions appear to be initiated by oxidized LDL cholesterol. This process is accelerated in diabetes. HDL cholesterol and antioxidants impair the oxidation of LDL cholesterol and are antiatherosclerotic. In diabetes, HDL cholesterol levels tend to be low and LDL cholesterol levels are elevated. With lower HDL cholesterol levels, reverse transport of cholesterol from established lesions is impaired. Emerging data suggest that hyperglycemia and CAD may both arise from hyperinsulinemia/insulin resistance (see Figure 3).26 Common risk factors for both are increased blood pressure, elevated lipids (especially LDL cholesterol), increased age, and obesity (especially central pattern fat distribution). Research from Denmark's Steno Diabetic Center indicates that a strong relationship exists between proteinuria in Type 1 diabetes and CAD: The genesis of this vascular complication is based on defective heparin sulfate metabolism.27 Diabetes patients may also have myocardial dysfunction in the absence of large vessel disease with an increased risk of heart failure. Exercise treadmill testing is recommended to detect ischemia and to determine the need for cardiac catheterization and therapeutic interventions in diabetes patients who have hypertension, hyperlipidemia, and a history of tobacco abuse.8 Diabetes patients with CAD risk factors should take one aspirin per day to improve circulation and help prevent blood clots that can cause myocardial infarctions, strokes, and deep vein thrombosis in the lower extremities. Intervention Therapies for Diabetes Complications Improvements have been made in the production of insulin, and now fewer allergic reactions occur. Long-acting insulins, short-acting insulins, and combination insulins may be used. Insulin is usually adjusted by 2 units/day or 5 units/week (see Table 2).28 In addition to insulin and pharmacologic therapy to stimulate insulin production in the pancreas, drugs exist that enhance insulin use in the peripheral cells to decrease hyperinsulinemia (see Table 3). For example, thiazolidinediones increase peripheral insulinmediated glucose disposal and reduce hepatic glucose production by enhancing tissue sensitivity to the actions of insulin. Thiazolidinediones increase the number of glucose transporters at the cellular level without affecting the number or affinity of insulin receptors.29 Pharmacologic therapy for risk markers of vascular disease in diabetes include drugs to prevent blood clots or increase blood viscosity, decrease lipids, normalize thyroid-stimulating hormone levels, protect kidney function, and aid in smoking cessation (see Table 4).
Patient Education Patients and their families are important participants in the prevention of diabetes complications and the monitoring of risk markers for vascular disease (see Table S). Patient recognition of weight gain, elevated blood glucose, calluses on the feet, elevated blood pressure, and complication symptoms are essential for early intervention. Patient education should focus on teaching the importance of daily aerobic exercise, food portion control, a low-fat and low-sugar diet, home glucose monitoring, drug compliance, daily foot evaluations, regular health care appointments, and regular ophthalmologic appointments. If the patient is a smoker, referral to a smoking cessation clinic is recommended. Depending on the patient's exercise capacity, aerobic exercise is recommended 4 to 5 days per week, including a minimum of 20 to 30 minutes of sustained activity A warm-up and cooldown stretch should be performed before and after exercising. A 1,500 to 2,000-calorie daily diet should include whole-grain breads, vegetables, fruits, 3 ounces of meat, 4 to 6 glasses of water, and broiled, baked, or boiled foods. Only one-third of the calories should come from fat. Desserts should be limited to fruit, non-fat pudding, or no-sugar and low-fat products. Home glucose monitoring is most beneficial for Type 1 diabetes patients, although all diabetes patients should monitor their blood glucose for optimum control. Urine testing is no longer part of the standard of care, because the results are inaccurate. Alcohol can elevate blood glucose and should only be used in moderation. Conclusion Diabetes complications can have a devastating impact on the patient and on the health care system. Diabetes management has been broadened over the past 10 years to include drugs for risk markers for vascular disease. Clinicians must provide comprehensive monitoring of the patient's lifestyle, appropriate laboratory tests, and complication indications to intervene early. Preventing diabetic vascular complications is the goal of diabetes management. m REFERENCES 1. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20(7):1183-94. 2. Karam JH: Diabetes mellitus and hypoglycemia. In: Tierney LM, McPhee SJ,Papadakis MA: Current medical diagnosis and treatment, 37th edition. Stamford, Conn.: Appleton & Lange, 1998:1098-1121. 3. Bloomgarden Z: Topics in cardiovascular disease and diabetes. Diabetes Care 1997;12(9):1624-27. 4. Staker L: Diabetes outcomes chain. American Association of Diabetes Educators Symposium. Denver, Colo., October 1997.
5. Forrest K, Maser RE, Piambianco G, et al.: Hypertension as a risk factor for diabetic neuropathy. Diabetes 1997;46(4):665-69. 6. Dagogo-Jack S, Santiago JV: Pathophysiology of type 2 diabetes and modes of action of therapeutic intervention. Arch Intern Med 1997;157(9):1802-14. 7. Deckert T, KofoedEnevoldsen A, Norgaard K, et al.: Microalbuminuria: implications for micro- and macrovascular disease. Diabetes Care 1992;15(9):1181-88. 8. Colucci WS, Braunwald E: Cardiac tumors, cardiac manifestations of systemic diseases, and traumatic cardiac injury. In: Fauci AS, Braunwald E, Isselbacher KJ, et al.: Harrison's principles of internal medicine, 14th edition. New York, N.Y: McGraw-Hill, 1998:1342-44. 9. Haas LB: Chronic complications of diabetes mellitus. Nursing Clin North Am 1993;28(3):71-85. 10. O'Keefe JH, Miles JM, Harris WH, et al.: Improving the adverse cardiovascular prognosis of type 2 diabetes. Mayo Clinic Proceedings 1999;74:171-80. 11. Haffner SM: Risk factors for cardiovascular complications in type 2 dia betes. In: Roberts WO: Managing type 2 diabetes new science and new strategies. A Postgraduate Medicine Special Report 1998;7. 12. Haas LB: Impact and cost of particular outcomes. American Diabetes Association Workshop: Improving outcomes in diabetes mellitus: Practical approaches to complex problems. Denver, Colo., 1997. 13. Riordan-Eva P, Vaughn DG: Eye. In: Tierney LNl, McPhee SJ, Papadakis MA: Current medical diagnosis and treatment, 37th ed. Stamford, Conn.: Appleton & Lange, 1998;198. 14. Akbari CWI, Gibbons GW; Habershaw GM, et al.: The effect of arterial re construction on the natural history of diabetic neuropathy. Arch Surg 1997:132(2):148-52. 15. Chipkin SR, Gottlieb PA, Bogorad DD, et al.: Diabetes mellitus. In: Noble J: Textbook of primary care medicine, 2nd edition. New York, N.Y.: Mosby,1996;495. 16. Malik RA: The pathology of human diabetic neuropathy. Diabetes 1997;46(9)(suppl):S50553. 17. Alfrey AC, Chan, L: Chronic renal failure: Manifestations and pathogenesis. In: Schrier RW: Renal and electrolyte disorders, 4th edition. Boston, Mass.: Little Brown and Co., 1992;141-42. 18. Vijan S, Hofer TP, Hayward RA: Estimated benefits of glycemic control in microvascular complications in type 2 diabetes. Ann Intern Med 1997;127(9):788-94. 19. Mogensen CE: How to protect the kidney in diabetic patients with special reference to IDDM. Diabetes 1997;46(9)(suppl 2):5104-St [0.
20. Vlassara H: Recent progress in advanced glycation end products and diabetic complications. Diabetes 1997;46(suppl 2):519-523. 21. Jensen T: Pathogenesis of diabetic vascular disease: Evidence for the role of reduced heparin sulfate proteoglycan. Diabetes 1997;46(suppl 2):598-99. 22. Schror K: Blood vessel wall interactions in diabetes. Diabetes 1997; 46(9)(suppl2):511517. 23. Hanssen KF: Blood glucose control and microvascular and macrovascular complications in diabetes. Diabetes 1997;46(9)(suppl 2):S 101-03. 24. Aiello JH; Preventing diabetic nephropathy: The role of primary care. Nurs Pract 1998;23(2):12-31. 25. Heesom AE, Hibberd ML, Millward A, et al.: Polymorphism in the p'-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type 1 diabetes. Diabetes 1997;(2):287-40. 26. Deedwania PC: The deadly quarter revisited. The cardiovascular dysmetabolic syndrome. Am J Med 1998; 05(lA)(7)(suppl):25. 27. Donahue RP, Orchard TJ: Diabetes mellitus and macrovascular complications: An epidemiological perspective. Diabetes Care 1992;15(9):1141-54. 28. Karch AM: 1999 Lippincott's Nursing Drug Guide. New York, N.Y.: Lippincott Williams & Wilkins, 1999. 29. Ghazzi IN, Perez JE, Antonucci TK, et al.: Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997;46(3):433-39. ABOUT THE AUTHORS Sheila Winters, RN, FNf? MEd, is a family nurse practitioner with the Veterans Affairs Medical Center in Denver, Colo. Verna Jernigan, ANP, MSN, is an adult nurse practitioner with the Veterans Affairs Medical Center, in Denver, Colo.
ABC of arterial and venous disease

