11 - Screening, Diagnosis, and Management of Diabetes-related Complications

Authors: Unger, Jeff

Title: Diabetes Management in the Primary Care Setting, 1st Edition

> Table of Contents > 11 - Screening, Diagnosis, and Management of Diabetes-related Complications

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Screening, Diagnosis, and Management of Diabetes-related Complications

Take Home Points

Microvascular complications include neuropathy, nephropathy, and retinopathy.
Macrovascular complications include myocardial infarction, stroke, coronary heart disease, and peripheral vascular disease.
The pathologic triggers for diabetes-related complications are prolonged exposure to hyperglycemia, glycemic variability, and the production of reactive oxygen species within complication-prone cells.
Complication rates can be delayed or reduced by intensively managing all patients immediately following their initial diagnosis.
Screening for diabetes-related complications is necessary because interventional strategies are available that can reverse or delay the progression of these disease states.
Patients with diabetes should be screened for evidence of chronic kidney disease. Many interventional strategies are available that may delay disease progression, including management of hypertension, smoking cessation, dietary restrictions, reversal of anemia, reduction in low-density lipoprotein cholesterol (LDL-C), and use of aspirin.
Specialty referrals to nephrologists and cardiologists are indicated for patients with advanced microvascular and macrovascular complications.
Patients who are insensate should be advised to use monofilaments each night to test for any return of sensation. Although this is unlikely to occur, using the monofilaments forces patients to inspect their feet on a daily basis. Any ulcerations or calluses can be reported to the physician quickly, prompting actions that should reduce the risk of amputation.
In addition to targeting hemoglobin A1C levels in diabetes management, physicians should treat blood pressure and lipid levels according to American Diabetes Association (ADA) guidelines while making certain that patients are placed on aspirin therapy unless contraindicated.

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Case 1

This is not the first time Les has had this discussion with you. At age 34, he has been using twice-daily insulin injections since being diagnosed with type 1 diabetes mellitus (T1DM) 8 years ago. Presenting for his annual physical exam, Les is informed that he has evidence of peripheral sensory neuropathy, background diabetic retinopathy, and microalbuminuria. His A1C is 8.6%. After suggesting that a more intensified approach be taken toward managing all aspects of his diabetes, Les states, I have never felt better, doctor. In fact, I am working out 5 days a week and have lost 5 lb since my last visit. Gave up smoking 4 years ago, thanks to you! Sure, on special occasions I'll drink a beer or two, but I stay away from the hard stuff all together. I really don't think I need more shots or pills. None of my friends are even checking their blood sugars as much as I am. Give me a chance to work this out on my own. I'll just stop eating those weekend desserts. Next time you see me everything will be better. Right?

You reply: Les, although I am proud of your efforts to improve your lifestyle, I am very concerned about your health at this time. Based on your examination and lab studies you already have evidence of long-term diabetes complications, which are affecting your eyes, kidneys, and nervous system. There is a high likelihood that you have underlying heart disease as well. Your home blood glucose monitoring downloads consistently demonstrate wide glycemic variability. On any given day your blood glucose levels may range from 50 to 400 mg per dL. You are already experiencing some significant complications, some of which may be progressive and irreversible.

Remember, people don't die of diabetes anymore; they die of the complications that result from having diabetes. We have the tools and ability to intervene on your behalf to delay and possibly reverse some of the complications you have at this time. However, we will need to place you on medications for your blood pressure and cholesterol, start you on aspirin, and intensify your diabetes treatment plan. I may even consider starting you on an insulin pump. The longer we wait, the more difficult time I will have to help control these complications.

Why is this happening to me all of a sudden, doctor? asks Les.

Les, the blood from a person without diabetes is pure, fresh, and cool, kind of like a mountain stream. Flowing through the body, this blood caries oxygen and nutrients to the muscles, heart, and lungs without any difficulty. Unfortunately, the blood of someone with poorly controlled diabetes is like maple syrup: thick, sticky, and gooey. Flowing slower through the blood vessels, this sugary blood sticks to everything your eyes, kidneys, nerves, heart, muscles, skin, and blood cells. After awhile your body begins to feel the effects of this thick blood. Your vision may suffer, your gums bleed, your feet and hands tingle or hurt, and you develop joint stiffness. That shoulder stiffness you are complaining about is not tendinitis. Your pain is most likely due to the deposition of advanced glycosylated end products in your joint capsule, which is commonly seen in association with poorly controlled diabetes. Even though you feel good today, you may suffer a heart attack without feeling any chest pain, because the sensory nerves to your heart are damaged from your diabetes. We call this silent ischemia. The best way to make your blood less sticky is to intensify your diabetes program with insulin. We also have to focus on repairing some of the damage that has been done inside your body over the past few years. Are you willing to give this a try?

Let's do it, doctor! Les agrees.

By the time of the discovery of insulin in 1922 by Fredrick Banting and Charles Best, only 2% of the population of industrialized countries had diabetes. Patients managing to survive the effects of severe calorie-restricted diets prescribed as the only means of treatment for diabetes often suffered from cataracts, blindness, severe foot and leg infections, sterility, boils, and tuberculosis. Infectious diseases that could be managed successfully in nonimmune compromised patients proved fatal to diabetics. Patients with gangrene or postoperative infections would often be left to linger until death because little could be done to promote acceptable wound healing or reduce their emotionally charged neuropathic pain. Women who were able to conceive rarely were able to carry the fetus to term. The life expectancy of patients with T1DM diabetes was less than 1 year from the time of diagnosis.

The wasting away of the flesh from lack of nourishment could be dreadful in itself. When he came to the hospital he was emaciated, weak and dejected; his thirst was unquenchable; and his skin dry, hard and harsh to the touch, like rough parchment when the doctors found an abundance of ketones in the urine, they knew the diabetes was entering the final states. They could smell it, too, for some ketone bodies were also volatile and were breathed out. It was a sickish-sweet smell, like rotten apples, that sometimes pervaded whole rooms or hospital wards.¹

There is little doubt that the introduction of insulin has had the most significant effect on global health than any other drug in history. For the first time, physicians had a truly effective and powerful weapon against a particular disease. Yet insulin was not a cure for diabetes. Following the awarding of the Nobel Prize in medicine (1923) for the discoverers of insulin, Dr. Elliott Joslin predicted that the era of the coma as the central problem of diabetes would give way to the era of complications.¹ The miracle of insulin has been to multiply the life expectancy of patients with diabetes 25-fold. No longer are patients dying of diabetic ketoacidosis; their life expectancy is lessened by the gradual onset of long-term complications.

Historians view the success of insulin with stunning irony. Insulin has allowed patients with diabetes to live longer and to propagate. The number of people worldwide with diabetes is continuing to rise. Many of these individuals who are not aggressively managed, especially from the onset of their disease, will develop complications that are costly to themselves as well as to society. Although so many people worldwide were celebrating the discovery of insulin, others were prophesying that diabetes management would become more costly

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to society. In 1923, Dr. Otto Leyton of London urged that insulin be given free to poor diabetics only on the condition that they have no progeny. ² The prediction in the 1920s that prolonging the lives of patients with diabetes would result in economic hardship has certainly become a modern reality. Thus, with the discovery of insulin, the true complexity of the diabetic state was beginning to unfold. The era of death from coma was transformed into an era of death from complications. When Banting received his standing ovation on being presented the Nobel Prize, the attendees believed that the mystery of diabetes had been solved. Physicians now are keenly aware of the fact that as patients are living longer with diabetes, the disease is, in fact, becoming more mysterious.

The Economics of Diabetes Complications

The discovery of insulin is considered by many to be the beginning of the era of diabetes complications, one that has placed a huge financial burden on society (Tables 11-1 and 11-2). A single patient with type 2 diabetes mellitus (T2DM) is expected to accrue costs on average of $47,200 for managing diabetes-related complications over 30 years. Of this total, 52% ($24,330) will be devoted to the care of coronary artery disease (CAD) and strokes; $9,912 for kidney disease; $8,024 for neuropathy; and $4,720 for retinopathy³ (Fig. 11-1).

The costs of managing early complications before they have become progressive or irreversible are relatively low. For example, performing a screening test for microalbuminuria within the office setting costs approximately $62. A patient diagnosed with microalbuminuria can be treated with dietary interventions, advised to discontinue smoking, and be placed on medications to manage hypertension, hyperlipidemia, and hyperglycemia. However, when early intervention is delayed, the resulting complication affects not only the patient's quality of life but also the financial responsibilities. As complications become

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more significant, so will the financial impact to society. The direct costs of managing a single case of end-stage renal failure exceed $57,000 per year.⁴

TABLE 11-1 Annual Costs Associated with Diabetes-related Complications

Complication	Total Cost for 1 Year after Onset of Acute Event^a
Stroke	$26,000
Acute myocardial infarction	$24,500
Amputation	$37,600
End-stage renal failure + peripheral vascular disease + hypertension^b	$57,200
^aFor subjects who survived first year. ^bEnd-stage renal failure patients who require dialysis or renal transplantation for survival. Adapted from Brandle M, Zhou H, Smith BRK, et al. The direct medical cost of type 2 diabetes. Diabetes Care. 2003;26:2300 2304, with permission.

TABLE 11-2 Direct Costs Associated with Diabetes-related Complications

Diagnosis	Cost of Management/Wk
Neuropathy
Painful DPNP	$5.90
Foot ulcer (not infected)	$179
Foot ulcer (with cellulitis)	$473
Foot ulcer (with osteomyelitis)	$877
Retinopathy
Proliferative retinopathy (ophthalmology consult, fluorescein angiography, photocoagulation)	$1,100 (per event)
Annual disability costs related to blindness	$3,486
DPNP, diabetic peripheral neuropathic pain. From Medical Economics Staff, ed. 2002 Drug Topics Red Book. Montvale, NJ: Thomson Medical Economics; 2002; and O'Brien JA, Shomphe LA, Kavanagh PL, Raggio G, Caro JJ. Direct medical costs of complications resulting from type 2 diabetes in the US. Diabetes Care. 1998;21:1122 1128, with permission.

Figure 11-1 Estimated Cumulative Cost (Average per Patient) of Managing Complications of Type 2 Diabetes According to Type of Complication. (From

Caro JJ, Ward AJ, O'Brien JA. Lifetime costs of complications resulting from type 2 diabetes in the US. Diabetes Care. 2002;25:476 481, with permission.

)

The level of hemoglobin A1C is directly linked to the economics of diabetes management. Every 1% increase in A1C from 6% to 10% increased charges by 4%, 10%, 20%, and 30%, respectively. Lowering the A1C to less than 8% will reduce complication risk as well as the financial burden of diabetes.⁵

Benefits of Intensive Diabetes Management in Reducing Diabetes Complications

Little doubt exists today regarding the benefits of intensively managing all forms of diabetes with the intent of delaying or preventing long- and short-term complications. Prior to the publication of the Diabetes Control and Complication Trial (DCCT)⁶ in 1993, twice-daily NPH/regular insulin using two thirds of the total dose before breakfast and one third before dinner was the most popular treatment for T1DM. Although this treatment protocol was simple and popular, the outcomes were often predictably poor.⁷ The DCCT investigated the effects of intensive therapy (three or four insulin injections daily or insulin pump therapy) versus the conventional (one to two daily injections therapy) on the development and progression of microvascular complications of T1DM. Patients were followed up for an average of 6.5 years and assessed for the presence or progression of retinopathy, nephropathy, and neuropathy. Intensively managed patients achieved an average A1C that was, on average, 2.1% lower than that of their conventionally managed counterparts. Table 11-3 outlines the microvascular disease state risk reductions associated with a 2% lowering of one's A1C.

When speaking to patients regarding the positive outcomes associated with intensive diabetes management, the importance of statistics is often lost in the details. Perhaps a better approach⁸ would be to remind patients

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that they could gain 15 years of complication-free life and live 5 years longer if they were to intensively manage their diabetes while striving to achieve an A1C lower than 7%. Achieving the ideal or targeted A1C in some patients may be very difficult, time consuming, and frustrating. However, the treating physician must never lose sight of the fact that intensive diabetes therapy may also be defined as any treatment strategy that successfully reduces the initial A1C (Fig. 11-2). A patient who begins treatment with an A1C of 11% but who is having difficulty lowering his or her A1C to below 9% has already achieved a relative risk reduction in microvascular disease of 60%.

TABLE 11-3 Microvascular Complication Risk Reduction in the Intensively Managed Type 1 Diabetes Cohort of the Diabetes Control and Complications Trial (DCCT)

Complication	Risk Reduction Resulting from a 2% Improvement in A_1C (%)
Retinopathy	63
Nephropathy	54
Neuropathy	60
Adapted from 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;329:977 986.

Figure 11-2 Relative Risk of Developing Diabetes-related Microvascular Complications. The American Diabetes Association recommends targeting a hemoglobin A1C goal of 7%. As the A1C rises above 7%, the relative risk of developing diabetes-related microvascular complications increases significantly. There is no glycemic threshold. The lowest A1C that can be safely attained should be the patient'fs target. A patient who presents initially with an A1C of 10% and is able to reduce the A1C to 7.4% in 6 months is being intensively managed. Any therapy that reduces the A1C will likely limit the likelihood of developing long-term diabetes-related complications.

The United Kingdom Prospective Diabetes Study (UKPDS)⁹ determined that intensively managing patients with T2DM can also benefit from improved glycemic control. Each 1% reduction in A1C is accompanied by a 35% decrease in the risk of microvascular complications (Table 11-4).

The UKPDS confirmed that hyperglycemia is a toxic metabolic state regardless of the etiology of diabetes or the age at which the patient is affected. Both the DCCT and UKPDS illustrate the importance of not only treating patients to target but also attempting to achieve as close to a normal metabolic state as is safely possible.

Early intervention toward glycemic normalization is as important as intensive diabetes management. The Epidemiology of Diabetes Interventions and Complications study (EDIC)¹⁰ followed graduates from the DCCT patient population after their management was assumed by their community physicians. The conventionally managed patients from the DCCT who were switched to intensive therapies showed an overall improvement of their average A1C from 9.1% to 8.2% during the 4-year extension study. Once the

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DCCT was published, physicians and patients understood the importance of intensive versus conventional therapy. The conventionally treated patients and their physicians most often opted for intensive management at the conclusion of the DCCT. The average A1C levels from the intensively managed DCCT group of patients deteriorated from 7.2% to 7.9%, most likely due to a reduction in the level of coaching and individualized management patients received while in the DCCT. Although the original intensively managed cohort's mean A1C levels rose during EDIC, they had 42% fewer cardiovascular events, 57% fewer fatal stroke and myocardial infarcts, and 52% less retinopathy and urinary albumin excretion compared with their conventional associates. Intensively managing diabetes soon after one is diagnosed with the disorder and maintaining that level of intensification for 4 to 6 years can result in a state of metabolic memory. Patients with diabetes develop protection against complications, which are less likely to occur despite future deterioration in A1C levels.

TABLE 11-4 Beneficial Effects for Each 1% Lowering in Hemoglobin A_1C as Demonstrated by the Intensively Managed Type 2 Diabetes Cohort of the United Kingdom Prospective Diabetes Trial^a

Complication	Risk Reduction (%)
Microvascular complication rate	35
Diabetes-related mortality	25
All-cause mortality	7
Fatal and nonfatal myocardial infarction	18
^aAIC dropping from 9% to 8%. From UK Prospective Diabetes Study (UKPDS) 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;352:837 853, with permission.

Patients with T2DM have a two to four times higher increased risk of cardiovascular events than those with normal glycemia.¹¹ Diabetes is a multidimensional metabolic disorder in which hypertension and hyperlipidemia can have a profound effect on both microvascular and macrovascular disease. Therefore, physicians must target glycemic control as well as blood pressure (BP) and hyperlipidemia in their patients with diabetes. The Steno Diabetes Study¹² evaluated 160 patients with T2DM and microalbuminuria. Half of the patients received conventional treatment in accordance with the national guidelines of Denmark. The other half received multifactorial intensive treatment interventions. The intensive intervention consisted of a stepwise introduction of lifestyle and pharmacologic programs targeting an A1C lower than 6.5 %, BP lower than 130/80 mm Hg, total cholesterol below 175 mg per dL, and triglycerides (TGs) below 150 mg per dL. Patients were provided with dietary instructions to reduce their fat intake and were encouraged to partake in regular exercise. Smoking cessation education was provided. Intensively

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treated patients were also advised to take aspirin and a dietary supplement (vitamins E and C, folic acid, and chromium picolinate) and were given an angiotensin-converting enzyme (ACE) inhibitor regardless of their BP.

TABLE 11-5 Effect of Multifactorial Intervention on Microvascular and Macrovascular Complication Events in Patients with Type 2 Diabetes Mellitus (T2DM) and Microalbuminuria^a

Complication	Conventional Group (n = 80)^b	Intensive Group (n = 80)^c
Nephropathy	31^d	16
Retinopathy	51^e	38
Progression of autonomic neuropathy	43	24
Progression of sensory polyneuropathy	37	40
Hypoglycemic events	39^f	42
Death from cardiovascular disease	7	7
Nonfatal myocardial infarctions	17	5
Coronary artery bypass grafts	10	5
Percutaneous coronary interventions	5	3
Stroke	20	3
Amputations	14	7
Surgical interventions for vascular disease	12	6
^aResults of the Steno Diabetes Study (Gaude P, Vedel P, Larsen N, Jensen GVH, Parving H, Pedersen O. Multifactorial interventions and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383 393) in which 160 patients were randomized to either the conventional or the intensively treated group and then followed for over 7 years. ^bPatients in the conventional group were managed in accordance with the national guidelines of Denmark. ^cPatients in the intensively treated group were treated to targeted goals: hemoglobin A_1c (A1C) <6.5%, blood pressure <130/80 mm Hg, total cholesterol <175 mg/dL, triglycerides <150 mg/dL. Dietary instructions were provided to reduce fat intake and patients were encouraged to partake in regular exercise. Smoking cessation education was provided. Patients were placed on aspirin, various nutritional supplements, and angiotensin-converting enzyme inhibitors (ACE) inhibitors regardless of their blood pressure levels. ^dThree patients in the conventional therapy group progressed to end-stage renal disease (ESRD) requiring dialysis. None progressed to ESRD in the intensive group. ^eSeven patients in the conventional therapy group became blind in one eye compared with one in the intensive group. ^fTwelve patients in the conventional therapy group and five in the intensive therapy group had at least one major hypoglycemic event that impaired consciousness. Seventy-five percent of major events occurred in insulin-treated patients.

After 7.8 years of follow-up, the intensively managed patients had a 50% reduction in the incidence of macrovascular and microvascular disease when compared with the conventionally managed group (Table 11-5). Thus,

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approaching diabetes from a multifactorial prospective is critical in successfully managing patients at risk for complications.