Vascular complications of diabetes
Richard Donnelly, Alistair M Emslie-Smith, Iain D Gardner, Andrew D Morris. Adults with diabetes have an annual mortality of about 5.4% (double the rate for non-diabetic adults), and their life expectancy is decreased on average by 5-10 years. Although the increased death rate is mainly due to cardiovascular disease, deaths from non-cardiovascular causes are also increased. A diagnosis of diabetes immediately increases the risk of developing various clinical complications that are largely irreversible and due to microvascular or macrovascular disease. Duration of diabetes is an important factor in the
pathogenesis of complications, but other risk factors for example, hypertension, cigarette smoking, and hypercholesterolaemia interact with diabetes to affect the clinical course of microangiopathy and macroangiopathy.
Vascular complications of diabetes
Microvascular Retinopathy Nephropathy Neuropathy
Macrovascular Ischaemic heart disease Stroke Peripheral vascular disease
Risk of morbidity associated with all types of diabetes mellitus
Complication Blindness End stage renal disease Amputation Myocardial infarction Stroke *Compared with non-diabetic patients
Relative risk* 20 25 40 2-5 2-3
Top Microvascular complications Macrovascular complications Surveillance and management in...
Microvascular complications
A continuous relation exists between glycaemic control and the incidence and progression of microvascular complications. Hypertension and smoking also have an adverse effect on microvascular outcomes. In the diabetes control and complications trial a landmark study in type 1 diabetes the number of clinically important microvascular endpoints was reduced by 34-76% in patients allocated to intensive insulin (that is, a 10% mean reduction in glycated haemoglobin (HbA1c) concentration from 8.0% to 7.2%). However, these patients also had more hypoglycaemic episodes. Similarly, in the UK prospective diabetes study of patients with type 2 diabetes, an intensive glucose control policy that lowered glycated haemoglobin concentrations by an average of 0.9% compared with conventional treatment (median HbA1c 7.0% v 7.9%) resulted in a 25% reduction in the overall microvascular complication rate. It was estimated that for every 1% reduction in HbA1c concentration there is a 35% reduction in microvascular disease.
Relation between glycaemic control (HbA1c) and risk of progression of microvascular complications (retinopathy) and severe hypoglycaemia in patients with type 1 diabetes. Data from the diabetes control and complications trial. Dotted lines represent 95% confidence intervals View larger version (34K): [in this window] [in a new window]
Classification and features of diabetic retinopathy
Grade I Background retinopathy
Examination features Microaneurysms Small blot haemorrhages Hard exudates Not affecting macula Leakage in macular region Capillary occlusion Hard exudates Cotton wool spots None
Symptoms
II Background with maculopathy III Preproliferative
Central visual loss (such as reading difficulty) None
retinopathy
IV Proliferative retinopathy V Advanced diabetic eye disease
Venous abnormalities Large blot haemorrhages Intraretinal microvascular abnormalities New vessels on disc or elsewhere on retina Extensive fibrovascular proliferation Retinal detachment Vitreous haemorrhage Thrombotic glaucoma
None, but complications cause visual loss Severe visual loss
Retinopathy Diabetic retinopathy is a progressive disorder classified according to the presence of various clinical abnormalities. It is the commonest cause of blindness in people aged 30-69 years. Damage to the retina arises from a combination of microvascular leakage and microvascular occlusion; these changes can be visualised in detail by fluorescein angiography. A fifth of patients with newly discovered type 2 diabetes have retinopathy at the time of diagnosis. In type 1 diabetes, vision threatening retinopathy almost never occurs in the first five years after diagnosis or before puberty. After 15 years, however, almost all patients with type 1 diabetes and two thirds of those with type 2 diabetes have background retinopathy.
Background retinopathy showing microaneurysms and small blot haemorrhages
View larger version (108K): [in this window] [in a new window]
Diabetic maculopathy
Effect of antihypertensive treatment ( blockers and diuretics) on mean arterial pressure, glomerular filtration rate, and albuminuria in patients with type 1 diabetes and nephropathy. Reproduced with permission from Mogensen, Diabetic Med 1995;12:756-9. View larger version (37K): [in this window] [in a new window] Vision threatening retinopathy is usually due to neovascularisation in type 1 diabetes and maculopathy in type 2 diabetes. Depending on the relative contribution of leakage or capillary occlusion, maculopathy is divided into three types: exudative maculopathy (when hard exudates appear in the region of the macula), ischaemic maculopathy (characterised by a predominance of capillary occlusion which results in clusters of haemorrhages), and oedematous maculopathy (extensive leakage gives rise to macular oedema). Treatment of maculopathy and proliferative retinopathy with laser photocoagulation prevents further loss of vision rather than restores diminished visual acuity. Nephropathy Diabetic nephropathy is characterised by proteinuria >300 mg/24 h, increased blood pressure, and a progressive decline in renal function. At its most severe, diabetic nephropathy results in end stage renal disease requiring dialysis or transplantation, but in the early stages overt disease is preceded by a phase known as incipient nephropathy (or microalbuminuria), in which the urine contains trace quantities of protein (not detectable by traditional dipstick testing). Microalbuminuria is defined as an albumin excretion rate of 20-300 mg/24 h or 20200 g/min in a timed collection and is highly predictive of overt diabetic nephropathy, especially in type 1 diabetes.
The rate of decline in glomerular filtration rate varies widely between individuals, but antihypertensive treatment greatly slows the decline in renal function and improves survival in patients with diabetic nephropathy.
Data from WHO multinational study of vascular disease in diabetes showing survival in patients with type 1 and type 2 diabetes according to degree of proteinuria (none, slight, or heavy) at baseline. Reproduced with permission from Stephenson et al, Diabetic Med View larger version (26K): 1995;12:149-55 [in this window] [in a new window] In patients with type 1 diabetes complicated by diabetic nephropathy, angiotensin converting enzyme inhibitors have renoprotective effects above those that can be attributed to reduced blood pressure; they are beneficial even in normotensive patients and ameliorate other associated microvascular complications such as retinopathy. In patients with type 2 diabetes, achieving good blood pressure control (which often requires combination therapy) is more important than the choice of antihypertensive drug, although angiotensin converting enzyme inhibitors are the preferred first line treatment
Clinical features of "high risk" diabetic foot