Behavioral and pharmacologic strategies can reduce the risk of diabetes-related complications. Smoking cessation clearly lowers the risk of cardiovascular disease (CVD) and may decrease the risk of microvascular complications.¹³ Thirty minutes of daily exercise improves A1C in patients with T2DM and prevents the progression of diabetes and CVD.¹⁴ In the UKPDS, pharmacologic treatment that produced a relatively modest lowering in BP resulted in a significant fall in the risk of CVD among patients with diabetes and a 37% reduction in the risk of microvascular endpoints.⁹

The benefits of lipid lowering in diabetes were demonstrated in the Collaborative Atorvastatin Diabetes Study (CARDS).¹⁵ In this study, patients with T2DM ages 40 to 75 years were randomized to treatment with atorvastatin 10 mg (n = 1,428) or placebo (n = 1,410) for a median duration of 3.9 years. Statin treatment reduced the risk of myocardial infarction (MI), coronary revascularization, and stroke by 37%. Other studies have also demonstrated beneficial effects of statins on cardiovascular risk.¹⁶^,¹⁷^,¹⁸

Microvascular Complications

Diabetic Neuropathy

Neuropathy Fast Facts

Neuropathy is one of the most common complications of diabetes, with a lifetime prevalence between 25% and 50% in persons with diabetes.¹⁹
In developed countries, diabetic neuropathy accounts for 50% to 75% of nontraumatic amputations.²⁰
Nerve conduction velocity slows considerably as the A1C surpasses 9%. Impairment of nerve conduction velocity results in irreversible loss of nerve fiber density, resulting in neuropathic pain.²¹
Diabetic peripheral neuropathic pain (DPNP) can occur in patients with impaired glucose tolerance and impaired fasting glucose.²²
Mortality in patients with autonomic neuropathy is 25% to 50% within 10 years of the onset of symptoms.²³
Major clinical manifestations of diabetic autonomic neuropathy (DAN) include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction (ED), sudomotor dysfunction, abnormal circadian pattern of BP control, silent myocardial ischemia, and hypoglycemic unawareness.
Cardiovascular autonomic neuropathy (CAN) is the primary risk factor for sudden death due to MI in patients with diabetes.²⁴
The mortality rate for silent ischemia is 47% versus 35% for patients who experience pain in association with an acute MI.²⁵

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The only U.S. Food and Drug Administration (FDA) approved treatments for DPNP pain result in 50% symptom relief in the majority of patients within 2 weeks of initiating drug therapy.
The treatment of choice for DAN is improvement in glycemic control. Behavioral interventions and medical management of other coexisting metabolic abnormalities should not be overlooked.

Introduction to Neuropathic Disease

The neuropathies are among the most common of the long-term complications of diabetes, affecting up to 50% of patients.²⁶ Their clinical features vary immensely, and patients may present to a wide spectrum of specialties, from dermatology to podiatry, or from urology to cardiology. Neuropathies are characterized by a progressive loss of nerve fibers and nerve fiber density, resulting in altered nerve conduction velocity. There is increasing evidence that measures of neuropathy, such as electrophysiology and quantitative tests, are predictors of not only endpoints, including foot ulceration, but also mortality.²⁷

An expert panel has defined diabetic neuropathy as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. ²⁸ Neuropathy cannot be diagnosed without an appropriate neurologic examination. Because up to 75% of patients may be asymptomatic, all patients with diabetes must be screened frequently to determine the presence of signs suggestive of diabetic peripheral and autonomic neuropathy.

Neuropathy is one of the most common complications of diabetes, with a lifetime prevalence between 25% and 50% in persons with diabetes.¹⁹ In developed countries, diabetic neuropathy accounts for 50% to 75% of nontraumatic amputations.²⁰ Mortality in patients with autonomic neuropathy is 25% to 50% within 10 years of the onset of symptoms.²³

Approximately 50% of patients with diabetes experience symptomatic diabetic peripheral neuropathy (DPN), whereas 15% have symptoms severe enough to warrant treatment.²⁹ Estimates of the number of people in the United States with DPNP range from 600,000 to 3.6 million.³⁰ Diabetic neuropathy can be identified in patients with prediabetes and impaired glucose tolerance (IGT). Although frequent screening during all stages of diabetes does decrease the future risk of lower extremity amputation, reversing existent neuropathy is difficult to achieve.³¹^,³² Perkins et al.³³ demonstrated a 30% reduction in sural nerve fiber density in patients with diabetic neuropathy in comparison to nondiabetic individuals. Prolonged hyperglycemia (A1C >9%) not only reduces nerve fiber density but also results in delayed nerve conduction velocity.²¹ Alterations in normal nerve conduction velocity will be perceived as neuropathic pain and may contribute to autonomic dysfunction.

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Pathophysiology

Pathogenesis of Diabetic Neuropathy

The mechanism by which hyperglycemia mediates vascular and neuronal cell dysfunction is not completely understood. A number of biochemical mechanisms may be involved, including nonenzymatic glycosylation, increases in oxidative stress, neuro-inflammation, activation of the polyol pathway, and activation of the protein kinase C (PKC) pathway. Certainly, the length of time that nerve fibers are exposed to ambient hyperglycemia is critical in upregulating these biochemical pathways (Fig. 11-3).

Figure 11-3 Pathophysiology of Diabetes-related Neuropathic Complications. The polyol (sorbitol) pathway was first implicated as mechanistic for diabetes-related complications more than 30 years ago. When hyperglycemia is present, the enzyme aldose reductase (AR) converts glucose into sorbitol, which is slowly metabolized to fructose by sorbitol dehydrogenase (SDH). The polyol pathway is activated, which brings about multiple metabolic imbalances in tissues and end organs, which subsequently undergo insulinindependent uptake of glucose. In the ocular lens, hyperosmotic swelling is caused by the accumulation of sorbitol. In nerve fibers and endothelial cells, the reduction of nitric oxide levels results in oxidative stress. Nerve conduction velocities slow and endothelial cell damage occurs. Elevation in fructose levels also results in accelerated glycation linking protein and sugar moieties. The resulting advanced glycosylated end products (AGEs) are inflammatory and painful.

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Nonenzymatic glycosylation and oxidation of proteins are natural phenomena of aging that occur at a very slow rate. As glucose becomes incorporated into proteins, advanced glycated end products (AGEs) are formed in an irreversible chemical reaction. During this process, reactive oxygen species, such as superoxide and hydrogen peroxide, are also produced. When ambient glucose levels are elevated, the extent of glycation increases as sugars become attached to free amino groups on proteins, lipids, and nucleic acids, which alter the function and metabolism of these macromolecules.³⁴ AGE receptors (RAGEs) on macrophages induce monocytes and endothelial cells to increase the production of inflammatory cytokines and adhesion molecules.³⁵ The resulting basement membrane thickening can cause symptoms such as joint stiffness and diffuse pain in response to light touch. AGEs can also bind to AGE receptor sites on endothelial cell surfaces, leading to increased inflammatory responses, vascular permeability, and procoagulant activity.³⁶ The ability to form and detoxify AGE byproducts may be genetically predetermined. This may explain why some patients with poor glycemic control are fortunate to experience no diabetes-related complications, whereas less fortunate individuals with IGT may develop retinopathy or painful diabetic neuropathy.

The clinical presentation of patients with AGE neuropathy is very similar to what may be seen in fibromyalgia. Patients complain of pain and stiffness throughout their entire body. They do not like to be touched as even light contact may induce a painful response. Pain is often worse at night, resulting in sleep disturbance, fatigue, and depression. Patients with AGE deposition often insist on being referred to a specialist such as a rheumatologist or orthopedist. Physicians caring for patients with diabetes must recognize that neuropathic pain can be diffuse, not just localized to the hands and feet.

In response to ambient hyperglycemia, the polyol pathway activates increasing intracellular levels of fructose and sorbitol.³⁷ Aldose reductase is an enzyme strategically placed in tissues whose intracellular glucose levels are not regulated by insulin or ambient glucose levels such as peripheral nerves and the ocular lens (Fig. 11-3). As glucose levels rise within the lens, glucose is converted into sorbitol via the enzymatic action of aldose reductase. Sorbitol is then converted into fructose. Neither sugar is able to exit the cell as easily as glucose originally entered into the cell. This results in an osmotic gradient, leading to water penetration into the lens, a precipitation of lens proteins, and cataract formation. Elevated sorbitol levels in peripheral nerves causes edema within axons, altering the normal neurologic function. As the resulting pain intensifies, peripheral nerves become highly sensitive to light touch. Patients develop an exaggerated response to pain (hyperalgesia) and experience painful responses to stimuli that are not normally painful (such as bed sheets touching the feet and inducing pain, a process known as allodynia).

Current research into neuropathic treatment is actively targeting the PKC pathway. Hyperglycemia activates PKC production, which initiates a complex intracellular signaling cascade, affecting gene expression in many organs and tissues throughout the body. PKC activation increases retinal and renal blood

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flow, as well as vascular contractility and permeability. PKC activation has been linked most closely with retinopathy and neuropathy.³⁸

Over the past 35 years, several major molecular mechanisms have been implicated in glucose-mediated vascular damage. Each of these mechanisms has been studied independently of the others, without regard to a possible universal origin. Recent discoveries have determined that these seemingly unrelated pathogenic mechanisms may arise from a single, hyperglycemia-induced process: the overproduction of the reactive free radical molecule superoxide.³⁹^,⁴⁰^,⁴¹ In response to hyperglycemia, cellular mitochondria activate superoxide production, which amplifies the cytotoxic effects induced by other pathogenic pathways. Superoxide production within the mitochondria is also enhanced through an increase in cellular free fatty acid oxidation.⁴² Oxidative stress is triggered more so by postprandial glucose fluctuations than by sustained hyperglycemia.⁴⁰

The effects of oxidative stress on long-term diabetes outcomes have significant implications in clinical practice. Why do some patients with normal A1C levels lower than 6% develop diabetes-related complications, whereas others with poorly controlled diabetes (A1C >9%) remain complication free their entire lives? In the DCCT, the diabetic retinopathy (DR) risk at identical sustained levels of A1C was significantly reduced by intensive treatment.⁴³ For example, in the group of patients with a sustained A1C of 9% for the entire study duration, the risk of retinopathy was reduced by more than 50% in the intensive control group, even though both the conventional and intensively treated patients had identical A1C levels. The reason the intensively managed patients had less retinopathy is believed to be due to a minimization of their daily glycemic variation when compared with the glucose profiles of the conventionally treated patients. Thus, regardless of the A1C level, home blood glucose monitoring should be performed frequently to monitor for glycemic variability that triggers oxidative stress.

A potential therapeutic option for managing oxidative stress may be found in -lipoic acid (LA), a powerful antioxidant scavenger. In the ALADIN II study, diabetic patients with symptomatic polyneuropathy were randomly assigned to 5 days of intravenous LA followed by oral treatment for 2 years and demonstrated a significant improvement in sural sensory nerve conduction velocity (NCV), sensory nerve action potential, and tibial motor NCV but not neuropathic disability score.⁴⁴ ALADIN III randomized 509 diabetic patients to LA intravenously for 3 weeks, followed by oral treatment compared with placebo. Symptoms scores did not change, yet neuropathy impairment scores did improve after 3 weeks of intravenous therapy and was maintained as long as the patient remained on oral LA.⁴⁵

Autoimmune mechanisms may play a role in both the initiation and rate of deterioration of neuropathy. The production of free radicals and superoxide can disrupt the normal neuroprotection achieved by the neurovascular unit.⁴⁶^,⁴⁷ The neurovascular unit consists of a neuron surrounded by astrocytes and microglial cells. The astrocytes play a pivotal role in regulating the fundamental physiologic response coupling dynamic changes in neuronal

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blood flow to neuronal synaptic activity.⁴⁸ Their primary function is in the transportation of ions into the neuron to maintain homeostasis.⁴⁹ Microglial cells are the resident macrophages of the central nervous system.⁵⁰^,⁵¹ As a type of sensor, these cells continually survey the neurons, making certain that normal neurophysiologic mechanisms are active. Microglial cells are capable of mounting both an inflammatory and reparative response when they become activated. Once the microglial cells become activated, they produce inflammatory cytokines [interleukin-6 (IL-6)], which can be damaging to neuronal structures and alter neurologic activity.⁵¹^,⁵² Cytokines are powerful inflammatory proteins, normally released by hematopoietic cells in response to a pathologic event. Cytokine levels remain sustained as long as the disease process continues. Elevated levels of tumor necrosis factor (TNF), IL-1, and IL-6 are observed in patients with psoriasis, rheumatoid arthritis, and Crohn disease, whereas drugs that are able to neutralize these cytokines (such as monoclonal antibodies) have been highly successful in managing these disorders.⁵³ Patients with diabetes who are exposed to long-term opioid administration may not demonstrate lowered improvement in their neuropathy pain scores. In fact, I have observed that placing patients with diabetic neuropathy on chronic opioids frequently results in a worsening of their pain scores, sleep disturbances, deterioration in function, and clinical depression. In some individuals, opioids can activate microglial cells, causing the production of inflammatory cytokines, resulting in disabling pain.⁴⁸^,⁵¹^,⁵⁴

Risk Factors for Developing Diabetic Neuropathy

Of the 1,172 patients with T1DM who participated in the DCCT, neuropathy developed in 23% who had no evidence of neuropathic disease at baseline.⁵⁵ The highest rates of neuropathy in patients with T2DM occurs in those who have had hyperglycemia for more than 25 years. Factors other than glycemic control appear to be influential in determining risk for developing neuropathy. Elucidating the risk factors for neuropathy is important, given the association between the risk factors and increased diabetes-related morbidity and mortality. Mortality in patients with neuropathy is high, and the cause of death is often coronary heart disease (CHD).⁵⁶ Risk factors for the development of neuropathy may be categorized as modifiable and nonmodifiable. (See table below⁵⁶^,⁵⁷ and Fig. 11-4.)

Neuropathy Modifiable Risk Factors	Neuropathy Nonmodifiable Risk Factors
Obesity Hypertriglyceridemia Cigarette smoking Hypertension Glycemic variability A1C	Family history Advancing age Duration of diabetes

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Figure 11-4 Nonmodifiable Risk Factors for Development of Diabetic Neuropathy. (Adapted from

Tesfaye S, Stevens LK, Stephenson JM, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996;39:1377 1384.

)

Many of the risk factors for the development of diabetic neuropathy are associated with insulin resistance and metabolic syndrome. Of interest is the fact that up to 35% of patients with IGT have painful neuropathy.⁵⁸ Although these individuals have normal A1C levels, a 2-hour glucose challenge test reveals evidence of blood glucose levels between 140 to 199 mg per dL.⁵⁸

Definition and Classification

The common neuropathies associated with both T1DM and T2DM can be divided into two broad categories: sensorimotor and autonomic (Table 11-6). Sensory neuropathies can be classified as peripheral neuropathy, proximal neuropathy, focal neuropathy, or distal symmetrical polyneuropathy. Peripheral neuropathy is the most common type of neuropathy seen in clinical practice and causes either pain or loss of feeling in the toes, feet, legs, hands, and arms. By contrast, proximal neuropathy (amyotrophy) causes pain in the thighs, hips,

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or buttocks, leading to weakness in the legs. Focal neuropathy involves sudden dysfunction of one group or a group of nerves, resulting in muscle weakness or pain. Distal symmetrical polyneuropathy is the most common type of diabetic neuropathy and causes paresthesias and pain in a stocking-and-glove distribution.

TABLE 11-6 Clinical Classification of Diabetic Sensorimotor Neuropathy

Sensorimotor Neuropathy

Distal symmetric polyneuropathy
Focal neuropathy
- Diabetic mononeuropathy (entrapment syndromes and cranial, truncal, or peripheral mononeuropathies)
- Mononeuritis multiplex
Diabetic amyotrophy

Autonomic Neuropathy

Hypoglycemic unawareness
Abnormal papillary function
Cardiovascular autonomic neuropathy (abnormal heart-rate control, orthostatic hypotension, silent ischemia)
Altered exercise tolerance
Abnormal circadian blood pressures
Sudomotor neuropathy
Gastrointestinal autonomic dysfunction (gastroparesis, diarrhea, constipation, fecal incontinence, malabsorption, dysphagia)
Genitourinary autonomic neuropathy (bladder dysfunction, sexual dysfunction)

Mononeuropathies

Focal and multifocal neuropathies are confined to the distribution of a single peripheral nerve (mononeuropathy) or multiple peripheral nerves (mononeuropathy multiplex). Mononeuropathies are caused by vasculitis and subsequent ischemia or nerve infarcts.⁵⁹ Commonly, a cranial nerve (CN III, IV, VI, or VII) or a peroneal, sural, sciatic, femoral, ulnar, or median nerve is involved. A typical mononeuropathy begins acutely, is associated with pain, and resolves spontaneously within 6 weeks.
Nerve entrapment syndromes begin gradually and may become disabling over time without intervention. Most often, the median, ulnar, or peroneal nerve or the lateral cutaneous tibial nerve within the tarsal tunnel is involved. Entrapment syndromes affect up to 30% of patients with diabetes and should be evaluated carefully in all those with signs and symptoms of neuropathy.⁶⁰

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Carpal tunnel syndrome (median neuropathy) is a clinically relevant problem in 6% of patients with diabetes.⁶¹ Painful paresthesias of the fingers may progress to a deep-seated ache that radiates up the forearm. Symptoms are worse at night. Motor weakness can become progressive, and thenar wasting occurs over time.

Two clinical tests with a high false-positive rate are commonly used to detect carpal tunnel syndrome. The Phalen test forearms held vertically and hands held in complete flexion for 1 minute is positive if paresthesia develops in the median nerve distribution within 30 seconds. The Tinel sign percussion over the median nerve that induces paresthesia over the distribution of the nerve is suggestive of carpal tunnel syndrome. However, nerve conduction studies are required to confirm the diagnosis. Treatment options include wrist splints for nocturnal symptoms. Cortisone injections in the carpal tunnel may provide symptomatic relief; however, they often need to be repeated. Surgical intervention is required for pain relief and to prevent the acceleration of muscle wasting.
Ulnar neuropathy occurs in 2% of diabetic patients as a result of nerve compression immediately distal to the ulnar groove beneath the edge of the flexor carpi ulnaris aponeurosis in the cubital tunnel. Alcoholism is a risk factor. Typical symptoms include painful paresthesias in the fourth and fifth digits associated with hypothenar and interosseous muscle wasting. Treatment is conservative; however, patients with motor loss and muscle wasting may require surgical intervention.
Compression of the lateral femoral cutaneous nerve (meralgia paresthetica), although uncommon in diabetes, can result in pain, paresthesias, and sensory loss over the lateral aspect of the thigh. Most cases resolve spontaneously. In cases associated with severe pain, allodynia, and disability, corticosteroid injections using focal nerve blocks at the inguinal ligament or surgical decompression may be indicated.
Tarsal tunnel syndrome is a painful lower limb entrapment that involves the tibial nerve, which passes through the tarsal tunnel. The tibial nerve innervates only the muscles of the sole. This results in severe burning pain over the plantar aspect of the foot when the patient stands or walks. Tinel sign on the underside of the medial malleolus with atrophy of the sole muscles is typical. Sensation over the dorsum of the foot is normal; however, nerve conduction studies demonstrate asymmetry compared with the normal leg. Ankle reflexes are maintained.