Impaired sensation (monofilament) Past or current ulcer Maceration Fungal or gryphotic (thickened or horny) toenails Biomechanical problems (corns or callus) Fissures Clawed toes
The development of proteinuria is a marker of widespread vascular damage and signifies an increased risk of subsequent end stage renal disease and macrovascular complications, especially coronary heart disease. Microproteinuria and proteinuria are strongly associated with decreased survival in both type 1 and type 2 diabetes. Neuropathy The diabetic neuropathies present in several ways. The commonest form is a diffuse progressive polyneuropathy affecting mainly the feet. It is predominantly sensory, often asymptomatic, and affects 40-50% of all patients with diabetes. Reduced sensation can be detected with a monofilament, and patients with sensory neuropathy as well as other high risk
features need advice on foot care to minimise the risk of ulceration. Neuropathic foot ulcers can be distinguished from vascular ulcers, although a mixed aetiology is common.
Clinical features that distinguish neuropathic and vascular foot ulcers
Neuropathic Painless Located at points of high pressure "Punched out" appearance surrounded by callus Warm foot Bounding foot pulses
Vascular Painful Often located at the extremities Cool ischaemic foot Absent foot pulses
Macrovascular complications
Atherosclerotic disease accounts for most of the excess mortality in patients with diabetes. In the UK prospective diabetes study, fatal cardiovascular events were 70 times more common than deaths from microvascular complications. The relation between glucose concentrations and macrovascular events is less powerful than for microvascular disease; smoking, blood pressure, proteinuria, and cholesterol concentration are more important risk factors for atheromatous large vessel disease in patients with diabetes.
Predictors of cardiovascular mortality
Type 1 diabetes
Type 2 diabetes
Overt nephropathy Presence of coronary heart disease Hypertension Overt proteinuria Smoking Glycated haemoglobin Microalbuminuria Hypertension Age Taken from BMJ 1996:313:779-84, Diabetes1995;44:1303-9
Estimated hazard ratios for significant risk factors for coronary heart disease occurring in 335 out of 3055 patients with type 2 diabetes. Reproduced from Turner et al, BMJ 1998;316:823-8.
Hyperlipidaemia is no more common in patients with well controlled type 1 diabetes than it is in the general population. In patients with type 2 diabetes, total and low density lipoprotein cholesterol concentrations are also similar to those found in non-diabetic people, but type 2 diabetes is associated with a more atherogenic lipid profile, in particular low concentrations of high density lipoprotein cholesterol and high concentrations of small, dense, low density lipoprotein particles. Hypertension affects at least half of patients with diabetes. In the UK prospective diabetes study tight blood pressure control (mean 144/82 mm Hg) achieved significant reductions in the risk of stroke (44%), heart failure (56%), and diabetes related deaths (32%), as well as reductions in microvascular complications (for example, 34% reduction in progression of retinopathy). One third of patients required three or more antihypertensive drugs to maintain a target blood pressure <150/85 mm Hg. In another recent study (hypertension optimal treatment study) rates of cardiovascular events in patients with type 2 diabetes were reduced even further when combination treatment was used to aim for target diastolic blood pressures <80 mm Hg. Coronary heart disease The incidence and severity of coronary heart disease events are higher in patients with diabetes, and several clinical features are worth noting. The diabetes subgroups in the major secondary prevention studies of cholesterol reduction (Scandinavian simvastatin survival study (4S) and cholesterol and recurrent events (CARE) trial) show a beneficial effect of statins.
Features of coronary heart disease in diabetic patients
Acute myocardial infarction Prevalence of fatal and In-hospital and non-fatal coronary heart 6 month mortality double disease events 2-20 that in non-diabetics higher than for nonComplications (eg, diabetics of similar age arrhythmias, heart failure, Protective effect of death) more common female sex is lost Reperfusion rates after Higher incidence of thrombolysis are similar diffuse, multivessel to those of non-diabetics, disease but reocclusion and Plaque rupture leading to reinfarction rates are unstable angina and higher myocardial infarction is Mortality reduced by more common insulin glucose infusion Superimposed immediately after thrombosis more likely myocardial infarction
Atherosclerosis
Revascularisation 5 year survival rates after coronary artery bypass graft or percutaneous coronary angioplasty lower than for nondiabetics 5 year survival better after coronary artery bypass graft than percutaneous coronary angioplasty because of higher restenosis rates with angioplasty (81% v 66%)
Rates of serious cardiovascular events according to target diastolic blood pressure in 1500 patients with hypertension and type 2 diabetes. Drawn from Hansson et al, Lancet 1998;351:1755-62.
Peripheral vascular disease Atheromatous disease in the legs, as in the heart, tends to affect more distal vessels for example, the tibial arteries producing multiple, diffuse lesions that are less straightforward to bypass or dilate by angioplasty. Medial calcification of vessels (Mnckeberg's sclerosis) is common and can result in falsely raised measurements of the ankle brachial pressure index.
This index is therefore less reliable as a screening test in patients with diabetes and intermittent claudication. Stroke Roughly 85% of acute strokes are atherothrombotic, and the rest are haemorrhagic (10% primary intracerebral haemorrhage and 5% subarachnoid haemorrhage). The risk of atherothrombotic stroke is two to three times higher in patients with diabetes, but the rates of haemorrhagic stroke and transient ischaemic attacks are similar to those of the non-diabetic population. Patients with diabetes are probably more prone to irreversible rather than reversible ischaemic brain damage, and small lacunar infarcts are common. Stroke patients with diabetes have a higher death rate and a poorer neurological outcome with more severe disability. Maintaining good glycaemic control immediately after a stroke is likely to improve outcome, but the long term survival is reduced because of a high rate of recurrence. Antihypertensive treatment is effective in preventing stroke.
Kaplan-Meier plot of proportions of patients who developed fatal or non-fatal stroke, according to blood pressure control. Reproduced from Turner et al, BMJ 1998;317:703-13. View larger version (22K): [in this window] [in a new window]
Erectile dysfunction Erectile dysfunction is a common complication of diabetes, occurring in up to half of men aged over 50 years (compared with 15-20% in age matched non-diabetic men), although the exact prevalance is unknown because of likely underreporting. The underlying pathogenesis is multifactorial, with autonomic neuropathy, vascular insufficiency, and psychological factors contributing to the clinical picture. The condition causes appreciable social and psychological problems for many patients, and its importance should not be underestimated. The recent introduction of sildenafil, which is reported to have a 50-70% success rate in patients with diabetes, is an important advance.
Transition from normal renal function through to end stage renal disease requiring dialysis or transplantation. Increasing proteinuria and renal impairment is associated with an increasing risk of fatal or non-fatal coronary heart disease, especially in older patients with type 2 diabetes and other risk factors
Recommendations on prevention of coronary heart disease in clinical practice
Glycaemic control Blood pressure control Target Glycated 140/80 mm Hg without haemoglobin macrovascular disease 7.0% Fasting blood 130/80 mm Hg with glucose 4-7 mmol/l macrovascular disease
Lipid control
Treatment (in addition to lifestyle and dietary advice)
Serum cholesterol <5.0 mmol/l in patients with established coronary heart disease Primary prevention in those with >30% risk of coronary heart disease over 10 years Metformin (first Angiotensin converting Statins (regular line if body mass enzyme inhibitors: monitoring of liver index>25) renoprotective but caution function) Sulphonylurea in renal artery stenosis Acarbose (17% of hypertensive Glitazones (not yet diabetics) Diuretics available in United blockers Kingdom) blockers
Insulin Combination therapy
Long acting calcium antagonists 50% of patients will require 3 drugs for optimum control
Surveillance and management in general practice

Screening for diabetes Up to half of people with type 2 diabetes have vascular complications at the time of diagnosis. Early detection of diabetes is therefore essential. Screening (by measuring fasting blood glucose concentration) should be considered for high risk patients, especially those who are middle aged and obese, are of Asian or Afro-Caribbean origin, have a history of gestational diabetes, or have a family history of diabetes. Eye screening The small number of patients with retinopathy in any one practice (about 50 patients per 10 000 practice list) does not allow most general practitioners to develop and maintain their funduscopic skills. Innovative approaches, including the use of trained community optometrists and mobile retinal photography units that visit practices annually, can provide a high standard of retinal screening in the community. Cardiovascular risk prediction Identification of patients at highest risk of developing cardiovascular events allows efforts and resources to be channelled most effectively. Coronary risk prediction charts and computer programs such as that recently produced as part of the joint British recommendations on prevention of coronary heart disease in clinical practice will help general practitioners to implement the findings of recent major clinical trials. Annual complications assessment All patients with diabetes should be offered an annual clinical assessment concentrating on the prevention, detection, and management of macrovascular and microvascular complications.
Annual complications assessment
Physical examination Body mass index calculation (weight (kg)/(height (m))2) Blood pressure measurement with patient sitting and appropriate sized cuff Palpation of foot pulses Measurement of foot sensation by one or more of following: 10 g monofilament weight (not detected = impaired) Vibration of 128 Hz tuning fork over medial malleolus (perception for <5 secs=impaired) Assessment of ankle jerk with tendon hammer (less reliable in elderly people) Inspection of feet for nail care, callosities, fissures, fungal infection, blisters, ulcers, claw toes, prominent metatarsal heads, and Charcot arthropathy Visual acuity in corrected state, using standard 6 m (or 3 m) Snellen chart. Use pin hole if corrected acuity is 6/9 Retinal examination by one of:
Biochemical analysis Dipstick urine analysis for proteinuria Urine testing for microalbuminuria in type 1 diabetes Blood testing of: Glycated haemoglobin Serum creatinine Serum total cholesterol and high density lipoprotein cholesterol History, advice, and education
Smoking history
Education and reinforcement of advice on diet, aerobic exercise, and lifestyle Review treatment, including side effects and compliance Assess knowledge of diabetes and self management skills, including warning signs for complications (intermittent claudication, angina pectoris, foot problems) Review footwear provision Review need for contact with dietetics, chiropody, orthotics, and diabetes specialist nurse support Advice on erectile dysfunction in men Prepregnancy counselling, where appropriate Calculate and discuss risk of coronary heart disease and modification of risk factors
Direct ophthalmoscopy through pupils dilated with 1% tropicamide Combination of direct ophthalmoscopy and slit lamp biomicroscopy Retinal photography through fixed site or mobile non-mydriatic fundus camera
Areas of debate in surveillance of diabetes complications The value of routine measurements of microalbuminuria in patients with type 2 diabetes is
less clear than in type 1 diabetes. Arrangements to allow the testing of microalbuminuria in general practice are not universally available.
Neuropathic ulcer is a common complication in patients with diabetes
Use of monofilament to detect impaired sensation during annual assessment
View larger version (106K): [in this window] [in a new window] The presence of left ventricular hypertrophy is a powerful predictor of the risk of a cardiovascular event, but screening by echocardiography or electrocardiography is often not included as part of the routine annual assessment. Unlike total cholesterol concentrations and the total cholesterol to high density lipoprotein cholesterol ratio, the importance of raised triglyceride concentrations in the risk profile of patients with type 2 diabetes is unclear.
Team approach to integrated diabetic care The ongoing care of patients with diabetes, in particular once they have developed vascular complications, includes a wide spectrum of healthcare professionals. A systematic, integrated, and collaborative approach must be developed at a regional level, with clear lines of communication and the adoption of locally agreed guidelines for treatment and referral based on national guidelines for example, those from the Scottish Intercollegiate Guideline Network (www.show.scot.nhs.UK/sign/home.htm).
Etiology Coronary artery disease (CAD), nephropathy, retinopathy, and neuropathy are considered diabetes complications. However, diabetes patients in less affluent societies have fewer cardiovascular complications than those in the United States. Other factors that may influence complications include diet, body weight, physical activity, and tobacco use. Platelet function abnormalities and blood viscosity are known to influence micro- and macrovascular disease in diabetes. Some researchers believe that a connection exists between chronic hyperglycemia and decreased oxygen delivery (relative hypoxia), leading to the pathogenesis for several diabetes complications. The hypoxia is related to capillary and arteriole dysfunction in diabetes.5,6 Glycemic control has not been proven to be an independent factor in preventing macrovascular disease. Heparin sulfate may be a common factor between vascular disease and diabetes. Heparin sulfate has antiatherogenic properties and contributes to the structural integrity of large vessel walls and basal membrane cells. If heparin sulfate is elevated, there is less possibility of cholesterol plaque development in the vascular structures.7 If blood sugar is chronically elevated, the heparin sulfate level decreases. Another common factor of vascular disease and diabetes is thyroid function in the body. Hypothyroidism can lead to decreased insulin production, elevated glucose levels, decreased heparin sulfate production, elevated albumin, increased basement membrane thickening, and increased insulin resistance.8 As with decreased heparin sulfate, the process outcome in large blood vessels may result in atherosclerosis and CAD. In the kidneys, a decreased renal glomerular filtration rate and chronic renal insufficiency development may occur. In ocular blood vessels, this process may lead to retinopathy and cataracts. CAD risk factors that contribute to atherosclerotic plaque development include smoking, elevated cholesterol, hypertension, genetic predisposition, insulin resistance, and fibrin deposition on the surface of endothelial cells leading to platelet adhesion. Other pathophysiologic mechanisms that may influence vascular complications include protein glycosylation, disruption in the polyol pathway, decreased myoinositol, impaired glucose tolerance, and beta cell dysfunction in the pancreas.9 Pathophysiology
Four theories emerge in the literature on the pathophysiology of diabetes and vascular disease. The common factor in all of the theories is hyperinsulinemia and/or increased insulin resistance. Insulin resistance is a state where tissues, such as skeletal muscle, have a reduced sensitivity to the effects of insulin-stimulated glucose uptake. This impairment leads to hyperinsulinemia, which sometimes evolves into overt Type 2 diabetes.10 Insulin resistance is expressed in the liver through overproduction of glucose and in peripheral tissues through impaired utilization of glucose by skeletal muscle and adipose tissue." Each theory has a different starting point in the cascade of factors leading to vascular complications in diabetes (see Figure 1). Risk Markers The significance of monitoring and treating risk factors for vascular disease is not only to prevent end-stage renal disease and death, but also to improve quality of life and increase life expectancy. Microalbuminuria is a significant factor in a complex chain of events that can lead to premature atherosclerosis, increased basement membrane thickening, and increased insulin resistance. Precipitating factors for microalbuminuria are decreased heparin sulfate, chronically elevated blood glucose, and increased low-density lipoprotein (LDL) cholesterol.
Clinical review
Prevention and early detection of vascular complications of diabetes
Sally M Marshall, professor of diabetes1, Allan Flyvbjerg, professor in experimental medical research2 Diabetes Research Group, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, 2 University of Aarhus, Denmark, DK 8000 Correspondence to: S M Marshall s.m.marshall@ncl.ac.uk
1
Introduction
Diabetes reduces life expectancy by five to 10 years. Premature cardiovascular disease is the most common cause of morbidity and mortality, but the microvascular complications specific to diabetes (box 1) are also contributory factors. Diabetes is the most common reason for renal replacement therapy worldwide, the most common cause of blindness in the under 65s, and the most common cause of non-traumatic amputation. With our current knowledge, most of these devastating events could be prevented or delayed, or their impact minimised. This review focuses on the prevention, early detection, and initial management of the vascular complications of diabetes in adults.
Why are the complications of diabetes important?