Treatment options include night-time splinting in a neutral position and targeted injections of local anesthetics and corticosteroids into the tarsal tunnel. Surgical decompression remains a controversial option in patients with diabetes who have severe pain and abnormal nerve conduction studies.⁶⁰
Cranial neuropathy in diabetic patients is rare, typically affecting older persons with a long history of diabetes.⁶² CN III, IV, or VI may be involved. The classic presentation is acute-onset diplopia with ptosis and papillary
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sparing associated with ipsilateral headache. Neurologic deficits resolve on average within 2 months. Recurrence rates are 25% in patients with diabetes.⁶³ Advise patients with a cranial neuropathy to wear a patch over the affected eye and to adhere to strategies that improve glycemic control.
Diabetic truncal radiculoneuropathy affects middle-aged and elderly men. The primary feature is pain of acute onset that resolves spontaneously within 4 to 6 months. The pain which is worse at night is described as an aching or burning sensation with superimposed lancinating stabs. Patients describe the location of pain as being in a girdlelike distribution over the lower thoracic or abdominal wall. The pain may be unilateral or bilateral. Patients may experience profound weight loss associated with the onset of their symptoms. Clinical findings range from no abnormalities to sensory loss and hyperesthesia in a complete dermatomal pattern.

Diabetic truncal radiculoneuropathy shares many features with diabetic amyotrophy, except the latter is much more painful and occurs in patients whose glycemic control is much worse.⁶⁴

Sensorimotor Neuropathy

Diabetic amyotrophy typically occurs in patients aged 50 to 60 years with T2DM. Presenting symptoms include severe pain and unilateral or bilateral muscle weakness associated with atrophy of the proximal thigh muscles.⁶⁵ The cause is unknown; however, it may be related to infarcts in the lumbosacral plexus.⁶³ Diabetic amyotrophy results in significant pain and difficulty in climbing stairs or getting out of cars. Patients have difficulty standing from a sitting position without placing their hands on their knees and pushing down to overcome their proximal muscle weakness (Gower sign). On standing, patients exhibit tremors in their hands. Walking is slow and deliberate. Some patients may walk like a duck with a broad-based gait and feet externally rotated. Neuropathic pain may accompany diabetic amyotrophy.

Recognition and Diagnosis of Diabetic Neuropathy in the Office Setting

Although complex electrophysiologic and autonomic function tests are required to confirm the diagnosis of diabetic neuropathies, a simple neurologic examination in the primary care office often can be used for screening purposes.

Screening for diabetic neuropathy is an important component of routine diabetes care. Most patients with mild sensory neuropathy have no detectable clinical findings. One should evaluate all patients with newly diagnosed diabetes, as well as those who are new to the practice, for peripheral neuropathy and re-examine patients every year. Screening at an early stage may forestall progression to more severe, disabling, or irreversible disease.

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TABLE 11-7 Risk Factors for Amputation Associated with Diabetic Peripheral Neuropathy

Loss of protective sensation
Altered biomechanics
Evidence of increased pressure (erythema and hemorrhage under a callus)
Foot deformities
Duration of diabetes for more than 10 years
Male gender
Prolonged poor glycemic control
Cardiovascular, retinal, or renal complications
Alcohol abuse
Peripheral vascular disease
Obesity
Elevation of the forefoot-rearfoot pressure ratio

Adapted from Unger J. Diabetic neuropathy. Early clues, effective management. Appl Neurol. 2005;9:23 30; and Sosenko J. The epidemiology of neuropathic foot ulcers in individuals with diabetes. Curr Diab Rep. 2002;2:477 481, with permission.

Inspection of the feet. This is mandatory for all patients with diabetes at the time of their initial visit and annually thereafter. Dry skin, distended veins, callosity, and multiple deformities (such as clawfoot and prominent metatarsal heads) may suggest Charcot foot. In this condition, increased pressure on the plantar surface may lead to ulceration. Foot ulceration and amputation are the most common consequences of diabetic neuropathy and are major causes of morbidity and disability in persons with diabetes. Table 11-7 lists risk factors for amputation.
Monofilament test (Fig. 11-5A). This is the most commonly used method for assessing foot ulcer risk. Most screening is performed with the 10-g monofilament. The device is placed perpendicular to a foot surface until it bends, and the patient is asked whether sensation is perceived. Protocols differ as to the number of sites on the foot that are tested and the criteria for a positive test for ulcer risk. The most common algorithm recommends four sites per foot: generally the hallux and metatarsal heads 1, 3, and 5. However, there may be little advantage gained from multiple site assessments. There is also no universal agreement as to what constitutes an abnormal result (i.e., one, two, three, or four abnormal results from the sites tested). Despite these problems, the 10-g monofilament is widely used for the clinical assessment of neuropathy.²⁹ When reporting the results of monofilament testing, one should mention the number of times the patient was able to perceive the sensation of each foot. For example, patient perceived 3/5 monofilament tests on the left foot and 1/5 on the right foot.

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Quantitative sensory testing. Risk of ulceration can also be determined by quantification of the results of sensory testing using the neuropathy disability score.⁶⁶ (Table 11-8). One sensory test is performed by applying a 128-Hz tuning fork on the hallux (Fig. 11-5B) and asking the patient whether he or she can perceive vibration. Loss of vibration sense indicates that the patient has significant sensory neuropathy. The same tuning fork can be used to assess hot and cold sensation, which is altered in diabetic neuropathy (Fig. 11-5C).
Check for loss of ankle reflexes a sign of advanced peripheral neuropathy.

Self-inspection. The clinician should educate patients who have clinical evidence of neuropathic disease about how to prevent the development

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of foot ulcers. One should discuss self-inspection of the feet and the use of properly fitting footwear. Table 11-9 lists the important teaching points for patients with peripheral sensory neuropathy that can help reduce the risk of ulcerations and amputations. Patients who are insensate are at an inherently higher risk of developing ulcerations and infections that may require amputation. Simply advising patients to inspect their feet each day may not motivate patients to perform this visual inspection. Instead, the clinician should give a monofilament to each patient who is insensate and advise him or her to check the feet each night and contact the doctor whenever any sensation returns to the feet. Physicians are encouraged to call their insensate patients 1 week after they receive their monofilament to ask if they have noticed any change in sensation. This reinforces the importance of using the instrument. In reality, return of sensation will not occur. However, the use of the monofilament essentially forces the patient to make a visual examination of the feet. When a small blister or ulcer is

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seen, the patient will most likely contact the healthcare provider at which time a detailed foot inspection can be performed. This technique may save limbs through early detection of neuropathic ulcers.

Figure 11-5 Examination for Diabetic Peripheral Neuropathy. A: Monofilament examination of the foot. The monofilament is placed on different areas of the dorsal and plantar surfaces of the foot. The patient is asked to identify when and where the monofilament is felt. Sensing less than 5 monofilament placements is strongly suggestive of neuropathy. B: The vibrating 128-Hz tuning fork is placed on the hallux of the patient. The examiner asks the patient first if the vibration is perceived. Next, the patient should inform the examiner when the vibration stops. The examiner then places the tuning fork on his or her own wrist. As a general rule, if the examiner perceives the vibration for 10 seconds longer on his or her wrist than was originally perceived on the patient's toe, neuropathy can be diagnosed. C: The tuning fork may also be applied to the foot to assess the patient's temperature perception.

TABLE 11-8 Neuropathy Disability Score in Patients with Diabetes

Sensation	Test	Score^a
Vibration	Apply a 128-Hz tuning fork to apex of great toe.
	Normal can distinguish between presence and absence of vibration.	0
	Abnormal	1
Temperature	Apply a tuning fork that had been placed in ice water or warm water to dorsum of the foot.
	Normal can distinguish between hot and cold.	0
	Abnormal	1
Pinprick	Apply pin proximal to great toenail, barely depressing the skin.
	Normal can distinguish sharpness or lack of sharpness.	0
	Abnormal	1
Achilles reflex	Present	0
	Present with reinforcement	1
	Absent	2
Total for one foot		0 5
^aA total score (for both feet) of 6 or greater is predictive of foot ulceration. The annual risk of ulceration is 1.1% if the score is less than 6 and 6.3% if 6 or higher. Adapted from Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med. 2004;351:48 55; and Unger J. Diabetic neuropathy. Early clues, effective management. Appl Neurol. 2005;9:23 30, with permission.

TABLE 11-9 Foot Care Instructions for Patients with Diabetes

Check your feet and toes daily for any cuts, sores, bruises, bumps, or infections, using a mirror if necessary.
Wash your feet daily, using warm (not hot) water and a mild soap. If you have neuropathy, you should test the water temperature with your wrist before putting your feet in the water. Doctors do not advise soaking your feet for long periods, because you may lose protective calluses. Dry your feet carefully with a soft towel, especially between the toes.
Cover your feet (except for the skin between the toes) with petroleum jelly, a lotion containing lanolin, or cold cream before putting on shoes and socks. In people who have diabetes, the feet tend to sweat less than normal. Using a moisturizer helps prevent dry, cracked skin.
Wear thick, soft socks and avoid wearing slippery stockings, mended stockings, or stockings with seams.
Wear shoes that fit your feet well and allow your toes to move. Break in new shoes gradually, wearing them for only an hour at a time at first. After years of neuropathy, as reflexes are lost, the feet are likely to become wider and flatter. If you have difficulty finding shoes that fit, ask your doctor to refer you to a podiatry specialist who can provide you with corrective shoes or inserts.
Examine your shoes before putting them on to make sure they have no tears, sharp edges, or objects in them that might injure your feet.
Never go barefoot, especially on the beach, hot sand, or rocks.
Cut your toenails straight across, but be careful not to leave any sharp corners that could cut the next toe.
Use an emery board or pumice stone to file away dead skin, but do not remove calluses, which act as protective padding. Do not try to cut off any growths yourself, and avoid using harsh chemicals such as wart remover on your feet.
Test the water temperature with your elbow before stepping in a bath.
If your feet are cold at night wear socks. (Do not use heating pads or hot water bottles.)
Avoid sitting with your legs crossed. Crossing your legs can reduce the flow of blood to the feet.
Ask your doctor to check your feet at every visit, and call your doctor if you notice that a sore is not healing well.

Adapted from Unger J. Diabetic neuropathy. Early clues, effective management. Appl Neurol. 2005;9:23 30, with permission.

Cardiovascular evaluation. CAN occurs in 17% of patients with T1DM and 22% of patients with T2DM, with an additional 10% of patients exhibiting
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borderline dysfunction. ⁶⁷ The 5-year mortality rate in patients with symptomatic autonomic neuropathy is three times greater than patients without autonomic involvement.⁶⁸ For this reason, all patients should be screened for signs of CAN at their initial visit and annually thereafter. The screening evaluation tests for CAN are listed in Table 11-10.

TABLE 11-10 Diagnostic Tests for Cardiovascular Autonomic Neuropathy

Parameter Tested	Comment
Resting heart rate	>100 beats/min is abnormal.
Beat-to-beat heart rate variation	Patient should abstain from drinking caffeine overnight.
	Do not perform test if patient experienced nocturnal hypoglycemia.
	When the patient lies supine and breathes 6 times per minute, a difference in heart rate of <10 beats/min is abnormal.
	An expiration:inspiration R-R ratio >.17 is abnormal.
Hear rate response to standing	Measure R-R interval at beats 15 and 30 after the patient stands.
Hear rate response to standing	A 30:15 ratio of less than 1.03 is abnormal.
Heart rate response to Valsalva maneuver	The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hg for 15 s.
Heart rate response to Valsalva maneuver	A ratio of longest to shortest R-R interval of less than 1.2 is abnormal.
Systolic blood pressure response to standing	Measure systolic blood pressure when the patient is lying down and 2 min after patient stands.
	A fall of >30 mm Hg is abnormal.
	A fall of 10 29 mm Hg is borderline.
Diastolic blood pressure response to isometric exercise	Patient squeezes a dynamometer to establish his or her maximum force.
	The patient then squeezes the grip at 30% maximum for 5 min.
	A rise of less than 16 mm Hg in the contralateral arm is abnormal.
Electrocardiography	A QTc of more than 440 ms is abnormal.
	Depressed very-low-frequency peak or low-frequency peak indicates sympathetic dysfunction.
	Depressed high-frequency peak indicates parasympathetic dysfunction.
	Lowered low- /high-frequency ratio indicates sympathetic imbalance.
Adapted from Vinik AI, Erbas T. Recognizing and treating diabetic autonomic neuropathy. Cleve Clin J Med. 2001;68:934.

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Simple Historical Clues Can Diagnose Diabetic Neuropathy

The neuropathic pain associated with diabetes is chronic and progressive, unlike acute pain, which most often results from tissue damage and serves a protective function. The chronic pain of diabetic neuropathy serves no protective function, degrades health and functioning, and may contribute to comorbidities such as depression or sleep disturbances. Neuropathic pain may be stimulus evoked (e.g., allodynia) or stimulus independent (spontaneous) as well as continuous or intermittent. Spontaneous pain is paroxysmal and described by patients as sharp, stabbing, or shocklike in nature. Patients often experience an uncomfortable sensation (hyperalgesia) wearing stockings or shoes and do not sleep well when bed sheets come in contact with their legs. Placing a cold item on a neuropathic extremity may elicit a painful sensation known as allodynia, which is a painful response to a nonpainful stimulus. Patients can understand allodynia by suggesting that they may have had a similar type of pain after having their last sunburn. Although the sunburn may have been uncomfortable, the pain became severe as soon as they attempted to shower. Since when should taking a shower be uncomfortable? When the skin is already sensitized, the act of bathing (a nonpainful stimulus) becomes painful.

Neuropathic pain can be diagnosed clinically based on distinct features and simple questionnaires that help rule out other pain etiologies. Several excellent pain assessment scales (Table 11-11) can be used to differentiate neuropathic and nociceptive pain (pain arising from outside of the nervous system).

TABLE 11-11 Validated Pain Rating Scales Useful for Office Assessment of Neuropathic Pain

Leeds Assessment of Neuropathic Symptoms and Signs^a

7-item questionnaire
Differentiates between neuropathic and nonneuropathic pain
Maximum score is 24; score 25 is suggestive of neuropathic pain

Neuropathic Pain Questionnaire^b

12-item questionnaire
Assesses pain qualities distinct to neuropathic pain
Useful in assessing treatment efficacy

Brief Pain Inventory for Diabetic Peripheral Neuropathy^c

11-item questionnaire (4-item pain severity scale and 7-item pain interference scale)
Assesses the severity of pain, its impact on daily functioning, pain location, and efficacy of treatment

^aBennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92:147 157.
^bKrause SJ, Backonja MM. Development of a neuropathic pain questionnaire. Clin J Pain. 2003;19:306 314.
^cZelman DC, Gore M, Dukes E, et al. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manage. 2005;29:401 410.

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Paradoxically, some patients with diabetic neuropathy may present with severe pain but have only minimal neurologic deficits, whereas others may have no pain yet sport large calluses, deformities, and foot ulcerations. Commonly, diabetic neuropathy affects the feet and lower extremities initially before gradually moving into the hands in a symmetrical stocking and glove pattern. Patients eventually lose vibration sense and proprioception, making ambulation difficult. Balance becomes impaired. As the pain of diabetic neuropathy is typically worse with rest, over time, patients' sleep patterns become impaired. Some may not be able to sleep lying down, preferring to sit up all night in a chair. Unfortunately, this results in sleep fragmentation, increasing the level of anxiety and depression. Quality of life becomes minimized as patients attempt to deal with the consistent hopelessness of their chronic pain.

Several questions may be useful in establishing a rapid and accurate diagnosis of DPN:

Do your feet burn, hurt, or tingle?
Is your pain worse at rest or with activity?
If you have worse pain while at rest, does the pain lessen when you become more active?
Are you having difficulty maintaining your balance?
Does wearing stockings or shoes bother you?
Is your pain making you feel helpless or disabled?
Is your pain affecting your sleep?
Is your pain affecting your quality of life?
Can you stand up from a sitting position without using your hands?

Other questions may help establish the presence of autonomic neuropathy that may occur in conjunction with peripheral neuropathy:

When you stand up do you feel light-headed as if you were going to pass out?
Do you have difficulty obtaining or maintaining erections?
Is vaginal penetration uncomfortable for you? (for women)
Do you get short of breath quickly after you begin any type of exertion?
Have you noticed that you never perspire from the chest up; only from the chest down? Do you frequently perspire after eating?
At what blood glucose level do you perceive that your sugar is low ?
Do you have difficulty emptying your bladder completely?
Do you have nocturnal diarrhea, intermittent constipation, abdominal bloating, or fullness after eating just a few bites of food? Do you ever lose control of your bowels or bladder?

Small unmyelinated C fibers, when damaged by neuropathic disease, produce typical symptoms and clinical findings on general exam. The loss of large myelinated neurons results in loss of ankle jerks, difficulty with proprioception and balance, and abnormalities in nerve conduction studies. When

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examining patients with peripheral neuropathy, one can ascertain the extent of the disease based on the patient's neurologic history and physical examination as depicted in Table 11-12. Patients with poorly controlled diabetes may develop neuropathic symptoms of moderate intensity after being initially placed on insulin therapy.²⁹

TABLE 11-12 Clinical Presentation of Diabetic Peripheral Neuropathy Based on Fiber Size

Small C-fiber Neuropathy
   Hot, shooting, symmetrical distal pains in hands and feet
   Tingling common
   Worse at rest
   Decreased with walking
   Allodynia and hyperalgesia on exama
   Loss of vibration sense, hot and cold differentiation, light touch
   Risk for pressure ulcers on plantar surfaces

Large Fiber Neuropathy
   Loss of balance
   Shuffling gaitb
   Loss of proprioception
   Loss of ankle reflexes
   Fear of falling

^aAllodyndia is defined as a painful response to a nonpainful stimulus. Patients complain of limb discomfort when their feet or legs come in contact with clothes or bedding. Hyperalgesia is defined as an exaggerated response to pain. When a patient with diabetic peripheral neuropathy has the leg squeezed with even mild pressure, the pain is perceived as severe. A cold tuning fork placed on the leg may also cause pain.
^bPatients tend to walk with a slow, shuffling gate due to their loss of joint proprioception and the fear of falling.

Pharmacologic Management of Diabetic Peripheral Neuropathic Pain

Although the primary objective of managing the painful symptoms of diabetic neuropathy is total elimination of pain, in most cases this may be unrealistic. Physicians should strive to reduce the patient's initial presenting pain by 50% by using medications and other therapeutic modalities that are safe and well tolerated. Treatments should target improved function, sleep disturbance, and psychogenic comorbidities such as anxiety and depression.

Many types of agents have been reported as being effective in case studies of individual patients, yet few have demonstrated good efficacy in larger

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randomized clinical trials with placebo comparators. None to date reliably relieves 100% of pain for every patient. The classes of drugs and individual agents with the best evidence of effectiveness in treating DPNP include antidepressants and anticonvulsants (Table 11-13). Duloxetine and pregabalin are currently FDA approved for treatment of DPNP.

Magnesium supplementation. Observational studies suggest that intracellular magnesium deficiency in patients with diabetes may account for abnormal nerve conduction studies.⁶⁹ Oral magnesium oxide supplements

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(250 to 750 mg taken on an empty stomach at bedtime) have been shown to improve the acute and chronic painful paresthesias of diabetic neuropathy.²²^,⁷⁰ Magnesium is a noncompetitive N-methyl d-aspartate (NMDA) receptor antagonist that affects the perception of pain within the spinal cord in animal models.⁷¹ Diarrhea is the most common adverse effect associated with magnesium use.

TABLE 11-13 First-line Medications for Neuropathic Pain

Medication	Starting Dose	Titration	Maximum Dose	Duration of Adequate Trial	Potential Drug Interactions	Precautions
₂ ligand
Gabapentin	300 mg tid	Increase 300 mg tid q 7 d	1,200 mg tid	3-8 wk for titration + 1-2 wk at maximum dose	Antacids reduce bioavailability. Therefore, take gabapentin 2 h after using an antacid. May significantly increase norethindrone levels	Category C pregnancy safety rating has not been established. Use with caution in patients with severe renal disease.
Pregabalin	50-75 mg tid or bid	Increase to 300 mg/d after 3-4 d, then by 150 mg/d as tolerated	600 mg/d	2-4 wk	May increase sedative effects of ethanol and lorazepam	Pregnancy safety category rating pending. Side effects include dizziness, somnolence, peripheral edema without cardiovascular implications. Can induce sedation. Reduce dose by 50% for creatine clearance <60 mL/min.
Antidepressants
Duloxetine	30 mg q with breakfast	After 1 wk increase to 60 mg q d with breakfast	120 mg q d	2 4 wk	Coadministration of drugs that inhibit CYP2D6 (paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels. Duloxetine moderately inhibits elimination of CYP2D6 substrates (TCAs, type 1C antiarrhythmics). Duloxetine + monoamine oxidase inhibitors can cause malignant hyperthermia.	Category C pregnancy safety rating has not been established. Titration from 30 60 mg minimizes nausea. Other side effects include somnolence, agitation, dizziness, and constipation.
Tricyclic antidepressants (TCAs)	10-100 mg taken 2h before bed-time	25 mg every 7 d as tolerated	75-150 mg daily; if blood level of active drug and its metabolite is below 100 mg/mL, continue titration with caution	6-8 wk with at least 1-2 wk at maximum tolerated dose	Use with cimetidine, quinidine, and duloxetine may increase levels of TCAs. May interact with thyroid medications and alcohol	Rated Category D (unsafe) for use during pregnancy. Side effects include cardiac conduction disturbances, arrhythmias, seizures, glaucoma, urinary retention, syncope, dry mouth. Avoid in patients >60.
Venlafaxine	37.5 75 mg/d	Increase by 75 mg/d weekly	375 mg/d standard venlafaxine or 225 mg/d extended release formulation	2 4 wk	Contraindicated with concomitant use of MAOI	May raise blood pressure 10-15 mm Hg. Pregnancy category C
Topical medications
Capsaicin cream		Apply to painful area on limb bid 2 wk. Rub in with vigor	Discontinue at 2 wk, even if no improvement seen	None	None	OTC. Category C pregnancy safety rating has not been established. Warn patient that drug will burn when applied to skin surface. Exercise immediately after application may exacerbate burning sensation.
Lidoderm patch	5%	Apply to painful area for 12 h daily	Can apply to multiple areas of the body if needed. OK to cut patches in halves as well. This saves money.	2 4 wk	None	Category B pregnancy safety rating
Anticonvulsants
Topiramate	25 mg at hs	Increase by 25 mg at hs weekly as tolerated	400 mg/d	2 4 wk	Dose adjustments are necessary when used with carbamazepine, phenytoin, and ethinyl estradiol. Reduce dose for renal dysfunction	Side effects include increase in paresthesias, cognitive difficulty, weight loss, glaucoma, kidney stones, and metabolic acidosis. Pregnancy category C
Lamotrigine	Weeks 1 2 = 25 mg/d	Weeks 3 4 = 50 mg/d Week 5 = 100 mg/d Week 6 = 200 mg/d	400 mg/d	4 6 wk	Titrate dose very slowly. Dose adjustments needed for patients taking phenytoin, phenobarbital, primidone, rifampin, and valproate	Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. Most common side effects include nausea, epigastric pain, headache, drowsiness, dizziness.
Analgesics
Tramadol	12.5 mg qid		200 mg/d	2 wk	Side effect common: nausea (23%), constipation (21%), headache (17%), somnolence (12%)	4-times daily dosing is a drawback. Increase risk of seizures in patients taking concomitant SSRIs, TCAs, opioids. Higher risk of seizures in patients with head trauma, coexisting seizure disorders, and substance abuse
Oxycodone CR	10 mg every 12 h	60 mg every 12 h	60 mg	4 wk	Side effects: constipation (42%), nausea (36%), dizziness (32%) may exacerbate preexisting diabetic autonomic neuropathy.	If long-term use is prescribed, an opioid agreement should be signed with the patient.
tid, three times daily; bid, twice daily; TCAs, tricyclic antidepressants; MAOI, monoamine oxi-dase inhibitor; OTC, over-the-counter; qid, four times daily; hs, bedtime dosing; SSRI, selective serotonin reuptake inhibitor.

Topical agents
- Drugs that reduce the production and release of substance P from peripheral pain receptors (called nociceptors) can lessen neuropathic pain. Capsaicin selectively stimulates unmyelinated C fibers to release substance P thereby reversibly depleting stores of this neurotransmitter from sensory nerve endings. As substance P levels are reduced, the transmission of painful stimuli from the peripheral nerve fibers to higher cortical centers is minimized. The Capsaicin Study Group⁷² evaluated the
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  use of capsaicin for the treatment of DPNP in a randomized trial. When compared with patients using only a vehicle cream, capsaicin patients noted improvement in walking, sleeping, work ability, and participation in recreational activities. Over-the-counter capsaicin ointment must be applied with a gloved hand and rubbed into the neuropathic limb for 5 minutes twice daily for 2 weeks. Contact with the face and eyes should be avoided.
- The 5% lidocaine patch is also effective in the treatment of peripheral neuropathic pain. Evidence from small randomized or open-label trials supports the efficacy of topical lidocaine for relief of DPNP with minimal adverse events.⁷³^,⁷⁴ The patches can be cut in half to save money and then placed on different areas of the body to alleviate pain. Most patients prefer wearing these patches on the soles of their feet while sleeping, as neuropathic pain tends to be more significant at rest often interfering with patients' sleep patterns. The patches can be worn only 12 hours each day. Patients using the lidocaine patch not only report improved quality of life measurements but may be able to taper off other analgesics.⁷⁵
Opioids. These are standard treatments for the management of moderate to severe nociceptive pain. Evidence of efficacy in the treatment of DPNP is available for oxycodone⁷⁶ and tramadol,⁷⁷ although the prolonged use of these drugs often raises ethical and legal concerns regarding the physical dependence caused by these drugs. The doses for managing neuropathic pain are higher than for nociceptive pain. Elderly patients treated with opioids may have an elevated risk of falls, resulting in fractures secondary to cognitive and mobility impairment.
- Although oxycodone CR is effective in improving symptomatic DPNP, patients experience high rates of adverse events such as constipation, sedation, dizziness, and dry mouth.⁷⁶ When considering the use of chronic opioid therapy for DPNP, patients must be evaluated for signs of possible abuse. The pros and cons of chronic opioid usage should be discussed and an opioid agreement signed between the provider and the patient. Information about chronic opioid usage and a downloadable opioid contract can be found at the American Academy of Pain Management Web site (http://www.aapainmanage.org/literature/Articles/OpioidAgreements.pdf).
Anticonvulsants
- Topiramate. Although useful in treating neuropathic pain, topiramate can increase paresthesias and cause cognitive dysfunction in dosages of more than 50 to 100 mg per day. Studies of patients with T2DM have demonstrated secondary positive metabolic effects from topiramate, such as weight reduction,⁷⁸ lower AIC levels,⁷⁹ and improved BP control.⁸⁰ Patients with T2DM who are obese may show improvement in neuropathic symptoms as well as in their overall metabolic control with topiramate.
- Lamotrigine. Lamotrigine is an anticonvulsant that also has antidepressant properties in patients with bipolar depression. Lamotrigine reduces neuropathic pain by two mechanisms: (a) stabilization of neural membranes through voltage-gated sodium channels and (b) inhibition of presynaptic release of the neurotransmitter glutamate. Lamotrigine must be titrated slowly (over several weeks) to avoid Stevens-Johnson syndrome and/or toxic epidermal necrolysis rashes.⁸¹ At dosages of 200 to 400 mg per day lamotrigine appears to effectively reduce neuropathic pain symptoms in patients with DPNP. Because the drug has an antidepressant effect, patients with coexisting depression who are unable to tolerate or do not respond to duloxetine, pregabalin, venlafaxine, or tricyclic antidepressants (TCAs) may have success with lamotrigine as a second-tier drug.
- Pregabalin. Pregabalin is an analog of the neurotransmitter gamma-amino butyric acid and possesses analgesic, anticonvulsant, and anxiolytic activity. As pregabalin binds to the 2 (alpha-2-delta) subunit of voltage-gated calcium channels at presynaptic nerve terminals,⁸² pain-promoting neurotransmitters (glutamate, noradrenaline, and substance P) are inhibited from propagating peripheral pain.⁸³ Pregabalin has been shown to be effective in the treatment of DPNP. A double-blind, placebo-controlled trial⁸⁴ that involved 76 patients with a 1- to 5-year history of DPNP culminated in a 40% response rate (defined as achieving at least a 50% decrease in study pain endpoints) among patients receiving pregabalin 100 mg three times a day without dose titration. In comparison, a response rate of 14.5% was seen among patients maintained on placebo. Although this was a short trial, lasting only 8 weeks, patients seemed to show improvement in pain response, sleep function, and anxiety scores within 1 week of starting pregabalin. Efficacy was maintained throughout the length of the study.
  
  Pregabalin has been studied at dosages of 75, 150, 300, and 600 mg per day. Both the 75 mg per day and the 150 mg per day dosages were not found to differ significantly from placebo, but the 300 and 600 mg per day dosages showed good efficacy on pain and function measures.⁸³^,⁸⁴^,⁸⁵ Approximately 50% of patients can expect to achieve a 50% or greater improvement in average daily pain with 300 mg per day of pregabalin and 30% can achieve a 70% or greater improvement with 600 mg per day. Reduction in pain and improvement in function is often noticed within 1 week of initiating therapy. Although increased efficacy is associated with the 600 mg per day dosage, higher dosages are often accompanied by more significant side effects such as drowsiness and dizziness. An advantage of pregabalin is that there are no known drug-to-drug interactions, yet the major disadvantages include the necessity of dose titration as well as the requirement to take the drug three times daily for best efficacy. Pregabalin is FDA approved for DPNP, postherpetic neuralgia, and partial seizures.
- Gabapentin. Gabapentin was studied for the treatment of DPNP in one randomized trial⁸⁶ and is FDA approved for the treatment of partial seizures and postherpetic neuralgia but not for DPNP.⁸⁷ Although the drug is probably effective in treating patients with DPNP, one must consider the following disadvantages prior to initiating gabapentin:
  - Although usually well tolerated with few drug-to-drug interactions, side effects include weight gain, cognitive deficiencies, dizziness, and edema.
  - Multiple dose titrations are required over time until the proper dose is determined.
  - For best efficacy the drug must be dosed three times daily.
  - A dose response curve is noted, whereas dosing patients higher than 1,800 mg per day may actually reduce the drug's efficacy.⁸⁸
- The absorption of pregabalin increases proportionally with each dose, resulting in a linear and predictable pharmacokinetic response. Gabapentin absorption is nonlinear. Higher doses of gabapentin may result in a reduced clinical response.
- Pregabalin has a more rapid onset of action than gabapentin.
- Pregabalin is approved for use in DPNP, postherpetic neuralgia, and as adjunctive therapy in adults with partial onset seizures.
- Gabapentin is approved for the management of partial seizures in patients older than 12 years of age and in the treatment of postherpetic neuralgia in adults.
Antidepressants
- The TCAs are widely used to treat chronic pain syndromes. In high doses, the pharmacologic effects are most pronounced true antidepressant medications. However, in lower doses, the antidepressants have a more potent analgesic effect. The analgesic effects of the TCAs are thought to be related to inhibition of serotonin and norepinephrine reuptake.⁹⁰ Despite their widespread use in pain management, none of the TCAs has been approved by the FDA for treatment of DPNP or any type of pain. In fact, a review published in 1996 found the total number of patients in clinical trials of the various agents for treatment of DPNP to be less than 200 subjects, with no single study having more than 50 subjects.⁹¹ Amitriptyline is the best studied TCA in DPNP. Although the drug does appear to be effective at dosages ranging from 25 to 150 mg per day, patients seem to benefit most from higher doses.
  
  Unfortunately, the side effect profile of the TCAs limits their utility in primary care. The most common adverse effects associated with
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  this drug class include dry mouth, constipation, dizziness, blurred vision, cardiac arrhythmias, syncope, fatigue, and urinary retention. Before prescribing TCAs for DPNP, patients must be evaluated for autonomic dysfunction, because TCA side effects will exacerbate these symptoms, especially in elderly patients. Desipramine has the lowest risk of adverse events in this drug class, whereas the most commonly prescribed drug, amitriptyline, is the most problematic. Although the TCAs are less costly and do have demonstrated efficacy regarding pain management, high doses can affect patient treatment adherence, increase side effects and drug-to-drug interactions, and provoke sudden death in patients with cardiac arrhythmias.
- Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2004 for treatment of both major depressive disorder and DPNP. Although the exact mechanism of action is uncertain, the drug appears to increase the levels of norepinephrine and serotonin in the inhibitory pain pathway of the central nervous system, blocking the perception of pain. The pain management provided by duloxetine may result in rapid (within 1 to 2 weeks) improvement in sleep, quality of life, ambulation, balance, anxiety, and depression.
  
  Duloxetine has been studied in two randomized, double-blind, placebo-controlled trials for relief of pain in patients with DPNP⁹²^,⁹³ and is FDA approved for the treatment of DPNP in dosages of 60 and 120 mg per day.⁹⁴ Fifty-five percent of patients with T1DM or T2DM treated with duloxetine achieved an improvement of 50% or more compared with baseline over a 12-week trial. Improvement was seen within the first week of treatment and continued as long as patients remained on therapy. The most common side effect is nausea, which can be minimized by starting therapy with a dose of 30 mg with breakfast and increasing to 60 mg with breakfast after 1 week.
  
  As with all antidepressant therapies, duloxetine carries an FDA black box warning. Patients new to antidepressant therapy or whose dosage is changed should be closely observed for signs of clinical worsening or suicidality. Duloxetine is also FDA approved for use in major depressive disorder.⁹⁴
- Another SNRI, venlafaxine extended release (ER), has been studied for the treatment of DPNP in one randomized trial of 244 patients with T1DM and T2DM.⁹⁵ Doses of 150 to 225 mg were successful at reducing pain intensity by 50% from baseline in patients with DPNP within 6 weeks of initiating therapy. The most common adverse events were nausea and somnolence. Impotency was also reported in 6% of men, yet less than 10% of the patients in the active arm of the study discontinued therapy due to adverse events.
- Tramadol. Tramadol is a centrally acting analgesic with unique properties as a weak inhibitor of norepinephrine and serotonin reuptake
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  and low-affinity binding to opioid receptors. In a randomized, double-blind, placebo-controlled 6-week trial, tramadol (average dosage = 210 mg per day) significantly improved pain as well as physical and social functioning for patients with DPNP. However, patients did not experience any improvement in their sleep dysfunction.⁹⁶ Although tramadol is effective in pain management, adverse effects including a high incidence of nausea, constipation, headache, and somnolence limit the drug's utility in treating DPNP. The drug must also be administered four times daily.
- Alternative Therapies
  
  Although many patients use and perceive benefit from complementary approaches, limited scientific evidence exists that supports the efficacy of these treatments. Some of these approaches may be valuable as adjunctive therapy for individuals in conjunction with standard medical care. When discussing alternative therapies with patients, one should mention that, although some therapies have little or no risk, there is no evidence of true cost-benefit associated with these modalities. Acupuncture has minimal but not insignificant risks as well as some evidence of efficacy. In one study, 46 patients with DPNP, 29 of whom were receiving drug therapy, underwent six sessions of traditional Chinese acupuncture over 10 weeks.⁹⁷ Thirty-four patients (77%) reported significant improvement in symptoms including seven (21%) whose symptoms resolved completely. Following the completion of the 10-week study, 66% of patients reported they could stop or reduce pain medications and only 18% required additional acupuncture sessions. Thus, acupuncture may relieve pain and/or reduce the need for analgesics in selected patients with DPNP.

Treatment Recommendations for Diabetic Peripheral Neuropathic Pain

On reviewing the evidence-based consensus treatment guidelines published by the American Society of Pain Educators⁹⁸ and the ADA Standards of Medical Care⁹⁹ the following recommendations are suggested as a framework for managing symptomatic and disabling DPNP:

One should improve glycemic control and glycemic variability.
First-tier drugs should include duloxetine and pregabalin.
Second-tier drugs should include venlafaxine ER, TCAs, gabapentin, and lamotrigine.
Third-tier drugs should include topiramate, paroxetine, topical lidocaine, and topical capsaicin.
Adding magnesium oxide 250 to 500 mg at bedtime will reduce paresthesias in many patients.