Complications are common and the cost to the individual and society is enormous. The onset of complications reduces quality of life, particularly when both microvascular and macrovascular disease are present.w1 The CODE-2 study gathered data on 7000 people with type 2 diabetes from eight European studies72% had at least one complication and 24% had both (microvascular and macrovascular) complications.w2 Over six months, 13% of the patients were admitted to hospital for a mean of 23 days. The estimated average yearly cost per patient was 2834 (1934, $3585); 55% of this cost was attributable to hospital admissions and only 7% to the cost of insulin and oral drugs for lowering glucose.1
Who develops complications?

The risk of developing complications is variable (table 1). For nephropathy, in particular, a strong but unknown genetic influence exists. The duration of diabetes, glycaemic control, and hypertension are the strongest risk factors for microvascular disease; smoking, blood pressure, lipids, and albuminuria are the strongest risk factors for macrovascular disease.
View this table: Table 1 Risk factors and markers for the development of [in this window] complications of diabetes [in a new window]
Macrovascular disease Excess mortality from cardiovascular disease is seen in all age groups, particularly in young people with type 1 diabetes (box 2), and is exacerbated by social deprivation (table).w3 Premenopausal women with diabetes lose their protection against macrovascular disease (fig A on bmj.com).2 w4 w5 In type 2 diabetes, the risk of myocardial infarction and stroke is two to five times higher than in the general population.
Summary points Patients with diabetes have an average reduction in life expectancy of five to 10 years, mainly because of premature cardiovascular disease The microvascular complications specific to diabetes (retinopathy, nephropathy, neuropathy) also contribute to premature mortality and morbidity The risk of vascular complications can be greatly reduced by tight control of glucose and blood pressure and by aggressive management of cardiovascular risk factors Early detection of complications, by systematic annual screening, allows prompt
intervention that may prevent or delay the emergence of end stage disease A multifactorial approach to tightening the management of risk factors reduces the progression of microvascular and macrovascular complications
Retinopathy The World Health Organization estimates that diabetic retinopathy is the cause of blindness in 5% of blind people worldwide.3 Almost everyone with diabetes has some degree of retinopathy after 20 years (see appendix on bmj.com for the grading of diabetic retinopathy), but only 20-50% of patients develop sight threatening disease. In some centres the cumulative incidence of sight threatening retinopathy is falling.4 w6 w7 Nephropathy About half of patients with diabetes develop microalbuminuria at some point. Approximately one third will progress to proteinuria, one third will remain microalbuminuric, and one third will revert to normal albumin excretion (fig 1).w8 Microalbuminuria and proteinuria are more common in ethnic minorities worldwide.w9 w10 Once proteinuria is present, progression to end stage renal disease is inevitable. From 20% to 50% of patients who start renal replacement therapy have diabetes.5 w11 The rapid increase in the numbers of patients with diabetes requiring renal replacement in Europe in recent years is due mainly to the rise in the number of patients with type 2 diabetes (fig B on bmj.com).6
Fig 1 Development of nephropathy
Box 1: Long term vascular complications of diabetes Microvascular complications

Retinopathy Nephropathy Neuropathy
Macrovascular complications

Cerebrovascular disease Ischaemic heart disease Peripheral arterial disease
Neuropathy Patients with diabetes have a 30-50% lifetime risk of developing chronic peripheral neuropathy (box 3), and 10-20% of patients develop severe symptoms.7 w12 w13 Peripheral neuropathy contributes to foot ulceration and amputation of lower limbs.8 Erectile dysfunction occurs in up to 50% of men over 50 years, compared with 15-20% of men without diabetes. Other neuropathies are rare but have a major impact on quality of life and life expectancy.
Pathophysiology
Both the metabolic and haemodynamic abnormalities of diabetes contribute to the development of complications. Intracellular hyperglycaemia develops in cells that cannot downregulate the uptake of glucose. This stimulates biochemical and haemodynamic pathways (fig 2). Signalling molecules and growth factors are activated, with consequent tissue damage.9 Genetic factors and external "accelerators" also contribute. A mechanism that links the activation of these pathways to the overproduction of superoxide by the mitochondrial electron transport chain has been suggested.10
Fig 2 Metabolic pathways that contribute to vascular complications of diabetes
Sources and selection criteria
We searched PubMed with the keywords "diabetic complications", "retinopathy", "diabetic nephropathy", "microalbuminuria", "diabetic foot", "peripheral neuropathy", "cardiovascular disease", "ischaemic heart disease", "peripheral arterial disease", and "cerebrovascular disease". We gave preference to original articles published within the past three years and to reviews in journals with a high impact factor (rate of citation) We searched the Cochrane database of systematic reviews; Cochrane database of abstracts and reviews of effectiveness; and Cochrane central registry of controlled trials We searched personal archives of references
Microvascular complications are strongly associated with cardiovascular disease. A familial or genetic process may influence the development of both cardiovascular disease and microvascular pathology.w14-w16
How do I prevent complications?

Box 4 lists the main strategies to prevent the complications of diabetes. Glucose control The diabetes control and complications trial (DCCT) in type 1 diabetes and the UK prospective diabetes study (UKPDS) in type 2 diabetes showed that the lower the glycated haemoglobin achieved the lower the risk of microvascular complications.11 12 During the eight year open follow-up of the DCCT cohort, glycated haemoglobin values were similar in patients who had previously been managed intensively or conventionally.13 14 w17 Despite this, patients who had previously been in the intensively managed group were less likely to have microvascular complications (fig 3). Thus, a period of good glycaemic control reduces the risk of complications for longer than the duration of tight control, a phenomenon known as metabolic memory.
Fig 3 Prevalence of complications at open follow-up of patients who completed the diabetes control and complications trial. Prevalence of progression at *four years and eight years
The association between glucose control and cardiovascular disease is less strong but is still important. UKPDS found a 14% reduction in the risk of myocardial infarction for each 1% reduction in glycated haemoglobin.w18 In the long term follow-up of DCCT, the risk of a cardiovascular event was 42% lower in the intensively managed group (fig C on bmj.com).15
Box 2: Macrovascular disease in diabetes

Macrovascular disease is the main cause of death in type 1 and type 2 diabetes Excess mortality is seen in all age groups, especially the young Premenopausal women lose their protection against macrovascular disease Disease is diffuse, distal, and affects many vessels Reocclusion and reinfarction rates are higher after thrombolysis Restenosis rates are higher after angioplasty, although drug eluting stenting may help Five year survival after coronary artery bypass grafting is lower than in nondiabetic patients
Box 3: Neuropathies in diabetes Peripheral neuropathies

Distal symmetric sensorimotor neuropathy Femoral neuropathy (amyotrophy) Mononeuropathies (ocular or truncal) Pressure palsies (median, ulnar, or lateral popliteal)
Autonomic neuropathy

Postural hypotension Bladder dysfunction Gastric paresis Constipation or diarrhoea, or both Gustatory sweating (on the forehead, face, scalp, and neck after eating) Erectile dysfunction
Blood pressure In UKPDS, tight control of blood pressure (144/82 v 154/87 mm Hg) reduced the incidence of a microvascular event by 37%.16 A reduction in systolic blood pressure of 10 mm Hg was associated with a 13% reduction in risk for a microvascular event and an 11% reduction for myocardial infarction.w19 Other studies have shown that the reduction in relative risk is at least as great in the diabetic population as in the non-diabetic population, so that the absolute benefits of a reduction in blood pressure are greater.17 18 The choice of initial antihypertensive drug is less important than reducing blood pressure. Tight targets (< 130/80 mm Hg) are difficult to reach and require at least three antihypertensive drugs. Drugs that are taken once daily and that have good 24 hour cover should be used. A Cochrane review suggests that angiotensin converting enzyme inhibitors are the best drugs to prevent microalbuminuria and nephropathy.19 w20 A recent meta-analysis that did not support this conclusion has been criticised for many reasons.w21 Lipids Two placebo controlled trials have shown that treatment with statins reduces the risk of a major cardiovascular event by 37% in patients with type 2 diabetes without clinically apparent cardiovascular disease.20 21 The reduction in relative risk is as great in the diabetic population as in the non-diabetic population, so that the absolute benefit is greater.22 Thus, all patients with diabetes aged 40 years or more should be offered statins. Younger patients have a high lifetime risk of cardiovascular disease even though their 10 year risk is relatively low. Statins should be offered to those at particularly high risk (box 4). When fibrates should be prescribed is unclear. In a recent large, randomised, controlled trial, fenofibrate did not reduce the risk of primary coronary events in type 2 diabetes.23 Despite the lack of robust evidence, however, once low density lipoprotein-cholesterol and control of blood glucose are optimal, clinicians should consider adding a fibrate to statin therapy if triglycerides are still greater than > 2.3 mmol/litre.
Box 4: Preventing complications Glucose control
Glycated haemoglobin should be as low as possible (but avoid undue hypoglycaemia)aim for < 7.0% if the patient is on insulin or < 6.5% if not on insulin
Blood pressure Blood pressure should be as low as possible (avoiding symptoms of postural hypotension)aim for < 130/80 mm Hg or < 125/75 mm Hg if proteinuria is present, if the glomerular filtration is < 60 ml/min/1.73 m2, or if the patient has cardiovascular
disease Lipids

Statins should be prescribed for patients over 40 Statins should be prescribed for patients under 40 who have microvascular or macrovascular complications, hypertension, metabolic syndrome, or a strong family history of cardiovascular disease Total cholesterol should be < 4.5 mmol/litre Low density lipoprotein-cholesterol should be < 2.5 mmol/litre Fibrates should be prescribed if triglycerides are > 2.3 mmol/litre and low density lipoprotein-cholesterol values are < 2.5 mmol/litre
Aspirin
Aspirin should be prescribed for all patients over 40
Smoking
Patients should be encouraged to stop smoking
Lifestyle
Patients should be encouraged to lose weight if necessary, exercise, and eat healthily
Smoking It is essential that patients stop smoking to reduce the risk of cardiovascular disease and probably the risk of microvascular complications. Aspirin Although no studies have been performed on primary prevention of cardiovascular disease in diabetes, low dose aspirin is usually recommended, even in the absence of overt cardiovascular disease.
How do I detect and screen for complications?

Complications must be diagnosed earlyprompt intervention may prevent or delay the emergence of end stage disease such as blindness, the need for renal replacement therapy, or amputation. A systematic, structured screening programme, run annually, is most cost effective as a "one stop" package. Macrovascular disease Screening for macrovascular disease rests on symptoms of angina or claudication and with a low threshold for investigation. Routine exercise tolerance testing or stress echocardiography are not recommended. A 12 lead resting electrocardiogram has low sensitivity and specificity, although it does provide a useful baseline.
Box 5: Screening for peripheral neuropathy and peripheral arterial disease

Inquire about symptoms of peripheral neuropathy and peripheral vascular disease Ask about previous foot ulceration or amputation Ask about physical or visual difficulty in self management of foot care Inspect feet for evidence of deformity, neuropathy, ischaemia, infection Detect neuropathy with a 10 g monofilament or 128 Hz tuning fork or biosthesiometer. Use non-traumatic pin prick testing Assess arterial circulation by measuring dorsalis pedis and posterior tibial foot pulses; measure Doppler ankle: brachial pressure ratio if available
Retinopathy Corrected visual acuity should be measured and retinopathy assessed. Retinal photography, usually through dilated pupils and performed and interpreted by trained healthcare professionals, is the preferred method. Sensitivity and specificity must be acceptable, there must be an ongoing quality assurance programme, and the number of images that cannot be graded must be low.w22 Screening with static or "mobile" cameras can be performed in the community; the retinal images are read on site or at a distant centre. Nephropathy Urine albumin and serum creatinine should be measured annually (fig 4). Positive urine samples should be repeated at least twice. Trends in albumin excretion with time are important. An estimated glomerular filtration rate is a better reflection of glomerular filtration than serum creatinine. Laboratories in the United Kingdom now do such estimations automatically, and web based calculators are available. Table 2 shows the agreed classification of renal disease based on estimated glomerular filtration rate.
Fig 4 Screening for diabetic nephropathy
View this table: Table 2 Classification of chronic kidney disease [in this window] [in a new window]
Neuropathy and peripheral arterial disease Box 5 shows what needs to be done to identify the four classic risk factors for developing diabetic foot problems (deformity, neuropathy, ischaemia, and infection).24 Questions should be asked about erectile function. Tests of autonomic function are not performed routinely.
How do I manage early complications?

General Tight control of blood glucose and blood pressure reduces the risk of progression of background diabetic retinopathy to sight threatening disease and the progression of neuropathy.11 12 16 The effect of glucose control on progression of nephropathy is less certain. Blood pressure and lipid control are extremely important. Cardiovascular disease Most importantly, all patients with symptoms that might reflect vascular disease, particularly ischaemic heart disease, should be investigated. The absolute benefits of treatment with statins in secondary prevention of vascular disease are greater in people with diabetes.22 Retinopathy Frequent retinal examination may be required, with referral to the ophthalmology department when sight threatening disease is apparent (table 3).
View this table: [in this window] [in a new window]
Table 3 Urgency of referring patients with diabetic retinopathy to the ophthalmology department
Nephropathy All patients should be prescribed a long acting, once daily angiotensin converting enzyme inhibitor or angiotensin receptor blocker titrated up to the maximum recommended or tolerated dose.w23-w26 Additional antihypertensives should be used to achieve tight control of blood pressure. A target of 125/75 mm Hg is recommended for patients with proteinuria or an
estimated glomerular filtration rate less than 60 ml/min/1.73 m2, although these guidelines are not evidence based. Combining an angiotensin converting enzyme inhibitor with an angiotensin receptor blocker or adding an aldosterone antagonist further reduces urine albumin excretion and blood pressure in the short term.w27-w29 However, long term benefits are unclear. Box 6 lists the indications for referral to the nephrology department.
Box 6: Indications for referring patients to the nephrology department

The glomerular filtration rate is < 45 ml/min/1.73 m2 (if possible, refer when < 60 ml/min/1.73 m2) or serum creatinine is > 150 mol/litre The estimated glomerular filtration rate falls by more than 20% each year Presence of nephrotic syndrome The diagnosis is unclear Blood pressure is uncontrolled Haemoglobin is < 100 g/litre and other causes have been excluded Presence of abnormalities in bone chemistry
Neuropathy and peripheral arterial disease Patients whose feet have a high risk of ulceration or gangrene need support and education about foot care; they also need to be given prophylactic foot care and special footwear.24 These measures can reduce amputation rates by 30-50%.w30 w31 Early referral of patients with ulcers (and those who have had ulcers in the past) to a specialist multidisciplinary team is essential. Support and counselling should be available for men with erectile dysfunction. Investigations to exclude other causes (measurement of prolactin, follicle stimulating hormone, luteinising hormone, testosterone, and sex hormone binding globulin) may be necessary. Oral phosphodiesterase type 5 inhibitors are effective in about 60% of men with diabetes, less than in the non-diabetic population. Alternatives include sublingual apomorphine, intraurethral drugs, intracavernosal drugs, vacuum devices, and penile prostheses. The importance of multifactorial care A small randomised controlled trial of patients with type 2 diabetes, microalbuminuria, and hypertension showed the importance of a structured, protocol driven, multifactorial approach to managing the complications of diabetes.25 The intensively managed group received lifestyle advice, aspirin, and angiotensin converting enzyme inhibitors, with tight targets for glucose, blood pressure, and lipids in a specialist setting. The conventionally managed group received usual structured care in a primary care setting. Over eight years, the risks of progression of microvascular and macrovascular disease were reduced by 40-60% in the intensively managed group (table 4).
View this table: Table 4 Benefits of multifactorial intervention25 [in this window] [in a new window]
How well are we doing?