Patients who are being actively treated for DPNP should be asked at each visit whether their pain is improved, stable, or getting worse. Use of a pain

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index might be helpful in monitoring therapy. To calculate a pain index, one should ask the following questions at each visit:

TABLE 11-14 Pharmacologic Therapies for Diabetic Autonomic Neuropathy

Condition	Suggested Drug Therapy	Comments
Orthostatic hypotension	9-Alpha fluorohydrocortisone 0.5 2 mg/d Clonidine 0.1 0.5 mg at bedtime Octreotide 0.1 1.0 g/kg/d	May cause volume overload, CHF, hypertension May cause paradoxical hypertension, hypotension, sedation, and dry mouth Injection site pain and diarrhea but helpful for refractory cases
Gastroparesis	Erythromycin 250 mg with breakfast and dinner Tetracycline 250 mg with breakfast and dinner Insulin pump therapy	Usually effective within the first week. Stop either drug if ineffective within 14 days of starting therapy. Longterm use often necessary. Tetracycline is associated with sun sensitivity reactions. Erythromycin may cause diarrhea, abdominal cramps, or nausea. Patients on insulin pumps should use an extended wave bolus. As hyperglycemia improves, so will the symptoms.
Diarrhea	Metronidazole 250 mg three times daily for at least 3 weeks Tetracycline 250 mg with breakfast and dinner indefinitely Octreotide 50 g three times daily
Cystopathy	Bethanechol 10 mg four times daily Doxazosin 1 2 mg 2 3 times daily	Hypotension, headache, palpitations
Erectile dysfunction	PDE-5 drugs	See Table 11-16
Female sexual dysfunction	Vaginal lubricants (over the counter) Vaginal estrogen cream	Women experience dyspareunia, postcoital bleeding, and reduced sexual arousal.
CHF, congestive heart failure; PDE-5, phosphodiesterase-5.

On how many of the past 30 days have you experienced any pain?
On average, how would you rate the intensity of your typical daily pain from 0 to 10, where 0 is no pain and 10 is excruciating and disabling pain?
On average, over the past 30 days, how many hours per day do you perceive any pain? (The maximum answer would be 24 hours.)

To determine the pain index one should use the following formula:

Pain Index = Pain Intensity Duration + Frequency

For example, if a patient, prior to initiating pharmacologic therapy, reports daily pain with an average intensity of 7 and duration of 12 hours, the pain index = 7 12 + 30 = 114. If the patient returns for follow-up and reports daily pain with an intensity of 3 and duration of 3 hours, the pain index has been reduced to 3 3 + 30 = 39 representing a nearly 70% reduction in total pain.

Patients should experience at least a 50% reduction in pain from baseline from the first-tier drugs by week 3. If no improvement is seen, modification of therapy may be warranted. Doses of the first-tier drugs may be increased if the medication is well tolerated. Polypharmacy should be considered. Patients on SNRIs should not use concomitant TCAs or tramadol. Patients on tramadol should avoid using other opioids as this may increase the risk of seizures. However, patients using duloxetine may safely use topical agents, antiepileptic drugs, and opioids. Those on pregabalin may use TCAs, opioids, topical agents, and tramadol.

Patients who are treatment resistant should be referred to a pain specialist for further workup regarding the chronic pain status and for consideration to initiate long-term opioid therapy.

Table 11-14 summarizes the preferred drugs used to manage pain associated with diabetic neuropathy. A major goal in managing patients with DPNP is to improve function and quality of life. Reducing pain may also result in improved glycemic control.

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Case 2

This 60-year-old Hispanic woman, with a 12-year history of T1DM, was referred for management of disabling DPNP. Her neuropathic symptoms began 8 years ago and are progressive. At this time, she must sleep in a chair because any bed sheets touching her feet trigger intense pain. Two months prior to this visit, the patient was able to do some walking, but after falling 4 times in the past 3 weeks, she prefers to sit and watch TV during her waking hours. The pains are described as sharp jabs, which often leave her feeling as though her legs are on fire or as if a swarm of bees were stinging her feet. Despite being on multiple daily injections of insulin, her glycemic control is poor as reflected in her initial home blood glucose meter download (Fig. 11-6A).

Although duloxetine has no direct effect on glycemic control, the patient's symptoms of painful and disabling diabetic neuropathy improved to the point that she was able to begin a walking program. She was able to sleep in her bed once again and her balance normalized. Once the exercise program began, her usual diabetes treatment protocol successfully controlled her glycemia. However, immediately on stopping the drug, her symptomatology returned to baseline and she was unable to walk (Fig. 11-6B). A rise in blood glucose levels corresponded to the cessation of her walking program.

Figure 11-6 A: The patient was provided with samples of duloxetine on April 16 and within 10 days her blood glucose levels normalized. B: However, the patient discontinued duloxetine on May 26 because her sample supply ran out and her insurance refused to cover the cost of the drug. Immediately on stopping the drug, her blood glucose levels rose once again into the hyperglycemic range.

Diabetic Autonomic Neuropathy

DAN is a serious and common complication of diabetes. DAN impairs the ability to conduct activities of daily living, lowers quality of life, and increases the risk of death. Diabetes can cause dysfunction of any part of the autonomic nervous system, leading to a wide range of disorders. The most troublesome and dangerous conditions linked to DAN include silent MI and cardiac arrhythmias. Despite its relationship to an increased risk of cardiovascular mortality and multiple organ dysfunction, the significance of DAN has not been fully appreciated. Although DAN frequently coexists with other peripheral neuropathies, DAN may be isolated, frequently preceding the detection of other diabetic complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, sexual dysfunction, sudomotor dysfunction, and hypoglycemic unawareness.

Although peripheral and autonomic neuropathies are often considered to have similar risk factors and etiologies, DAN may be linked to a neuronal autoimmune disorder. In a prospective observational study, Granberg et al.¹⁰⁰ followed up 41 patients with T1DM over 14 years while intermittently performing tests of autonomic function on all patients. Periodic measurements of autonomic nerve autoantibodies (ANabs) were performed. The 56% of patients who tested positive for ANabs demonstrated significantly higher frequencies of at least one abnormal cardiac autonomic nerve function test.

The 5-year mortality rate in patients with DAN is three times higher than in diabetic patients without autonomic involvement.⁶⁸ The leading cause of death in patients with either symptomatic or asymptomatic autonomic neuropathy is heart disease.

CAN causes abnormalities of heart-rate control and vascular dynamics. Patients experience postural hypotension, exercise intolerance, and silent myocardial ischemia. CAN occurs in 17% of patients with T1DM and 22% of patients with T2DM.⁶⁷

Resting tachycardia is an early sign of CAN as is a lack of heart rate increase to mild exercise. Patients with postural hypotension also experience an abnormal circadian pattern of BP, which is the opposite of what is seen in the normal physiologic state. Ambulatory BP monitoring of patients with DAN demonstrate a rise in BP overnight and a fall in BP in the early morning.¹⁰¹

Perhaps the most frightening consequence of CAN is silent ischemia. In the Framingham study, 39% of patients with diabetes had an asymptomatic MI documented by electrocardiography.¹⁰² Silent ischemia is dangerous because patients cannot sense pain associated with an acute coronary event and are

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less likely to seek medical care. The mortality rate from a silent infarct is 47% versus 35% in patients able to perceive pain.²⁵ Physicians should consider pain in any part of the chest in a patient with diabetes as being of myocardial origin until proven otherwise. Other signs of silent MI include fatigue, edema, hemoptysis, nausea and vomiting, diaphoresis, arrhythmias, and dyspnea. The noninvasive, office-based diagnostic tests for CAN are listed in Table 11-10.

Orthostatic hypotension is diagnosed when a patient's systolic BP falls more than 30 mm Hg on standing. Patients may experience dizziness, weakness, visual impairment, headache, and loss of consciousness. Orthostatic hypotension may be exacerbated in patients who are volume-depleted from taking diuretics or who experience excessive sweating, diarrhea, or polyuria. Medications such as beta-blockers, TCAs, and phenothiazines can also contribute to orthostatic changes. Interestingly, patients often become abruptly hypotensive when eating or within 10 minutes of injecting insulin. Because the symptoms of orthostatic hypotension and hypoglycemia are similar, one should be advised to monitor blood glucose levels when they do become symptomatic. Insulin-provoked orthostatic hypotension usually occurs quickly after the injection is given. Exogenous insulin may mediate hypotension by increasing capillary permeability and causing a mild intravascular depletion. Insulin may also stimulate the release of nitric oxide a potent vasodilator from endothelial cells.¹⁰³ Hypoglycemia occurs most often prior to a meal or 1 to 2 hours after completing a meal.

Orthostatic hypotension is difficult to treat because the standing BP must be raised without causing hypertension when the patient becomes supine. Symptomatic patients should be advised to wear supportive stockings to increase venous return from the lower extremities, removing them at bedtime.¹⁰⁴ Caution should be taken when changing from a lying to a standing position. Bathing in hot water should be avoided and insulin injections should be administered while in the supine position.

The pharmacotherapeutic agents used for the treatment of orthostatic hypotension are listed in Table 11-14.

Fludrocortisone can increase BP in patients with orthostatic hypotension; however, it may also potentiate congestive heart failure (CHF), edema, and hypertension. Antihypertensive drugs may produce a paradoxical increase in BP by activating or antagonizing - or -adrenergic receptors that are inappropriately expressed as a result of autonomic denervation or dysfunction.⁵⁹

Subcutaneous octreotide may be used in patients with orthostatic hypotension refractory to other therapies. Octreotide has a pressor effect on patients with DAN, but in dosages of 1 g per kg per day it may cause abdominal cramping and nausea.¹⁰⁵

Because microvascular skin flow is regulated by the autonomic nervous system, patients with DAN may experience changes in skin temperature and texture. Patients will develop dry, cracked skin surfaces that can become a haven for pathogenic bacteria and fungi. Patients with diabetes should be warned to never walk barefoot, especially through an airport security

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screening area. A small cut or crack in the skin may quickly become infected, resulting in ulceration and gangrene. Socks should always be worn. Recently, disposable booties have been placed in some screening areas, which can be worn by patients as they cross through the metal detectors. Emollients should be used to soften the skin and prevent dryness.

Sudomotor (sweating) reflexes are abnormal in association with DAN. Patients may experience sweating in association with eating spicy foods and cheeses. Patients may avoid these embarrassing symptoms by simply eliminating these food triggers from their diet. Glycopyrrolate, an antimuscarinic compound, may benefit some patients with gustatory sweating.¹⁰⁶ Some individuals sweat only from the chest down and have no sweating around their face or head. Patients with sudomotor abnormalities are prone to heat stroke and dehydration. They should be extremely cautious while exercising, as they may experience rapid dehydration.

DAN related to gastrointestinal (GI) dysfunction is common in patients with diabetes. Gastroparesis should be suspected in individuals with erratic glucose control, bloating, early satiety, and postprandial nausea. Patients may experience diarrhea, but constipation alternating with diarrhea is not uncommon. Sixty percent of patients with diabetes experience constipation.¹⁰³

Before attributing constipation to DAN, hypothyroidism, colonic cancer, and side effects from drugs such as TCAs and calcium channel blockers (CCBs) should be ruled out as possible causes. Additional hydration and use of fiber products are useful in managing chronic constipation.²³

Gastroparesis occurs in 25% of patients with diabetes.¹⁰⁴ Hyperglycemia delays gastric emptying, whereas hypoglycemia results in rapid passing of gastric contents into the small intestine. Dosing insulin becomes problematic in patients with gastroparesis because the insulin is administered based on the time when the drug absorption is likely to coincide with the rise in blood glucose occurring after nutrients pass from the small intestine. However, one can never be certain when nutrients are being absorbed in patients with gastroparesis. In addition, patients may give a prescribed dose of insulin prior to eating, only to develop early satiety and abdominal pain after eating a small amount. The administered insulin will likely result in postprandial hypoglycemia. As the nutrient absorption is delayed for several hours, the patient will experience hyperglycemia 3 to 4 hours after eating as insulin peak absorption wanes while glucose levels rise. The postprandial hyperglycemia will result in persistent gastroparesis in time for the following meal.

Gastroparesis should always be suspected in patients with glycemic variability and chronic hyperglycemia. Although radiographic studies may be helpful in confirming a diagnosis of gastroparesis, they do not always correlate well with the degree of symptoms. In fact, some severely symptomatic patients may have normal radiographic studies.

Improvement in overall glycemic control is the primary goal of treatment of diabetic GI autonomic neuropathy. Hyperglycemia retards gastric emptying and reduces GI motility.¹⁰⁷ Management of insulin therapy can be

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challenging in patients with delayed gastric emptying (gastroparesis), because matching the timing of the injection with the anticipated rise in postprandial glucose absorption is difficult, if not impossible, to predict. One should advise patients with delayed gastric emptying who use an insulin pump to take an extended wave bolus at mealtime (see Chapter 6). Extended administration allows insulin to be absorbed over 3 to 4 hours rather than as a large dose with a meal. This reduces the incidence of postprandial hypoglycemia in patients with GI autonomic neuropathy.¹⁰⁸

Those patients who cannot use an insulin pump should consider injecting their insulin 30 to 45 minutes after finishing their meal rather than at the onset of eating to avoid immediate postprandial hypoglycemia. Some patients may experience relief of symptoms within 1 to 2 weeks of using twice daily tetracycline or erythromycin. In theory, these antibiotics reduce excessive bacterial overgrowth in the GI tract, allowing the normal GI flora to become stabilized. Patients who do not notice improvement in the GI symptoms within 2 weeks of starting antibiotics should be prescribed an alternative treatment.

Metoclopramide is effective in treating gastroparesis for the short term. However, long-term use of this agent increases the risk of extrapyramidal side effects and drug tachyphylaxis.¹⁰⁹ A recently completed pilot study demonstrated improvement in gastric emptying time with the use of botulinum toxin 200 units injected into the pylorus in patients refractory to other treatments.¹¹⁰

Neurogenic bladder (cystopathy) symptoms include difficulty urinating, urinary incontinence, pyelonephritis, and chronic urinary tract infections. The dysfunctional bladder may become distended up to three times its normal size. However, as patients have loss of sensation, bladder distention is asymptomatic. Voiding frequency is diminished and the voiding process is incomplete, which may lead to urinary tract infections and pyelonephritis. Dribbling and overflow incontinence are common. A postvoid residual volume of more than 150 mL is diagnostic of cystopathy.¹⁰³ Patients with cystopathy should be instructed to palpate their bladder and try to urinate when their bladder is full. If they are unable to start the urine flow, they can massage the abdomen just above the pubic bone to initiate urine flow (Crede maneuver). Self-catheterization may be needed in some patients and has a low risk of infection. Pharmacotherapy is directed at improving bladder emptying and reducing the risk of urinary tract infections (Table 11-14).

Patients with T1DM with autonomic neuropathy have a defective counter-regulatory catecholamine (norepinephrine) response to hypoglycemia.¹¹¹ These individuals are unable to perceive a rapid fall in blood glucose levels and cannot mount a physiologic response to reverse their own hypoglycemia. One should instruct patients with hypoglycemic unawareness to check their blood glucose levels more frequently, especially before driving, to detect low blood sugar levels. One should frequently discuss with patients the proper treatment of hypoglycemia (see Fig. 6-8). Use of continuous subcutaneous

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insulin infusion (CSII) therapy (insulin pumping) may help re-establish hypoglycemic awareness in patients with autonomic dysfunction.¹⁰⁸ Although normalization of glycemic control is usually the goal of treatment for patients with diabetes, patients with hypoglycemic unawareness require less intensive management and a higher ambient glucose level. Hypoglycemia must be avoided completely to allow the adrenergic response to recover. Eventually the insulin doses may be increased slowly to allow normalization of blood glucose levels.

The cornerstone of management for DAN is improving diabetes control. However, one must treat all of the patient's metabolic parameters to target. The overall risk of CAN can be reduced by 70% with physiologic management of hyperglycemia, hyperlipidemia, and hypertension, as well as with the use of ACE inhibitors.²³ Unless contraindicated, patients should be placed on aspirin. Behavioral issues such as nicotine and alcohol use must be addressed. The response to therapeutic intervention is dependent on the patient's baseline degree of autonomic dysfunction. Intensive glycemic control can reverse deterioration in heart-rate variability in as little as 1 year.¹¹² Often, symptomatic DAN may stabilize soon after glycemia improves.¹¹³

Erectile Dysfunction

Phosphodiesterase-5 Drug Fast Facts

Sexual stimulation is required for the phosphodiesterase-5 (PDE-5) inhibitors to successfully produce an erection. The impact of psychogenic stimulation diminishes with age and increased sensory input is needed to achieve erections.
PDE-5 inhibitors should not be used more than once daily.
The patient should take sildenafil and vardenafil on an empty stomach approximately 1 hour before initiating sexual contact. Vardenafil should be taken 1 hour and tadalafil 2 hours before sexual activity.
The three available PDE-5 inhibitors are similar in terms of onset of action, efficacy, and side effects. Tadalafil is more likely to be associated with muscle pain. Tadalafil has the longest duration of action of the PDE-5 inhibitors.
Patients can be switched readily from one PDE-5 inhibitor to another.
ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, CCBs, and thiazide diuretics may all be used safely with PDE-5 inhibitors.
The risk of severe, symptomatic hypotension is lower when PDE-5 inhibitors are used in conjunction with uroselective -1a and -1 d selective agents (alfuzosin and tamsulosin) rather than with nonselective ₁-adrenoreceptor blockers (terazosin or doxazosin).¹¹⁴^,¹¹⁵
The combination of nitrates with PDE-5 inhibitor drugs will result in profound, rapid, symptomatic, and life-threatening vasodilation and hypotension.

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The majority of men with diabetes suffering from ED may safely use PDE-5 inhibitors if the drugs are taken according to their specific instructions and guidelines.
PDE-5 inhibitor doses should be reduced when used in patients taking any of the following drugs that are strong inhibitors of the CYP3A4 metabolic pathway: clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, nelfinavir, ritonavir, and saquinavir.¹¹⁶

ED can be successfully managed with a variety of oral medications (PDE-5 inhibitors), transurethral alprostadil pellets, and intracavernosal injections.¹¹⁷ Table 11-15 lists the drugs that can be used to successfully manage men with ED. Table 11-16 lists the pharmacodynamics of these drugs. Table 11-17 lists recommendations for use of PDE-5 drugs in patients with cardiac disease.

PDE-5 inhibitors are generally safe and effective when used for the treatment of ED in men with CHD. However, these drugs are potent vasodilators and physicians should carefully consider whether their high-risk CHD patients [unstable or refractory angina, uncontrolled hypertension, New York Heart Association (NYHA) Functional Class III/IV, recent MI <2 weeks prior

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to consultation, hypertrophic cardiomyopathy, moderate/severe valvular disease] could be adversely affected by these vasodilatory effects.¹¹⁸ ED may also be a sensitive marker for occult CHD.¹¹⁹ PCPs may consider referring patients with ED to a cardiologist before initiating any pharmacologic treatment. The metabolic and cardiovascular demands of sexual activity are modest and patients with mild to moderate CHD who are not using nitrates or alpha-blockers should be able to use PDE-5 inhibitors safely.

TABLE 11-15 Efficacy of Phosphodiesterase-5 (PDE-5) Inhibitors in Men with Diabetes and Erectile Dysfunction

Parameter Measured	% Efficacy (Placebo/PDE-5 Drug)
Improved Erections
Placebo vs. sildenafil 50-100 mg^a	10/67
Placebo vs. vardenafil 20 mg^b	36/64
Placebo vs. tadalafil 20 mg^c	23/54
Successful Intercourse
Placebo vs. sildenafil^a	12/48
Placebo vs. vardenafil 20 mg^b	23/54
Placebo vs. tadalafil 20 mg^c	30/57
The most effective doses for patients with diabetes in clinical trials are sildenafil 100 mg, vardenafil 20 mg, and tadalafil 20 mg. ^aSource: Most data on file from the sildenafil package insert (Viagra, Pfizer, 1998). The sildenafil dose is 50 to 100 mg. These results are from a meta-analysis of 21 clinical trials of up to 6 months' duration in more than 3,000 men and in 10 open-label extension studies. ^bSource: http://www.fda.gov/cder/foilael/2003/0214000lbl.pdf. Accessed November 5, 2003. This study included 439 men; mean age, 57 years (range 33 to 81); 80% white, 9% black, 8% Hispanic, and 3% other. ^cSource: Tadalafil package insert (Cialis, Eli Lilly, 2003). In 22 clinical trials, patients taking tadalafil experienced successful erections 62% to 74% of the time. Adapted from Unger J. How to assess and treat erectile dysfunction. Emerg Med. 2004;36:28 37, with permission.

TABLE 11-16 Pharmacodynamics of the Phosphodiesterase-5 (PDE-5) Inhibitors

Drug	Available Doses	Onset of Action (min)	Duration of Action (h)	Comment
Sildenafil	25, 50, 100	14 20	8 12	Contraindicated with nitrates Take on empty stomach
Vardenafil	2.5, 5, 10, 20	30 120	8 12	Contraindicated with nitrates Take on empty stomach Caution with alpha-blockers because of risk of orthostatic hypotension
Taldalafil	10, 20	30 120	36	Coadministration with nitrates contraindicated Longest half-life of all PDE-5 drugs
Adapted from Unger J. How to assess and treat erectile dysfunction. Emerg Med. 2004;36:28 37 with permission.

Recent labeling changes to sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) reflect a small number of cases of sudden vision loss attributed

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to nonarteritic ischemic optic neuropathy (NAION). Although stating that a direct link between NAION and PDE-5 has not been found, the FDA has advised patients on these drugs to notify their physicians immediately in the event of any sudden vision loss in one or both eyes. Physicians should inquire about a history of prior severe vision loss prior to prescribing PDE-5 drugs to any patients with ED.

TABLE 11-17 Recommendation for Use of Phosphodiesterase-5 (PDE-5) Inhibitors in Men with Heart Disease

PDE-5 inhibitors are absolutely contraindicated with the concomitant use of nitrates.
Coadministration of a PDE-5 inhibitor and a nitrate within 24 h of each other may result in hypotension or death.
The risks and benefits of using PDE-5 inhibitors should be discussed with all cardiac patients whether or not they are using nitrates.
Consider monitoring blood pressure for 1 h in patients with heart failure or hypotension after a PDE-5 inhibitor is administered in the office setting.

TABLE 11-18 Phosphodiesterase-5 (PDE-5) Inhibitor Dosing Adjustments for Patients with Chronic Kidney Disease (CKD Stage 4 5)

Medication	Dose Adjustment
Sildenafil	Start dose of 25 mg when creatinine clearance is <30 mL/min.
Tadalafil	Start dose of 5 mg once daily (maximum 10 mg once every 48 hours) when creatinine clearance is 31 50 mL/min. Maximum dose of 5 mg when creatinine clearance is <30 mL/min and patient is on hemodialysis.
Vardenafil	No dose adjustment required for CKD 4. Vardenafil has not been evaluated in patients on renal dialysis.
Sources: Viagra (sildenafil citrate) Prescribing Information. http://www.fda.gov/cder/foi/label/2005/020895s021lbl.pdf (accessed January 9, 2007). Levitra (vardenafil HCl) Prescribing Information. http://www.univgraph.com/bayer/inserts/levitra.pdf (accessed January 9, 2007). Cialis (tadalafil) Prescribing Information. http://pi.lilly.com/us/cialis-pi.pdf (accessed January 9, 2007).

Tadalafil and vardenafil can be coprescribed at 50% maximum doses in patients with benign prostatic hypertrophy receiving alpha-blockers. Caution should be exercised when prescribing PDE-5 inhibitors to men with left ventricular outflow obstruction (aortic stenosis, idiopathic hypertrophic subaortic stenosis) and orthostatic hypotension. Patients who have suffered an MI, CHF, end-stage renal disease (ESRD), stroke, or life-threatening or cardiac arrhythmia within the past 6 months may not be candidates for PDE-5 drugs. The doses of sildenafil and tadalafil should be decreased in cases of stage 4 to 5 chronic kidney disease (CKD)¹²⁰^,¹²¹ (Table 11-18).

Sixty percent of men with diabetes experience ED.²⁶ Owing to the high prevalence of this diabetes-related and often significant complication, physicians should be able to identify patients proactively who suffer from this condition and offer them counseling on therapeutic interventions. Either direct inquiry can be made regarding the patient's erectile performance or a questionnaire may be provided (such as the Sexual Health Inventory for in Men, Fig. 11-7) to screen patients for ED. The laboratory workup for men with ED should include

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an A1C, lipid profile, thyroid-stimulating hormone, free thyroxin, prostate-specific antigen (PSA), serum prolactin, and free testosterone.¹¹⁷^,¹²²

Figure 11-7 Sexual Health Inventory For Men (SHIM). (From

Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11:319 326, with permission.

)

Women with sexual dysfunction attributable to diabetes may also experience a reduction in libido, pain with intercourse, and difficulty achieving orgasm. One should encourage women with vaginal dryness to use vaginal lubricants before sexual intercourse. Vaginal estrogens, when appropriate, may be beneficial for patients experiencing dyspareunia, incontinence, and atrophic vaginitis.

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Case 3

Marion was referred to you by one of your associates for the evaluation and management of bilateral knee pain. The 65-year-old patient, with a 5-year history of T2DM, is convinced that she has arthritis in her knees and wants a referral to an orthopedic surgeon. The pain is so unbearable that she is demanding to see the specialist this afternoon.

Marion's pain developed over 10 years ago, 5 years prior to the time of her diagnosis of T2DM. She describes the pain as a burning, cramping, and numbing sensation worse in the knees but also present in the feet. The pain is worse at night as well as at rest and is improved with ambulation. She is unable to tolerate any bed sheets touching her feet or legs. Even stockings placed on her feet intensify the pain. She is sleeping in a chair, due to the pain's intensification associated with rest. Marion has also fallen three times in the past 6 weeks and she is unusually unsteady on her feet as of late.

Marion is 62 inches tall and weighs 100 kg (220 lb). Her BP is 140/92 mm Hg and she appears very anxious. Examination of her extremities reveals symmetrical loss of hot and cold sensation, joint sense (proprioception), ankle reflexes, light touch, and vibratory sense. When a vibrating tuning fork is placed lightly on her knees, she complains of moderate pain (allodynia). Gentle palpation around the knee joint is extremely painful (hyperalgesia). Full range of motion is noted in the knee joints and there is no evidence of joint effusion, crepitation, erythema, or temperature variation. The patient's gait is slow and deliberate as her feet are never lifted far from the ground. Prior to making a turn, the patient makes a brief stop, then slowly turns in the appropriate direction.

Laboratory studies that were sent with the patient at the time of the consult reveal an A1C of 7%. Blood chemistries, complete blood count (CBC), liver function studies, thyroid tests, iron-binding studies, and plain x-ray films of the knees are all normal.

The patient is informed that she has clinical evidence of DPNP. After beginning duloxetine 30 mg with food daily for 1 week, the dosage is increased to 60 mg daily. On her return 4 weeks later, Marion reports that she her pain is reduced by at least 50%. Most importantly, she has begun to sleep in her bed and because her balance is improving, she is less dependent on using a walker for support when she is outside of the home.

Case 4

Mr. Duffy returns to your practice after seeking care for his diabetes elsewhere for the past 5 years. He was initially diagnosed as having T2DM at age 42, 13 years ago. Not always the most compliant patient, Mr. Duffy apologizes for not following the treatment plan he was given 5 years ago when his diabetes began to get out of hand. As his A1C had increased to 8.5%, he was advised to (a) begin insulin therapy; (b) begin a statin, ARB, and aspirin; (c) stop smoking and drinking alcohol; and (d) take a more active role in his own diabetes management. Instead, Mr. Duffy opted to treat his diabetes with nutritional supplements that he purchased on the Internet. He now returns complaining of weight loss, fatigue, blurred vision, frequent urination, difficulty walking, abdominal bloating, diarrhea alternating with constipation, ED, and severe pain in his legs. He has been experiencing pain and stiffness over his entire body. In fact, he is now unable to sleep or walk due to his increasing pain. He is taking no prescription medications and has recently changed his vitamin supplements in an attempt to improve his symptoms. The patient's initial physical and laboratory findings are as follows:

Weight: 70 kg
Body mass index (BMI): 32 kg per m²
Heart rate: 106 beats per minute
BP: 180/102 mm Hg supine; 130/75 mm Hg standing
Funduscopic exam: DR
Foot exam: Symmetrical loss of vibratory sense, ankle reflexes, proprioception, monofilament sensation, and hot-cold sensation. Gait is broad based with external rotation of the feet. Allodynia and hyperalgesia are noted on both legs. Patient has multiple tender points on the back, chest, neck, arms, and legs.
Genitourinary (GU) exam: Normal, including prostate
Point of service A1C: 12.2%
Random blood sugar: 345 mg per dL
Urine: 3+ protein; ketones

Mr. Duffy has a combination of different diabetes-related neuropathies. He has autonomic disease as shown by his resting sinus tachycardia and standing orthostatic hypotension. His ED is typical of DAN. His peripheral neuropathy is accompanied by proximal motor weakness and an unbalanced gait. The joint stiffness and diffuse pain is most likely due to the deposition of AGEs, which become oxidized within the target tissue. The AGE deposition may cause disabling and prolonged pain.

Treatment options must include behavioral interventions (stopping smoking and alcohol), enforcement of the daily use of aspirin, beginning of appropriate insulin therapy, and management of coexisting metabolic disorders. The patient should also be placed on either pregabalin or duloxetine in an attempt to reduce pain by 50% by the time of his next appointment. This regimen should reduce the patient's pain level by at least 50% within the next 4 weeks.

Mr. Duffy's ED could be treated with a low-dose PDE-5 inhibitor. However, because the patient has resting tachycardia and orthostatic hypotension, he may be at risk for silent ischemia. Therefore, a cardiovascular consultation will be obtained before prescribing any medication for sexual dysfunction.

The patient's gastroparesis will be managed with tetracycline 250 mg taken with breakfast and dinner daily. He is informed that his GI symptoms (diarrhea and bloating) should improve within 2 weeks of initiating this therapy. Overall, many of this patient's symptoms should improve in response to lowering his ambient hyperglycemia.

Late Sequelae of Diabetic Peripheral Sensory Neuropathy

The late sequelae of diabetic neuropathy are foot ulcerations (which may occasionally result in amputation) and, less commonly, Charcot arthropathy (Fig. 11-8). Both sensory and autonomic dysfunction have been implicated in the pathway to ulceration.¹²³ However, the neuropathic foot does not ulcerate spontaneously. A combination of neuropathy with either extrinsic factors

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(ill-fitting shoes or a foreign body in the shoe) or intrinsic factors (high foot pressures or plantar callus) will ultimately result in ulceration. The risk of lower extremity amputation depends on the nature of the patient's foot pathology. Patients with isolated peripheral sensory neuropathy have a 1.7-times increased hazard risk ratio of requiring an amputation. Those with neuropathy and a foot deformity (such as a hammertoe) have a 12-times increased hazard risk ratio, whereas patients with ulcerations have a 36-times increased hazard risk ratio of ultimately needing an amputation.¹²⁴

Figure 11-8 A: Charcot foot demonstrating erythema and swelling in an insensate patient with diabetic peripheral and autonomic neuropathy. B: Fractures in the foot and ankle in patients with Charcot arthropathy lead to mechanical instability and structural anomalies such as the rocker-bottom deformity seen in this patient. C: Patients with ulcerations and Charcot arthropathy have a 36-times higher likelihood of requiring a lower extremity amputation than a patient without peripheral sensory neuropathy. (Photos courtesy of Drs. Jerry and Danny Farber, Silver Spring, Maryland.)

Charcot arthropathy affects up to 7.5% of patients with diabetes, particularly those individuals with both somatic and autonomic neuropathy with intact circulation.¹²⁵ The patient with Charcot arthropathy may develop a deformed, mechanically unstable foot that is prone to ulceration. The usual clinical presentation is the rapid onset of swelling and erythema with varying degrees of pain. Insensate patients may be pain free. The early physical examination may indicate intact pulses, warm skin, and exuberant erythema. Initial radiographs may appear to be normal and the differential diagnosis of infection versus Charcot arthropathy is difficult. In the absence of any open wound, chills, or fever, a diagnosis of a Charcot foot or ankle must be considered. Diagnostically, elevation of the leg for a period of 24 hours will result in significant improvement in the swelling and erythema in an acute Charcot joint. Specialty consultation should be obtained for management of these difficult complications of peripheral neuropathy.

Summary

Neuropathy is a common and often asymptomatic complication of diabetes. Those patients who are symptomatic experience chronic pain, sleep deprivation, and loss of balance. Autonomic neuropathy is a life-threatening complication that may affect numerous organ systems. Physicians should screen and diagnose peripheral sensory neuropathy at least annually to prevent sequelae such as Charcot foot, neuropathic ulcers, and nontraumatic amputations. Controlling A1C, glycemic variability, and metabolic comorbidities while enforcing behavioral interventions are all important in limiting the development and progression of diabetic neuropathy. Once patients develop symptomatic neuropathy, antidepressants, antiepileptic agents, and topical agents are useful in limiting disabling pain.

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Diagnosis, Management, and Prevention of Diabetic Kidney Disease

Case 5

Mrs. Salcedo is a 53-year-old Hispanic woman with a 5-year history of T2DM. She has a family history of T2DM, CKD, and stroke. Over the past 12 months, she has gained 7 pounds and has continued her inactive lifestyle, because she continually feels tired. She has been adherent with her medications, which include triple oral hypoglycemic agents, three antihypertensive drugs, a statin, aspirin, and occasional anti-inflammatory drugs for sick headaches. She continues to smoke one-half pack per day (PPD). Mrs. Salcedo is 5 ft 4 in tall, and weighs 185 pounds Her BP is 170/98 mm Hg. Her random blood glucose level is 188 mg per dL and point-of-service A1C is 8.6%. A spot urine dipstick reveals 4+ protein. Additional lab studies are as follows:

Creatinine = 1.6 mg per dL
Spot urine albumin:creatinine ratio = 426 g per mg creatinine
Hemoglobin = 10 g per dL; hematocrit (Hct) = 29%
Glomerular filtration rate (GFR) = 36 mL per minute per 1.73 m²
Total cholesterol = 200 mg per dL
High-density lipoprotein cholesterol (HDL-C) = 32 mg per dL
LDL-C = 110 mg per dL
TGs = 275 mg per dL
Non-HDL-C = 168 mg per dL

Mrs. Salcedo has stage 3 CKD most likely secondary to glomerulosclerosis associated with poorly controlled diabetes. The reduction in GFR and her anemia increases her risk for rapid progression to stage 4 or 5 CKD and CVD. This patient's risk for acute MI is extremely high. She has albuminuria, poorly controlled hypertension, diabetes, and hyperlipidemia. Her non-HDL-C level is above 130 mg per dL, suggesting that her lipid profile has a prominent elevation of Apo B, further increasing her atherogenic risk. Management strategies would include placing the patient on intensive insulin therapy targeting an A1C of lower than 7%, making certain that appropriate antihypertensive agents are used to lower the BP to less than 125/75 mm Hg, aggressively managing the hyperlipidemia using a combination of a statin with nicotinic acid, using low-dose aspirin, and initiating erythropoietin therapy to raise the hemoglobin to 11 to 12 g per dL.

Because the patient is at high risk for silent ischemia, referral to a cardiologist should be provided. A nephrology consult would be warranted as soon as the GFR is lower than 30 mL per minute per 1.73 m². Finally, the patient should be advised that smoking cessation at this time is imperative. Treatment options could include pharmacologic and behavioral approaches including using combination nicotine replacement therapy drugs. Having the patient contact the self-help telephone hot line 1-800-QUITNOW would allow the patient to receive behavioral intervention and follow-up for smoking cessation free of charge.

Diabetic Nephropathy

Diabetic Nephropathy Fast Facts

Microalbuminuria is defined as a urine albumin excretion (UAE) rate of 30 to 299 mg per 24 hours.