Targets are not being met and drugs are not being prescribed appropriately in most patients with diabetes worldwide.w32 w33 Screening programmes for retinopathy and nephropathy are patchy or non-existent.w34 w35 In the UK, the uptake for retinal screening was 57.3% in 2005 (www.yhpho.org.uk). Patients find it difficult to comply with lifestyle advice, attendance for screening, and drugs,w36 w37 and those with most difficulty have worse outcomes.w38 w39
ources
s.org.uk)
ion (www.diabetes.org) International Diabetes Federation Clinical Guidelines Task Force. Global guidelines for type 2 diabe www.IDF.org)
onference on prevention of type 2 diabetes (www.diabetesconference.at)
ogramme for the prevention and care of diabetes in Finland (www.diabetes.fi/english/programme)
for renal services part 2. Chronic kidney disease, acute renal failure and end of life care. London: Department of Health 200 nsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPAmpGBrowsableDocument/fs/en?CONTENT_I
tee. Diabetic retinopathy screening workbook: guidance on setting up a systematic programme (www.nscretinopathy.org.uk)
rk. Results for England 2004/5 (www.icservices.nhs.uk)
How can we improve?

Many changes are needed to prevent the complications of diabetes and minimise their impact. Under the auspices of the Austrian presidency, the European Union has developed a national plan of action for care in diabetes (www.diabetesconference.at), and such a plan has already been enacted in Finland (www.diabetes.fi/english/programme). The most successful interventions include many components of care contained within the chronic care model,w40 w41 as described recently for foot care26:

Organisation of care Clinical information systems Support for clinical decisions
Delivery of care Support for self management.26
Many examples of novel ways of improving outcomes exist. In the UK, the "payment by results" scheme of the primary care quality outcomes framework has resulted in many practices reaching the specified targets (www.icservices.nhs.uk). Overall, practices attained 93.2% of the total available points for diabetes. Appreciable benefits are likely to be seen as the targets for glycated haemoglobin, lipids, and blood pressure values are tightened.
An appendix, extra references, and extra figures are on bmj.com. A long version of this paper is also on bmj.com SMM is guarantor. Both authors contributed equally to preparing and writing this review. Competing interests: SMM received payment from Novo-Nordisk for organising educational events and for attending conferences. She was a member of the International Diabetes Federation Clinical Guidelines Task Force. AF has been paid by Abbott Denmark, Astra Zenica R&D, GlaxoSmithKline Denmark, Novo-Nordisk A/S Denmark, Pfizer Denmark, Roche Pharmaceuticals, and Sanofi-Aventis/Bristol-Myers Squibb Denmark for speaking at educational programmes for nurses and doctors. He has served as a consultant for Pfizer International, Roche Pharmaceuticals, Sanofi-Aventis/Bristol-Myers Squibb Denmark, and Taisho Pharmaceuticals.
References
1. Jonsson B. CODE-2 advisory board. Revealing the cost of type II diabetes in Europe. Diabetologia 2002;45: S5-12.[CrossRef][ISI][Medline] 2. Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, et al. The British Diabetic Association cohort study II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabetic Med 1999;16: 46671.[CrossRef][ISI][Medline] 3. Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82: 844-51.[ISI][Medline] 4. Rossing P. The changing epidemiology of diabetic microangiopathy in type 1 diabetes. Diabetologia 2005;48: 1439-44.[CrossRef][ISI][Medline] 5. US Renal Data System. USRDS 2005 annual data report. Bethesda, MD: National Institute of Health, National Institute of Diabetes, Digestive and Kidney Disease, 2005 (www.usrds.org/adr.htm). 6. Van Dijk PC, Jager KJ, Dtengel B, Gronhagen-Riska C, Feest TG, Briggs JD. Renal replacement therapy for diabetic end-stage renal disease: data from 10 registries in Europe (1991-2000). Kidney Int 2005;67: 1489-99.[CrossRef][ISI][Medline]
7. Tesfaye S, Kempler P. Painful diabetic neuropathy. Diabetologia 2005;48: 8057.[CrossRef][ISI][Medline] 8. Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2005;366: 1719-24.[CrossRef][ISI][Medline] 9. Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev 2004;25: 971-1010.[Abstract/Free Full Text] 10. Brownlee M. The pathobiology of diabetic complications. A unifying mechanism. Diabetes 2005;54: 1615-25.[Free Full Text] 11. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329: 97786.[Abstract/Free Full Text] 12. UK Prospective Diabetes Study. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352: 837-53.[CrossRef][ISI][Medline] 13. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the epidemiology of diabetes interventions and complications (EDIC) study. JAMA 2003;290: 2159-67.[Abstract/Free Full Text] 14. Martin CL, Albers J, Herman WH, Cleary P, Waberski B, Greene DA, et al, DCCT/EDIC Research Group. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 2006;29: 3404.[Abstract/Free Full Text] 15. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353: 264353.[Abstract/Free Full Text] 16. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. BMJ 1998;317: 703-13.[Abstract/Free Full Text] 17. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al, ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethazide as required, in the Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366: 895-906.[CrossRef][ISI][Medline]
18. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288: 2981-97.[Abstract/Free Full Text] 19. Strippoli GF, Craig M, Craig JC. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 2005;4: CD004136. 20. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 highrisk individuals: a randomised placebo-controlled trial. Lancet 2002;360: 7-22.[CrossRef][ISI][Medline] 21. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al, CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364: 68596.[CrossRef][ISI][Medline] 22. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ 2006;332: 1115-24.[Abstract/Free Full Text] 23. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al, FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study): randomised controlled trial. Lancet 2005;366: 1849-61.[CrossRef][ISI][Medline] 24. National Institute for Clinical Excellence. Clinical guideline 10; type 2 diabetes. Prevention and management of foot problems. National Institute for Clinical Excellence 2004 (www.NICE.org.uk/CGO10NICEguideline). 25. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: 383-93.[Abstract/Free Full Text] 26. Reiber GE, Raugi GJ. Preventing foot ulcers and amputations in diabetes. Lancet 2005;366: 1676-7.[CrossRef][ISI][Medline]
Macrovascular Complications of Diabetes CME

Disclosures Zachary T. Bloomgarden, MD Mount Sinai Medical School
Introduction
It has long been observed that patients with diabetes are at increased risk for macrovascular complications, particularly coronary artery disease and myocardial infarction. The etiology and implications of this increased risk were discussed during a symposium on macrovascular complications at the 17th International Diabetes Federation Congress in Mexico City, Mexico.
Diabetes and Increased Cardiovascular Risk

In the United States, from the early 1970s to the early 1980s, the nondiabetic adult population demonstrated a decrease in coronary mortality.[1] However, noted Dr. Steven M. Haffner[2] of San Antonio, Texas, during the same period, the decrease was considerably less in adults with diabetes. Similarly, the risk of fatal myocardial infarction in The Framingham Study was double in men with diabetes and quadruple in women with diabetes.[3] Studies in Finland show high out-of-hospital fatality rates following a first myocardial infarction among men with diabetes; men with diabetes with no history of myocardial infarction have the same likelihood of coronary events as do men without diabetes who have previously had such an event.[4] The question that remains, however, is to what extent is the association between diabetes and vascular disease mediated by hyperglycemia? Epidemiologic analysis of the United Kingdom Prospective Diabetes Study (UKPDS) showed that an increase in HbA1c levels from 6% to 11% doubled the risk of myocardial infarction and conferred a 10-fold increase in risk of microvascular disease.[5] In truth, these patients were already at increased risk before the development of their diabetes because of insulin resistance, which manifests with hyperinsulinemia, increased triglyceride levels, and low high-density lipoprotein cholesterol (HDL-C) levels. Individuals with a defect in insulin secretion who subsequently develop diabetes have a tripling of cardiovascular disease (CVD) risk; those who have a defect in insulin sensitivity have a 5-fold increase in risk; and those with both abnormalities have a 20fold increase in risk. Comparing individuals with similar blood glucose levels who have insulin resistance or insulin deficiency alone, the former have higher blood pressure, higher triglyceride levels, and lower HDL-C levels. Thus, Dr. Haffner suggested, insulin-resistant individuals who subsequently develop diabetes are at increased risk for macrovascular disease years or even decades before the onset of illness.
Predicting CVD Risk in Nondiabetic Patients

There is a positive relationship between hyperinsulinemia and CVD risk in nondiabetic individuals as well. Results of the Quebec Heart study[6] demonstrated the additive effect of hyperinsulinemia on increasing levels of apolipoprotein B in conferring CVD risk, suggesting the need for treatment of both the lipid and insulin components. Among individuals without diabetes, the degree of insulin resistance was related to HDL-C levels, blood pressure, and fasting insulin levels. Comparing patients with the highest quintiles of fasting insulin levels to
those with the lowest quintiles, HDL-C was 12 mg/dL lower, blood pressure was 9 mm Hg higher, and triglyceride levels were doubled. After controlling for these factors, low-density lipoprotein cholesterol (LDL-C) , and glucose levels, the most insulin-resistant group demonstrated a 2.5-fold increase in their risk of vascular events. Dr. Haffner noted, however, that these observational studies have yet to be verified by clinical trials. An important additional aspect of risk in diabetes is the emerging relation between insulin resistance and inflammation. C-reactive protein (CRP) levels are strongly related to insulin levels and obesity, although one cannot yet be certain as to the direction of causality. If inflammation is a mediator of the adverse effects of insulin resistance, anti-inflammatory treatment may be useful. Interestingly, thiazolidinediones have been shown to lower CRP levels. CRP is strongly associated with the development of CVD, with a CRP level of more than 4 mg/L associated with a 6-fold increase in risk. CRP is also a risk factor for the development of diabetes, with the top quintile of the population demonstrating a 2.5-fold increased risk. Thus, Dr. Haffner concluded, inflammatory factors may be part of the link between diabetes and coronary artery disease.
Does Glucose Control Influence the Risk for Acute Myocardial Infarction?
Acute transmural myocardial infarction occurs less often than does subendothelial myocardial infarction or unstable angina, said Dr. Klaus Malmberg,[7] of Stockholm, Sweden. Data from the Organization to Assess Strategies for Ischemic Syndromes study (OASIS)[8] show increased mortality in patients with diabetes during the first several years after a coronary event, most typically from congestive heart failure, despite similar degrees of cardiac dysfunction initially. This suggests that diabetes itself decreases functional reserve of the heart or increases rates of subsequent infarction. Glucose control can influence either of these parameters by affecting both myocardial metabolism and the health of the vessel wall. This was illustrated best in the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study,[9] in which 620 patients with blood glucose levels of more than 11 mmol/L were randomized to either a control group (n=314) or an intensive treatment group (n=306) following acute myocardial infarction. Patients in the intensive treatment group received an insulin-glucose infusion during the first 24 hours of hospitalization whereas the control group was managed with conventional therapy. Eighty-seven percent of patients in the intensive treatment group were discharged with an intensive insulin treatment regimen, and 72% remained under the treatment 1 year after the acute event. Mortality was reduced from 44% to 33% at 3-year follow-up. Interestingly, the 46% of patients who were not treated with insulin before hospitalization (70% of whom were newly diagnosed), demonstrated a larger decrease in mortality compared with those initially treated with insulin, decreasing at 3 years from 33% to 18%. Risk factors for mortality included age, history of congestive heart failure, and duration of diabetes; higher blood glucose level on admission was associated with a greater difference in mortality between the control and intensively treated groups. The use of glucose-insulin-potassium infusion treatment in patients without diabetes during acute myocardial infarction was first proposed by de Micheli and colleagues in the 1970s[10] and was recently shown in a meta-analysis to be effective.[11] Recent studies combining reperfusion with this approach have suggested particular efficacy.[12] There is evidence that insulin infusion is also effective during acute myocardial infarction in patients with type 1 diabetes.[13] In addition to improving glycemia, intensive insulin treatment during myocardial infarction improves the fibrinolytic profile, a potential mechanism of benefit.[14]
Do Moderately Elevated Glucose Levels Influence CVD Risk?