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Macroalbuminuria is defined as a UAE rate of 300 mg or more per 24 hours.
Proteinuria is defined as a UAE of 500 mg or higher per 24 hours or a spot urine value of 430 mg per L or greater.
Only 30% to 45% of microalbuminuric patients progress to proteinuria over 10 years. Improved metabolic control can reduce the risk of progression.¹²⁶
CKD progression (Stage 1 to 5) can be predicted based on the patient's GFR. Mortality rates are so high in stage 4 that progression to stage 5 (GFR <15 mL per minute per 1.73 m²) is actually uncommon. Interventions at each stage of CKD can slow the rate of disease progression.
Anemia is a common occurrence in patients having CKD stage 3 to 5. Management of anemia using erythropoietic agents can reduce mortality from heart disease and slow the progression toward the necessity of dialysis.
Patients with short-duration microalbuminuria may experience improvement in their UAE levels when their A1C levels are reduced to less than 8%, systolic BP is less than 115 mm Hg, total cholesterol is lower than 198 mg per dL, and TGs are lower than 145 mg per dL.¹²⁷
Diabetes causes a unique pathologic alteration within the kidney known as glomerulosclerosis.
Patients with diabetic nephropathy should be carefully evaluated for other microvascular complications including retinopathy and neuropathy. (All diabetes-related complications share common determinants including prolonged exposure to hyperglycemia, hypertension, and hyperlipidemia.)
Patients with diabetic nephropathy have an inherently higher risk of CVD.¹²⁸ Patients with an estimated GFR below 60 mL per minute per 1.73 m² are therefore considered to be in the high-risk group for CVD. As such, they should undergo intensive evaluation and treatment of risk factors for cardiovascular disease, independent of the presence or absence of cardiac symptoms.
Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast dyes should be used only when the patient is well hydrated and no other diagnostic alternatives are available. The preferred contrast media used in high-risk patients is iodixanol.¹²⁹
Conditions that may accelerate the progression towards renal insufficiency include:
- Chronic, uncontrolled hyperglycemia
- Genetic factors
  - Anemia
- Cigarette smoking and hyperlipidemia
- Excessive dietary protein intake
- Hypertension: systolic BP of 135 mm Hg or higher and the diastolic BP of 85 mm Hg or higher (nearly all patients with nephropathy also have hypertension)
- Neurogenic bladder leading to hydronephrosis, chronic urinary tract infections, and obstructive nephropathy

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Diabetic Nephropathy Prevalence and Costs

Diabetic nephropathy is characterized by proteinuria, hypertension, and progressive kidney failure. In the United States, 45% of the 373,000 new cases of ESRD diagnosed in 2000 resulted from diabetic nephropathy (the majority of whom have T2DM).¹³⁰ In comparison, 27% of ESRD is caused by hypertension, 13% by glomerulonephritis, and 10% from other causes.¹³¹ In patients with T2DM, the prevalence of diabetic nephropathy varies from 5% to 10% in Caucasian patients, 10% to 20% in African Americans, and up to 60% in members of the Pima Indian tribe.¹³² Thirty percent to 40% of patients with T1DM will develop nephropathy.¹³¹ The medical costs incurred by patients with diabetes in the 24-month period preceding their initiation of dialysis are 76% higher in comparison with ESRD patients without diabetes ($134,054 vs. $76,192).¹³³ The annual per patient cost of managing ESRD in the United States is approximately $64,000. This emphasizes the importance of interventions among patients with diabetic nephropathy to prevent or delay progression to ESRD.¹³⁴

Diabetic dialysis patients and transplant recipients also have higher mortality and morbidity rates than their nondiabetic counterparts.¹³⁰ Diabetic patients with early diabetic nephropathy (proteinuria or a minimally elevated serum creatinine >0.5 mg per dL) have an even greater cardiovascular risk.¹²⁸^,¹³⁵

Definitions and Diagnosis of Diabetic Nephropathy

Diabetic nephropathy can be diagnosed based on the value of UAE in a spot urine sample.¹³⁶ Microalbuminuria is defined as having a UAE of 30 to 299 mg per 24 hours, whereas the UAE in patients with macroalbuminuria exceeds 300 mg per 24 hours. Not all patients with microalbuminuria progress to macroalbuminuria. In fact, UAE reduction has been shown to occur in T1DM patients with short duration microalbuminuria, A1C lower than 8%, systolic BP lower than 115 mm Hg, and normal lipid values. Therefore, improving metabolic parameters may slow or even reverse diabetic nephropathy in some patients.¹²⁶^,¹²⁷

For patients with T2DM, the presence of microalbuminuria doubles the risk of cardiovascular morbidity and mortality.¹³⁷^,¹³⁸ As urinary protein levels increase, the incidence of stroke, amputation, neuropathy, and retinopathy is also elevated.¹³⁹^,¹⁴⁰^,¹⁴¹ The clinical consequences of microalbuminuria are related to physical injury to vascular endothelium of the kidney and other end organs. Endothelial cell damage progresses in relation to the degree of microalbuminuria. Endothelial injury results in an increase in the release of renin, an enzyme produced primarily by the juxtaglomerular cells of the kidney. Renin catalyzes the conversion of angiotensinogen into an inactive substance: angiotensin I (A-1) (Fig. 11-9). ACE then converts A-1 to the physiologically active angiotensin II (A-II), which causes potent vasoconstriction, aldosterone secretion, sympathetic activation, and hypertension.¹⁴² ACE inhibitor drugs

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block the conversion of angiotensin I to angiotensin II. ARBs antagonize A-II induced biologic actions, which include smooth muscle contractions, sympathetic pressor mechanisms, and aldosterone secretion.

Figure 11-9 The Renin-Angiotensin-Aldosterone System: Physiology and Pharmacology. Renin is released from juxtaglomerular cells acting as pressure and renal profusion sensors. A reduction in plasma volume is perceived by the juxtaglomerular cell as a threat to maintenance of blood pressure homeostasis. Decreased dietary potassium (K⁺) intake, increased plasma sodium (Na⁺) levels, and sympathetic input from changes in posture also result in the renin release. Renin then catalyzes the conversion of angiotensinogen into angiotensin I (A-1). Angiotensin-converting enzyme (ACE) converts inactive A-1 into active angiotensin II (A-II). A-II results in vasoconstriction, sympathetic discharge, and hypertension. Angiotensin receptor blockers (ARBs) block the pharmacologic effects of A-II in the periphery: smooth muscle contraction, sympathetic discharge, and aldosterone secretion. Aldosterone secretion leads to sodium retention, an increase in circulation blood volume, and a rise in blood pressure. (Adapted from

Matsubara H. Pathophysiological role of angiotensin II receptor in cardiac and renal diseases. Circ Res. 1998;83:1182 1191.

)

In some patients, microalbuminuria may progress to CKD (Fig. 11-10). CKD is defined as either kidney damage or decreased kidney function (decreased GFR) for 3 months or more. Fortunately, progressive renal dysfunction is not inevitable as therapeutic approaches that target a number of modifiable risk factors can slow the progression of nephropathy in patients with diabetes. Early recognition, aggressive management, and timely referral to a nephrologist can reduce long-term complications related to diabetic nephropathy.¹⁴³

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Figure 11-10 Screening for Microalbuminuria and Nephropathy in Patients with Diabetes. The glomerular fi ltration rate (GFR) is the best measure of overall kidney function in health and disease. The normal GFR in young adults is 120 to 130 mL per minute per 1.73 m² and declines with age. A GFR less than 60 mL per minute per 1.73 m² represents loss of 50% of the adult level of normal renal function. Below this level, the prevalence of complications of chronic kidney disease increases. Ninety-eight percent of patients with chronic renal failure (CRF) in the United States begin dialysis when their GFR is less than 15 mL per minute per 1.73 m². Preparations for renal transplantation and dialysis should begin when the GFR approaches 30 mL per minute per 1.73 m². (The GFR calculator can be found online at: http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm.) A/C, albumin:creatinine. (Adapted from

American Diabetes Association. Clinical Practice Recommendations 2007. Diabetes Care. 2007;30[Suppl 1]:S19-S21.

)

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Kidney failure is not synonymous with ESRD. ESRD is a term that identifies patients as requiring dialysis or renal transplantation, conditions that are reimbursed by the Medicare ESRD program.¹⁴⁴ Although ESRD provides an operational classification of patients according to treatment needs, the specific level of kidney function is not addressed by this terminology. A patient can have CKD without having ESRD.

Screening for and Staging Nephropathy

Screening newly diagnosed patients with diabetes for nephropathy is imperative because 7% of these individuals will already have clinically significant kidney disease.¹⁴⁵ Approximately 18% of patients with T1DM develop microalbuminuria within the first 5 years after the diagnosis is made. Patients at high risk for microalbuminuria include those with poor glycemic control, hypertension, and hyperlipidemia. Puberty is an independent risk factor for microalbuminuria. Because microalbuminuria may be improved if treated early after onset, patients with T1DM should be screened 1 year after the initial diagnosis is made. If microalbuminuria is absent, annual screening should be performed¹⁴⁶ (Fig. 11-10).

The National Kidney Foundation guidelines¹⁴⁷ recommend that a standard urinalysis be performed to screen for proteinuria 5 years after the diagnosis in patients with T1DM and at the time of the diagnosis in patients with T2DM. If the urine dipstick test is positive, the degree of proteinuria should be quantified using either a 24-hour urine collection or an albumin-to-creatine ratio. A negative screening urinalysis should be followed by a nontimed screen for microalbuminuria. Microalbuminuria need not be evaluated in patients who have evidence of proteinuria.

In-office testing for microalbuminuria and macroalbuminuria can be performed using a Micral Test II.¹³⁶ Although the measurement of UAE is the cornerstone for the diagnosis of diabetic nephropathy, there are some patients with either type 1 or type 2 diabetes who have decreased GFR in the presence of normal UAE.¹⁴⁸ In patients with T1DM, this phenomenon seems to be more common among female patients with long-standing diabetes, hypertension, and/or retinopathy.¹⁴⁸ For patients with T2DM in NHANES III (Third National Health and Nutrition Examination Survey; n = 1,197), low GFR (<60 mL min^-1 1.73 m^-2) was present in 30% of patients in the absence of microalbuminuria or macroalbuminuria and retinopathy.¹⁴⁹ These studies indicate that normoalbuminuria does not protect from a decrease in GFR in type 1 and type 2 diabetic patients. Therefore, UAE should be used to screen patients for nephropathy, whereas the GFR is used to stage the disease process (Fig. 11-11).

A persistent (>3 month) reduction in the GFR to less than 60 mL per minute per 1.73 m² is defined as chronic kidney disease.¹⁵⁰ A normal GFR in young adults is 120 to 130 mL per minute and declines with age. Most importantly, a GFR less than 60 mL per minute represents a loss of 50% or more

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of the adult level of normal kidney function and predicts the high likelihood of ESRD defined as a GFR less than 15 mL per minute. In the United States, 98% of patients with ESRD begin dialysis when their GFR is less than 15 mL per minute.¹³⁷ Patients with markers of kidney damage such as proteinuria and abnormalities on imaging studies or on kidney biopsy have the disease, even if GFR estimates are 60 mL per minute per 1.73 m² or more. Patients without markers of kidney damage who have GFR estimates of 60 mL per minute per 1.73 m² or greater are unlikely to have the disease.

Figure 11-11 Five Stages of Chronic Kidney Disease Based on Glomerular Filtration Rate (GFR). (From

National Kidney Foundation Web Site: http://www.kidney.org/kidneydisease/ckd/knowGFR.cfm.

)

In clinical practice, the GFR is calculated using equations such as the Modification of Diet in Renal Disease (MDRD) study¹⁵¹ equation or the slightly less accurate Cockcroft-Gault equation. These formulas can be very cumbersome to use. Therefore, the GFR is best determined using the National Kidney Foundation's online GFR calculator: http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm.

Nephrology consultation should be obtained for patients whose GFR reaches 30 mL per minute per 1.73 m². Most patients will require either dialysis or renal transplantation once they progress into CKD stage 5. Unfortunately, few patients actually progress from CKD stage 4 to CKD stage 5.¹⁵² For patients with CKD stage 4 disease, death is twice as likely as progression to CKD stage 5.¹⁴³ Five percent to 20% of all patients in CKD stage 5 die annually.¹⁵³

Renal biopsy should be considered in newly diagnosed patients with T1DM with proteinuria and a rapid decline in renal function. Because nephropathy and retinopathy so often coexist, patients with CKD without evidence of eye disease should also undergo a renal biopsy to determine if the kidney disease is related to diabetes or an unrelated disorder.¹⁵⁴ Diabetes causes unique changes

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in kidney structure. Classic glomerulosclerosis is characterized by increased glomerular basement membrane width, diffuse mesangial sclerosis, hyalinosis, microaneurysm, and hyaline arteriosclerosis.¹⁵⁵ Areas of extreme mesangial expansion called Kimmelstiel-Wilson nodules or nodular mesangial expansion are observed in 40% to 50% of patients developing proteinuria.¹⁵⁶ The indications for performing renal biopsies in patients with T2DM are unclear.

Prevention and Treatment of Diabetic Nephropathy

Intensive glycemic control

The basis for prevention of diabetic nephropathy is treatment of known risk factors, including hypertension, hyperglycemia, and dyslipidemia. Lifestyle interventions are also critical to enforce. Smoking cessation is a necessity. Patients who stop drinking alcohol may notice an improvement in their BP readings.

The DCCT⁶ demonstrated that intensively managing T1DM reduces the incidence of microalbuminuria by 39%. Graduates from the intensively managed arm of the DCCT were able to reduce their incidence of microalbuminuria and hypertension by 40% even as their glycemic control deteriorated over time.¹⁰ Patients with T2DM in the UKPDS who were intensively managed demonstrated a 30% reduction in the development of microalbuminuria.¹⁴⁵ Thus, intensive treatment of glycemia targeting an A1C lower than 7% should be pursued as early as possible after the diagnosis of diabetes is made to prevent the development of microalbuminuria.
Intensive management of hypertension

Treatment of hypertension dramatically reduces the risk of cardiovascular and microvascular events in patients with diabetes. Hypertension is common in patients with diabetes, even in those with no evidence of renal disease. Forty percent of T1DM and 70% of T2DM patients with normal renal studies have BP levels exceeding 140/90 mm Hg.¹⁵⁷ In the Hypertension Optimal Treatment (HOT) study, a reduction of diastolic BP from 85 to 81 mm Hg resulted in a 50% reduction in the risk of cardiovascular events in diabetic but not in nondiabetic patients.¹⁵⁸ A reduction of the systolic BP from 154 to 144 mm Hg in the UKPDS¹⁵⁹ reduced the risk of developing microalbuminuria by 29%. The BP target for patients with diabetes is 130/80 mm Hg.¹⁶⁰

The role of ACE inhibitors in the prevention of diabetic nephropathy in patients with T1DM has not been defined. In patients with T2DM, ACE inhibitors and ARBs diminish the risk for diabetic nephropathy¹⁶¹^,¹⁶² and reduce the occurrence of cardiovascular events.¹⁶³ In a 5-year prospective study,¹⁶⁴ telmisartan (an ARB) 80 mg per day and enalapril (an ACE inhibitor) 20 mg per day had similar efficacy in preventing the progression of decline of GFR in 250 patients with T2DM with microalbuminuria. This reinforces the suggestion that ACE inhibitors and ARBs have similar renal protective effects.

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In the MICRO-HOPE (Heart Outcomes Prevention Evaluation) study,¹⁶³ ramipril (10 mg per day) decreased the risk of overt nephropathy by 24% and the risk of cardiovascular death in patients with T2DM who were older than 55 years of age with one additional cardiovascular risk factor by 37%. Moreover, ramipril reduced UAE at 1 year and at the end of the study. Therefore, ACE inhibitors have been shown to be beneficial for renoprotection and cardioprotection in patients with T2DM.

In patients with T1DM, ACE inhibitors have been shown to delay the progression of nephropathy in both microalbuminuria and macroalbuminuria.¹⁶⁵^,¹⁶⁶ Patients who are normotensive without evidence of microalbuminuria should be placed on ACE inhibitors for prevention of diabetic nephropathy.¹⁴⁶

Patients with T2DM with microalbuminuria or macroalbuminuria in clinical trials have had renoprotective benefits from either ACE inhibitors or ARBs.¹⁶⁷^,¹⁶⁸^,¹⁶⁹^,¹⁷⁰ However, conflicting data exist in terms of reducing the risk of nephropathy in patients with normoalbuminuria. However, both agents lead to a similar reduction in albuminuria in a 1-year study.¹⁷⁰ Therefore, the use of either ACE inhibitors or ARBs is recommended as a first-line therapy for T1DM and T2DM patients with microalbuminuria even if they are normotensive.¹³⁶ Patients excreting more than 1 g protein daily have been shown to stabilize their GFR for longer periods when their BP levels are reduced to less than 125/75 mm Hg.¹⁷¹ An acute increase in serum creatinine of up to 30% to 35%, stabilizing after 2 months, might occur in proteinuric patients with creatinine values higher than 1.4 mg per dL after starting ACE inhibitors. This rise in creatinine is associated with long-term preservation of renal function, and therefore ACE inhibitors should not be stopped.¹⁷² Greater increases should raise the suspicion of renal artery stenosis. Inhibition of the renin-angiotensin system, especially with ACE inhibitors, might raise serum potassium levels, particularly in patients with renal insufficiency. For these reasons, albuminuria, serum creatinine, and potassium should be checked monthly during the first 2 to 3 months after starting treatment with ACE inhibitors or ARBs.

Critical renal artery stenosis (>70%) occurs in approximately 17% of hypertensive T2DM patients¹⁷³ and may be associated with hypertension and renal insufficiency (ischemic nephropathy). In these patients, the use of ACE inhibitors or ARBs could reduce transcapillary filtration pressure, leading to acute or chronic renal insufficiency, especially if renal artery stenosis affects both kidneys or the sole functioning kidney. A rise in serum creatinine of higher than 50% after use of these agents is a clue for the presence of renal artery stenosis.¹²⁶ Other suggestive features are renal impairment with minimal or absent proteinuria, absent or minimal DR, presence of macrovascular disease in other sites (coronary, carotid, and peripheral arteries), vascular bruits (especially femoral), and asymmetric kidney shrinkage on renal ultrasound.¹⁷³

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Combination therapy with ACE inhibitors plus ARBs interrupts the renin-angiotensin system at different levels and has an additive effect on renoprotection (Fig. 11-11). The combination of candesartan (16 mg per day) with lisinopril (20 mg per day) in the Candesartan and Lisinopril Microalbuminuria (CALM) trial was more effective in reducing BP and UAE ratio in hypertensive T2DM patients than either drug alone.¹⁶⁹ Trials in nondiabetic subjects have proven the beneficial effects of dual blockade in slowing the progression of renal disease over 3 years.¹⁷⁴
Dietary intervention

Dietary management of renal disease is controversial. A moderately low protein-restricted diet (0.9 g kg^-1 day^-1) used in T1DM patients with progressive diabetic nephropathy reduced the risk of ESRD and death by 76% without affecting the decline in GFR.¹⁷⁵ Reducing red meat and saturated fat consumption¹⁷⁶ can reduce UAE by 46%. Although protein and calorie restriction slows the progression of diabetic nephropathy in high-risk patients, more long-term studies are necessary to access the true benefits of nutritional therapy as being renoprotective.
Management of hyperlipidemia

The goal for LDL cholesterol is lower than 100 mg per dL for diabetic patients in general and lower than 70 mg per dL for diabetic patients with CVD.¹⁷⁷ The effect of lipid reduction by antilipemic agents on progression of diabetic nephropathy is still unknown. So far, there have been no large trials analyzing whether the treatment of dyslipidemia could prevent the development of diabetic nephropathy or the decline of renal function. However, there is some evidence that lipid reduction by antilipemic agents might preserve GFR and decrease proteinuria in diabetic patients.¹⁷⁸ In the Heart Protection Study, 40 mg simvastatin reduced the rate of major vascular events and GFR decline in patients with diabetes, independent of cholesterol levels at baseline, by 25%.¹⁷⁹
Management of anemia in patients with CKD

Chronic kidney disease is a known cause of anemia. Anemia is associated with lower exercise tolerance, poorer quality of life, left ventricular hypertrophy, and heart failure among patients with chronic renal insufficiency.¹⁸⁰ Forty percent to 70% of patients beginning long-term hemodialysis in the United States have a history of congestive heart failure and left ventricular hypertrophy, both strong predictors of mortality.¹⁸¹ This suggests that the harmful effects of anemia are progressive and reflective of the patient's declining GFR. The anemia of CKD is related to erythropoietin deficiency.¹⁸²^,¹⁸³ Because anemia is considered a risk factor for progression of renal disease and retinopathy, early recognition and management are essential.¹⁸⁴ Treatment of anemia with erythropoietin (epoetin alpha) can slow the progression of nephropathy while reducing the risk of CHD and left ventricular hypertrophy.¹⁸⁵^,¹⁸⁶^,¹⁸⁷ Patients with diabetic nephropathy should have their hemoglobin levels maintained in the range of 11 to 12 g per dL.¹⁸⁸^,¹⁸⁹

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An assessment of the patient with CKD for anemia (hemoglobin <12 g per dL) should include a hemoglobin and/or hematocrit, red blood cell (RBC) indices, reticulocyte count, iron parameters (serum iron, total iron-binding capacity, percent transferrin saturation, and serum ferritin), and a test for fecal occult blood. Normal values for hemoglobin are 12.0 to 16 g per dL for menstruating women and 13.5 to 17.5 g per dL for men and postmenopausal women. Mean normal hematocrit values are 36% to 46% for menstruating women and 41% to 53% for men and postmenopausal women.