There is a great deal of evidence that diabetes itself is a risk factor for CVD, said Dr. Hertzel C. Gerstein[15] of Hamilton, Ontario. The magnitude of risk conferred by diabetes for cardiac complications is approximately the same as that of a prior cardiovascular event in nondiabetic patients. Indeed, an elevated glucose level alone has been shown to be a risk factor for cardiovascular complications in individuals with diabetes, most notably demonstrated in the UKPDS.[16] There are fewer data for type 1 diabetes, but here, too, it appears likely that the level of blood glucose is a cardiovascular risk factor.[17] Dr. Gerstein noted that the glucose criteria used for diabetes diagnosis were chosen because they predict subsequent retinal and renal disease. However, even lower glucose levels, or dysglycemia, may well predict CVD. A large gap exists between the criteria used to diagnose diabetes or glucose intolerance and those found in the general population in the Third National Health and Nutrition Examination Survey (NHANES III),[18] ie, a median fasting glucose level of 92 mg/dL and a 2-hour glucose level of 97 mg/dL. Similarly, in the Whitehall study,[19] the cardiovascular risk doubled among 18,403 men in the United Kingdom who had fasting glucose levels of 96 mg/dL compared with those who had fasting glucose levels of 110 mg/dL. An important further question is whether elevated fasting or postprandial glucose levels are more important as a cardiovascular risk, the latter relating the glycemic stress of carbohydrate ingestion. A number of recent studies have suggested that postprandial glycemia may be more strongly related to CVD.[20] Results of the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study[21] of more than 25,000 individuals who had undergone glucose tolerance tests suggest that the fasting glucose levels have less of an impact on prediction of cardiovascular outcome compared with the 2-hour glucose levels. The Hoorn study[22] similarly demonstrated a greater contribution of the 2-hour rather than the fasting glucose level to cardiac mortality. In an even larger group of nearly 100,000 persons with more than 1 million person-years of follow-up, a recent meta-analysis showed that a 2hour glucose level of 140 mg/dL was associated with a 58% increase in cardiovascular risk.[23] The blood glucose level at the time of a myocardial infarction may be another factor to consider. A meta-analysis showed that having an admission blood glucose level that exceeded 6 to 8 mmol/L was associated with almost a 4-fold increase in mortality.[24] Dr. Gerstein concluded that glucose is indeed a continuous risk factor for CVD in individuals with and without diabetes even at minimally elevated levels that are below the cutoff for impaired fasting glucose measurements and impaired glucose tolerance. Half of the men in the United States have a 2-hour glucose level that exceeds 5.9 mmol/L and may, therefore, have some increase in risk, leading to speculation as to what role the beta cell itself may plays in cardiovascular risk beyond diabetes. There is strong evidence to support the hypothesis that lowering glucose levels reduces cardiac disease in individuals with both type 1 and type 2 diabetes. However, it is as yet unknown whether lowering glucose levels can demonstrate similar benefits in nondiabetic patients. Potential mechanisms may include circulating free fatty acids acting as a mediator of adverse effects of dysglycemia, the presence of direct glucose toxic effects at the endothelium, or hyperglycemia acting as a marker of insulin resistance, of hypertension, or of dyslipidemia.
References
1. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291-1297.
2. Haffner SM. The epidemiology of macrovascular disease in diabetes. Macrovascular complications. Presented at the 17th International Diabetes Federation Congress; November 7, 2000; Mexico City, Mexico. 3. Abbott RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs women: The Framingham Study. JAMA. 1988;260:3456-3460. 4. Haffner SM, Lehto S, Ronnemaa T, Pyorl K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-224. 5. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412. 6. Despres J-P, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334:952-957. 7. Malmberg K. Acute coronary events and glycemic control. Macrovascular complications. Presented at the 17th International Diabetes Federation Congress; November 7, 2000; Mexico City, Mexico. 8. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Comparison of the effects of 2 doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Circulation. 1997;96:769-777. 9. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512. 10. de Micheli A, Medrano GA, Villarreal A, Sodi-Pallares D. Protective effect of glucose-insulin-potassium solutions in myocardial damage caused by emetine. Arch Inst Cardiol Mex. 1975;45:469-486. 11. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation. 1997;96:1152-1156. 12. Diaz R, Paolasso EA, Piegas LS, et al. Metabolic modulation of acute myocardial infarction: the ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Cirulation. 1998;98:2227-2234. 13. Lawson ML, Gerstein HC, Tsui E, Zinman B. Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes: a systematic review and meta-analysis. Diabetes Care. 1999;22(suppl 2):B35-B39. 14. Melidonis A, Stefanidis A, Tournis S, et al. The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients. Clin Cardiol. 2000;23:160-164. 15. Gerstein HC. Dysglycemia and macrovascular outcomes: an emerging risk factor. Macrovascular Complications. Presented at the 17th International Diabetes Federation Congress; November 7, 2000; Mexico City, Mexico. 16. United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837853. 17. Becker RC, Terrin M, Ross R, et al. Comparison of clinical outcomes for women and men after acute myocardial infarction: The Thrombolysis in Myocardial Infarction Investigators. Ann Intern Med. 1994;120:638-645.
18. Harris MI, Flegal KM, Cowie CC. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: the Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care. 1998;21:518-524. 19. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary-heart-disease risk and impaired glucose tolerance: the Whitehall study. Lancet. 1980;1:1373-1376. 20. Barzilay JI, Spiekerman CF, Wahl PW, et al. Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. Lancet. 1999;354:622-625. 21. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe: glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria: the DECODE study group. Lancet. 1999;354:617-621. 22. de Vegt F, Dekker JM, Ruhe HG, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia. 1999;42:926-931. 23. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233240. 24. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000;355:773-778.
Pioglitazone for Macrovascular Complications of Diabetes Although intensive glycemic control decreases microvascular complications of diabetes such as retinopathy and nephropathy, it provides little benefit in macrovascular complications or overall mortality. Persons with type 2 diabetes have a two to four times greater risk of macrovascular events than those without diabetes, and the life expectancy of a 40-year-old person newly diagnosed with diabetes is about eight years less than that of the general population. The pharmacologic actions of pioglitazone (Actos) suggest that this drug could reduce macrovascular changes independently of its effect on glycemic control. Dormandy and colleagues conducted a large, prospective, randomized controlled trial of pioglitazone therapy in patients with type 2 diabetes who had evidence of macrovascular complications. More than 5,000 patients with type 2 diabetes were recruited from 321 primary care and inhospital clinics in 19 European countries. Participants were 35 to 75 years of age and had A1C concentrations greater than 6.5 percent despite dietary modification alone or supplemented by oral hypoglycemic agents. About 30 percent of patients also used insulin. Evidence of macrovascular complications included a history of myocardial infarction, stroke, acute coronary syndrome, obstructive arterial disease in the legs, or recent invasive testing or medical procedures. After baseline assessment, 2,605 participants were randomly allocated to receive oral pioglitazone with their existing management, and 2,633 participants were assigned to placebo. Pioglitazone dosages were 15 mg daily for the first month, 30 mg daily for the second month, and 45 mg daily thereafter. Throughout the study, all medications were adjusted to the
clinically optimal dosages. Participants were seen monthly for two months, then every two months for one year, and every three months thereafter. The primary endpoints were time from randomization to death or occurrence of nonfatal myocardial infarction, stroke, acute coronary syndrome, or surgery for coronary or peripheral vascular disease. The principal secondary outcome was the composite of time from randomization to all-cause mortality, myocardial infarction, and stroke. An independent panel regularly reviewed patient records to monitor reporting of all endpoints and adverse events. The two groups were comparable on entry to the study. Two thirds of the participants were men; 99 percent were white; the mean age was 61.8 years; and the average time since diagnosis of diabetes was eight years. Nearly one half of the patients in each group had a history of myocardial infarction; 19 percent had a history of stroke; almost one half had evidence of two or more macrovascular complications; and 42 percent had microvascular disease. The average follow-up lasted 34.5 months. Only two patients were lost to follow-up. Pioglitazone was well tolerated: about 90 percent of patients were receiving the 45-mg dosage by the two-month visit, and 93 percent received the highest dosage for the remainder of the study. More than 95 percent of participants were compliant (i.e., used more than 75 percent of the tablets). Overall, 514 (19.7 percent) of the patients in the intervention group had at least one of the primary endpoints, as compared with 572 (21.7 percent) of the control group. This reduction was not statistically significant. For the main secondary outcomes in the intervention and placebo groups (11.6 versus 13.6 percent, respectively), the difference did achieve statistical significance. The groups also differed significantly in the initiation of insulin therapy: 11 percent of participants in the pioglitazone group who were not already taking insulin began permanent insulin therapy during the study, compared with 21 percent in the control group. The authors conclude that pioglitazone significantly reduced secondary endpoints and delayed initiation of insulin therapy in patients with type 2 diabetes at high risk of macrovascular complications. Although the difference in primary endpoints was not statistically significant, the authors estimate that treating 1,000 patients with pioglitazone would prevent 21 myocardial infarctions, strokes, or deaths over three years. ANNE D. WALLING, M.D. Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events). Lancet October 8, 2005;366:1279-89. EDITOR'S NOTE: The study by Dormandy and colleagues has profound implications but has raised considerable controversy. The authors stated in a public meeting that oral glucoselowering medication can prevent macrovascular events, and it was believed that the study results would change clinical practice.1 However, an accompanying editorial2 and an article1 published in the British Medical Journal criticize the study and caution against the general use of pioglitazone (Actos) in type 2 diabetes. The editorial2 expresses significant concerns about under-estimation of heart failure and edema in study participants and the lack of information about which patients could benefit from the additional therapy. The article1 is critical of the statistical analysis, concluding that the primary outcome results were not statistically significant and the secondary outcomes do not have sufficient statistical strength to prove an association. The article also questions why, if pioglitazone reduces macrovascular
events, it had no apparent effect on all-cause mortality, because more than 350 deaths occurred in the trial. Physicians can expect interest from patients and pressure from pharmaceutical companies to use drugs in this class to reduce the risks of the major causes of mortality in type 2 diabetes.-A.D.W. REFERENCES 1. Freemantle N. How well does the evidence on pioglitazone back up researchers' claims for a reduction in macrovascular events? BMJ 2005;331:836-8. 2. Yki-Jrvinen H. The PROactive study: some answers, many questions. Lancet 2005;366:1241-2.
Abstract: Micro- and macrovascular complications are major causes of disability and death in patients with diabetes mellitus. Functional impairment of endothelial activity precedes the development of morphological alterations during the progression of diabetes. This endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO), mainly due to accelerated NO degradation by reactive oxygen species (ROS). Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via several distinct mechanisms, increased oxidative stress seems to be the first alteration triggering several others. Mechanisms proposed to explain glucose- and lipid-induced vascular alterations in diabetes include accelerated formation of advanced glycation end-products (AGEs), protein kinase C activation, inflammatory signaling and oxidative stress. Insulin resistance with impaired PI 3kinase effects decreases insulin mediated production of NO and reduces vasodilation, capillary recruitment and antioxidant properties of endothelium. Compensatory hyperinsulinemia enhances activation of intact MAP-kinase pathways and contributes to proatherogenic events by increasing secretion of endothelin-1 (ET-1), stimulating expression of adhesion molecules such as VCAM-1 and E-selectin, and inducing production of ROS. Conventional therapies to reduce hyperglycemia, dyslipidemia and insulin resistance may effectively improve endothelial function and delay the onset of vascular complications. Novel therapeutic approaches designed to inhibit AGEs formation, reduce PKC activation, decrease inflammatory signals and restore the ox/redox balance of endothelium may be predicted to ameliorate vascular function in diabetic state. This review summarizes the current knowledge on the most important mechanisms involved in endothelial dysfunction during diabetes. In addition, novel therapeutic strategies that may result from recently identified targets are also described.

Macro Vascular Complications

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Macro Vascular Complications

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Macrovascular complications Atherosclerotic disease accounts for most of the excess mortality in patients with diabetes.

Oxidative stress and diabetic vascular complications.

Vascular disease risk markers in diabetes: Monitoring & intervention

ABC of arterial and venous disease

Vascular complications of diabetes

Microvascular Retinopathy Nephropathy Neuropathy

Macrovascular Ischaemic heart disease Stroke Peripheral vascular disease

Risk of morbidity associated with all types of diabetes mellitus

Relative risk* 20 25 40 2-5 2-3

Top Microvascular complications Macrovascular complications Surveillance and management in...

Classification and features of diabetic retinopathy

Grade I Background retinopathy

II Background with maculopathy III Preproliferative

Central visual loss (such as reading difficulty) None

IV Proliferative retinopathy V Advanced diabetic eye disease

None, but complications cause visual loss Severe visual loss

Background retinopathy showing microaneurysms and small blot haemorrhages

Clinical features of "high risk" diabetic foot

Clinical features that distinguish neuropathic and vascular foot ulcers

Top Microvascular complications Macrovascular complications Surveillance and management in...

Predictors of cardiovascular mortality

Features of coronary heart disease in diabetic patients

Recommendations on prevention of coronary heart disease in clinical practice

Treatment (in addition to lifestyle and dietary advice)

Insulin Combination therapy

Top Microvascular complications Macrovascular complications Surveillance and management in...

Surveillance and management in general practice

Annual complications assessment

Neuropathic ulcer is a common complication in patients with diabetes

Use of monofilament to detect impaired sensation during annual assessment

Why are the complications of diabetes important?

Who develops complications?

Fig 1 Development of nephropathy

Box 1: Long term vascular complications of diabetes Microvascular complications

Retinopathy Nephropathy Neuropathy

Cerebrovascular disease Ischaemic heart disease Peripheral arterial disease

Fig 2 Metabolic pathways that contribute to vascular complications of diabetes

Sources and selection criteria

How do I prevent complications?

Box 2: Macrovascular disease in diabetes

Box 3: Neuropathies in diabetes Peripheral neuropathies

Box 4: Preventing complications Glucose control

Aspirin should be prescribed for all patients over 40

Patients should be encouraged to stop smoking

How do I detect and screen for complications?

Box 5: Screening for peripheral neuropathy and peripheral arterial disease

Fig 4 Screening for diabetic nephropathy

How do I manage early complications?

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Box 6: Indications for referring patients to the nephrology department

How well are we doing?

onference on prevention of type 2 diabetes (www.diabetesconference.at)

ogramme for the prevention and care of diabetes in Finland (www.diabetes.fi/english/programme)

rk. Results for England 2004/5 (www.icservices.nhs.uk)

How can we improve?

Organisation of care Clinical information systems Support for clinical decisions

Delivery of care Support for self management.26

Macrovascular Complications of Diabetes CME

Diabetes and Increased Cardiovascular Risk

Predicting CVD Risk in Nondiabetic Patients

Do Moderately Elevated Glucose Levels Influence CVD Risk?

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