The anemia associated with diabetes is due to a reduction in erythropoietin production thought to be secondary to (a) renal denervation from diabetic neuropathy, (b) alterations in the structures within the renal cortex resulting in a reduced erythropoietin response to the hypoxic stimulus of anemia, and (c) a reduction in levels of androgen hormones that stimulate erythropoiesis.¹⁹⁰ Prior to the availability of recombinant human erythropoietin (rHuEPO, epoetin alfa), anemia was treated with iron supplements or blood transfusions. Both iron and erythropoietin are necessary for the formation of hemoglobin. Although epoetin therapy may improve outcomes in anemic patients with CKD and diabetic nephropathy, adverse events such as hypertension, seizures, hypercoagulation, hyperkalemia, and functional iron deficiency may occur.

In the United States, the available erythropoietic agents are epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp), both of which are indicated for use in CKD whether or not patients are undergoing dialysis. Both drugs have similar efficacy and safety profiles in CKD with pruritus occurring more frequently in patients using darbepoetin alfa.¹⁹¹ Patients may safely transition between either erythropoietic agent.

Although product labeling for epoetin alfa recommends initial dosing of 50 to 100 units per kilogram three times per week titrating to a hemoglobin value not exceeding 12 g per dL, 90% of patients are able to maintain hemoglobin values greater than 11 g per dL with either weekly or twice-monthly injections of 20,000 units per dose. Eighty percent of patients maintain targeted hemoglobin values when injected every 3 to 4 weeks.¹⁹²

For patients with CKD, either intravenous (IV) or subcutaneous (SQ) darbepoetin alfa is administered once weekly¹⁹³ at a starting dose of 0.45 g per kg, titrating to hemoglobin levels not exceeding 12 g per dL. After starting epoetin, the hemoglobin and hematocrit levels should be measured every 1 to 2 weeks until the target hemoglobin (11 to 12 g per dL) has been achieved. The hemoglobin/hematocrit should then be monitored every 2 to 4 weeks. One should consider increasing the dose of epoetin 50% after 4 weeks if the hematocrit does not increase by at least 2%. The weekly epoetin dose may also be reduced by 25% if the hemoglobin/hematocrit exceeds the target. Both the dose and the frequency of dosing may be adjusted depending on the response of the patient to the drug.¹⁸⁸

Aspirin use in patients with diabetic nephropathy

Patients with microalbuminuria or macroalbuminuria may be more aspirin-resistant to the benefits of primary and secondary cardiovascular

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protection.¹⁹⁴ Therefore, patients with diabetic nephropathy may benefit from higher aspirin dosages (>100 to 150 mg per day) with or without the combined use of antiplatelet agents such as clopidogrel.¹⁹⁵

Figure 11-12 Pathophysiology of Secondary Hyperparathyroidism Associated with Chronic Kidney Disease. Declining glomerular filtration rate (GFR) leads to reduced phosphate excretion and hyperphosphatemia. The elevated phosphate levels directly stimulate parathyroid hormone (PTH) synthesis, resulting in glandular hyperplasia. Hyperphosphatemia also suppresses the activation of calcitriol by the kidney. Low calcitriol directly enhances PTH secretion while reducing calcium absorption from the gut, leading to hypocalcemia and further increases in parathyroid production and secretion. Taken together, hyperphosphatemia, hypocalcemia, and reduced calcitriol synthesis all promote the production of PTH and parathyroid cell proliferation, resulting in secondary hyperparathyroidism.

Evaluation and management of secondary hyperparathyroidism in patients with diabetic nephropathy

Physicians should be aware that patients with CKD may develop secondary hyperparathyroidism, leading to renal osteodystrophy.¹⁹⁶ The pathophysiology of secondary hyperparathyroidism is shown in Figure 11-12. A decrease in GFR leads to renal retention of phosphate. Because the parathyroid glands are directly stimulated by elevated phosphate levels, hyperplasia of the glands occurs in response to hyperphosphatemia. As parathyroid hormone (PTH) levels rise, the absorption of calcitriol (vitamin D) is reduced, impairing the mobilization of calcium from bones. Calcitriol (1,25-dihydroxycholecalciferol) in a normal metabolic state would increase the absorption of both calcium and phosphate from the GI tract. Because calcitriol is a PTH suppressant, reduced absorption of calcitriol results in compensatory hyperparathyroidism. PTH levels will also
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rise independently in response to lower GI absorption of calcium from the gut. Patients with secondary hyperparathyroidism tend to have serum calcium levels that are either normal or marginally reduced despite an elevation intact parathyroid hormone levels (iPTH). Bone and joint pains may develop and slowly progress until the patient is bedridden. Clinically, patients may complain of pain that is usually vague and located in the lower back, hips, knees, and legs. Severe lower back pain occurs as a result of a collapsed vertebral body, and a spontaneous rib fracture can cause sharp chest pain. Joint pain may also occur as a result of periarticular deposition of hydroxyapatite crystals; this pain particularly occurs in marked hyperphosphatemia. Rarely, avascular necrosis of the femoral head may occur in association with renal osteodystrophy, causing pain and limping.

Patients with CKD should be have their serum levels of iPTH tested. If elevated due to secondary hyperparathyroidism, replacement vitamin D therapy is indicated. Patients receiving vitamin D supplementation should have serum calcium and phosphate concentrations performed every 1 to 2 weeks.¹⁹⁷

The optimal oral dosage of calcitriol ranges from 0.25 to 0.5 g daily. Calcium supplements are needed if patients are unable to consume the recommended daily amount of dietary calcium (600 mg per day). However, most physicians will prescribe calcium supplements because the efficacy of calcitriol in treating hypocalcemia is based on the assumption that patients consume adequate amounts of calcium. Initially, serum calcium levels should be monitored twice weekly during dose titration, then on a monthly basis. Calcium, phosphorus, alkaline phosphate, and creatine levels should be evaluated monthly for 6 months, then every 3 to 4 months while the patient is on calcitriol therapy.¹⁹⁸

Diabetic Nephropathy Fast Facts Summary

One should screen all patients with T2DM for microalbuminuria beginning at the time of their initial diagnosis. If negative for microalbuminuria, one should screen annually.
The clinician should screen all patients with T1DM for microalbuminuria 1 year after being diagnosed with diabetes. If negative for microalbuminuria, one should screen annually.
Screening for diabetic nephropathy should include a measurement of GFR as well as UAE. Thirty percent of patients with normal UAE have GFR levels suggestive of CKD.
UAE is used to screen nephropathy. GFR is used to stage nephropathy. A persistent reduction lasting 3 or more months in the GFR to less than 60 mL per minute per 1.73 m² is defined as CKD.¹⁴⁷
Patients with a GFR lower than 30 mL per minute per 1.73 m² should be referred to a nephrologist for a predialysis consultation.

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Patients with CKD are at high risk for CVD and should also be referred for a cardiovascular consultation.
Because diabetic nephropathy and retinopathy are coexisting conditions, one should make certain that patients with CKD undergo an annual comprehensive ophthalmologic evaluation.
CKD due to diabetes is best managed by aggressively improving glycemic control, lowering BP to target (<130/80 mm Hg) using either ACE inhibitor or ARB drug therapy, dietary intervention, reducing lipids to target, and using aspirin therapy and exogenous erythropoietin to maintain hemoglobin levels greater than 11 g.
Patients with CKD are at risk for developing secondary hyperparathyroidism. These patients should be screened with iPTH and serum calcium levels.
A proactive approach to managing patients with diabetic nephropathy should reduce cardiovascular mortality and preserve renal function.
The comprehensive approach to managing diabetic nephropathy is summarized in Table 11-19.

Agents in Development for the Treatment of Diabetic Nephropathy

Whereas current treatments directed at managing diabetic nephropathy focus on improving glycemic control and slowing the progression of CKD, newer compounds target preventing tissue damage resulting from prolonged exposure to hyperglycemia.

AGEs product formation can be prevented by compounds such as ALT-946, LR-90, and OPB-9195 in animal models.¹⁹⁹ AGE formation on glomeruli of diabetic rats and nephropathy are reduced using these drug. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking. The AGE inhibitors appear to block AGE formation and break AGE cross-links in glomerular tissue.¹⁹⁹ Several clinical trials using these or similar compounds are either in development or in progress.

A contributor to the pathogenesis of diabetic nephropathy is the polyol pathway, which is activated in the presence of hyperglycemia. Aldose reductase and sorbitol dehydrogenase are potential pharmacologic target enzymes within this pathway. Table 11-20 lists the drugs that are currently being studied to stabilize polyol pathway activation.

Glycosaminoglycans are thought to be important to glomerular basement membrane permeability. These compounds appear to prevent diabetic nephropathy in experimental animal models by normalizing the glomerular basement membrane and surrounding mesangial matrix.¹⁹⁹

Ruboxistaurin is an inhibitor of PKC-beta. In the presence of hyperglycemia, PKC-beta is upregulated and activated in the kidney leading to cell growth, fibrosis, and tissue injury. In a 1-year, double-blind, placebo-controlled trial for 123 patients with T2DM having persistent albuminuria despite being

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treated with conventional ACE inhibitor or ARB therapies, ruboxistaurin had favorable effects on albuminuria and renal function.²⁰⁰ Patients treated with ruboxistaurin did not experience a significant decline in renal function (GFR) in contrast to patients treated with placebo.

TABLE 11-19 Strategies and Goals for Renal Protection in Patients with Diabetic Nephropathy

Intervention	Goal
Intervention	Microalbuminuria	Albuminuria
ACE/ARB^a,¹	Reduction of microalbuminuria or reversion to normoalbuminuria Stabilization of GFR Blood pressure <130/80 mm Hg	Proteinuria as low as possible or <0.5 g/24 h + GFR decline <2 mL/min/y Blood pressure 125/75 mm Hg with increased serum creatinine or proteinuria >1.0 g/24 h
Glycemic control²	A1C <7%	A1C <7%
Statins³	LDL-C 100 mg/dL^b	LDL-C 100 mg/dL^b
Aspirin¹	Thrombosis prevention	Thrombosis prevention
Smoking cessation¹	Prevention of atherosclerosis	Prevention of atherosclerosis
Erythropoietin⁴	Maintain Hgb 11 12 g/dL	Improve quality of life Slow progression of chronic kidney disease Reduce risk of heart disease (left ventricular hypertrophy and coronary artery disease) Reduce risk of mortality after initiating dialysis
Dietary interventions⁵	Reduce red meat and saturated fat consumption Raise consumption of polyunsaturated fat in diet	Reduces UAE by 46%
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; GFR, glomerular filtration rate; AIC, hemoglobin A_1C; LDL-C, low-density lipoprotein cholesterol; Hgb, hemoglobin; UAE, urine albumin excretion. ^aACE inhibitors or ARBs are the initial drugs of choice for the treatment of hypertension in patients with diabetes. However, multiple medications are often necessary to reach the targeted blood pressure goals. Achieving the goals is more important than which agents are used for blood pressure management. ^bLDL-C <70 mg/dL in the presence of cardiovascular disease. References: 1. American Diabetes Association. Standards of medical care in diabetes 2007. Diabetes Care. 2007;30 (Suppl 1):S21 S23. 2. Gross JL, de Azevedo MJ, Silveiro SP, Canani H, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164 176. 3. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005 2016. 4. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2144 2146. 5. Gross JL, Zelmanovitz T, Moulin CC, et al. Effect of a chicken-based diet on renal function and lipid profile in patients with type 2 diabetes: a randomized crossover trial. Diabetes Care. 2002;25:645 651.

TABLE 11-20 Drugs Currently Being Evaluated for Treatment of Diabetic Neuropathy

Neuropathic Abnormality	Compound	Aim of Treatment	Summary of Important Findings to Date
Elevation of sorbitol in the polyol pathway	Fidarestat (aldose reductase inhibitor)	Reduce sorbitol level in neurons	Improves NCV and subjective symptoms of DPNP¹
Elevation of sorbitol in the polyol pathway	Epalrestat (aldose reductase inhibitor)	Improve mild autonomic and sensory neuropathy	Marketed only in Japan? efficacy in early neuropathy²
Oxidative stress	Alpha-lipoic acid	Potent antioxidant reduces free oxygen radicals	Reduced lancinating, burning and prick ling pain as well as numbness³
Protein kinase C (PKC) activation	Ruboxistaurin	PKC inhibitor	Improves neuropathic symptoms in patients with T1DM and T2DM⁴
Nitric oxide reduction	C-peptide injections	C-peptide increases nitric oxide levels	Significant improvement in sural nerve conduction velocities in T1DM⁵,⁶
NCV, nerve conduction velocity; DPNP, diabetic peripheral neuropathic pain; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. References: 1. Hotta N, Toyata T, Matsuoka K, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor for diabetic peripheral neuropathy. A 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care. 2001;24:1776 1782. 2. Nakayama M, Nakamura J, Hamada Y, et al. Aldose reductase inhibition ameliorates papillary light reflex and F-wave latency in patients with mild diabetic neuropathy. Diabetes Care. 2001;24:1093 1098. 3. The SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. Diabetes Care. 2003;26:770 776. 4. Isner JM, Ropper A, Hirst K. VEGF gene transfer for diabetic neuropathy. Hum Gene Ther. 2001;12:1593 1594. 5. Litchy W, Dyck PJ, Tesfaye S, Zhang D, Bastyr E, The MBBQ Study Group. Diabetic peripheral neuropathy (DPN) assessed by neurological examination (NE) and composite scores (CS) is improved with LY333531 treatment. Diabetes. 2002;45(suppl 2):S197. 6. Ekberg K, Brismar T, Johansson B-L, et al. Amelioration of sensory nerve dysfunction by Cpeptide in patients with type 1 diabetes. Diabetes. 2003;52:536 541.

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Diabetic Retinopathy

Diabetic Retinopathy Fast Facts

Dilated eye exams from an eye specialist trained in recognizing DR are necessary to prevent loss of vision.
Until retinopathy becomes advanced, patients remain asymptomatic. Once pathologic changes occur within the retina, management changes from prevention of retinopathy to stabilization of the disease process, so that vision may be preserved.
Prolonged exposure to hyperglycemia incites a cascade of events in genetically susceptible patients, leading to microvascular complications such as diabetic retinopathy. Maintaining A1C levels below 7% can reduce the risk of onset and progression of DR by 35% to 75%.
Hypertension, hyperlipidemia, smoking, and genetic factors play roles in DR pathophysiology.
DR may accelerate during pregnancy. A baseline dilated comprehensive eye exam is necessary before conception.

Of the 19 million Americans who have diabetes, 4 million have DR.²⁰¹ In the United States, DR is the leading cause of blindness in adults ages 20 to 74.²⁰² Within 20 years of being diagnosed, nearly 100% of patients with T1DM and 80% of patients with T2DM have clinical signs of DR.²⁰³ DR is often present in patients initially diagnosed with T2DM.²⁰⁴

The American Academy of Ophthalmology has introduced a simplified rating scale to assess DR severity (Table 11-21). Mild refers to the presence of microaneurysms only. Moderate nonproliferative diabetic retinopathy (NPDR) is defined as the presence of microaneurysms and either hard exudates or blot hemorrhages, which are due to the deposition of lipoproteins and the exudation of red blood cells from the retinal microaneurysms. Severe NPDR is characterized by a large number of retinal hemorrhages or the presence of cotton-wool exudates (microinfarcts within the nerve fiber layer of the retina) and the development of intraretinal microvascular abnormalities (collateral vessels) in the resulting ischemic areas of the retina. The progression of DR through these stages may be associated with leakage of fluids into the macular area that results in thickening (macular edema) and the gradual loss of visual acuity. Proliferative diabetic retinopathy (PDR) is associated with the development of abnormal new retinal blood vessels that may bleed into the vitreous cavity and become fibrotic. The resulting traction on the macula leads to visual loss.

In the most destructive form of proliferative changes, diabetes may induce neovascularization beyond the posterior segment of the eye and into the anterior chamber angle. Here, the vessels block aqueous outflow and cause a dramatic rise in intraocular pressure. This devastating neovascular glaucoma may result in total loss of the eye.

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TABLE 11-21 International Clinical Diabetes Retinopathy Severity Scale

Proposed Disease Severity Level	Retinal Pathology	Retina Photo
No apparent retinopathy	No abnormalities
Mild NPDR	Microaneurysms only
Moderate NPDR	More than just microaneurysms but less than severe NPDR
Severe NPDR	Any of the following: >20 intraretinal hemorrhages in each of 4 quadrants Definite venous beading in 2 or more quadrants Prominent IRMA in 1 or more quadrants and no signs of proliferative retinopathy
Severe NPDR	One or both of the following: Neovascularization Vitreous or preretinal hemorrhage
NPDR, nonproliferative diabetic retinopathy; IRMA, intraretinal microvascular abnormality. Adapted from Gardner TW, Antonetti DA, Barber AJ, et al. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002;(suppl):S253 S262, with permission. Fundus photos courtesy of Jack Carlson, MD, Loma Linda, California.

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As with other microvascular complications of diabetes, the pathophysiology of DR appears to be multifactorial. Hyperglycemia results in increased adherence of white blood cells that traverse the tiny vascular channels of the retina. As the veins and arteries become obstructed, retinal blood flow is reduced, resulting in the abnormal vasculature appearance typically seen in patients with diabetes. Cotton-wool spots appear clinically when capillaries are completely occluded. As the leukocytes bind to the endothelium, inflammatory mediators are released that increase vascular permeability, producing hard exudates and edema.

As hyperglycemia damages more small vessels, hypoxemia develops within affected areas of the retina. In response to this ischemic state, the retinal endothelial cells release growth factors [vascular endothelial growth factor (VEGF)]. The proliferative stage of DR is then initiated as neovascularization attempts to restore blood flow to the ischemic areas of the retina. Unfortunately, these tiny, delicate, and fragile new vessels tend to leak and hemorrhage, resulting in sudden and profound vision loss. The fibrous tissue that accompanies neovascularization is difficult to treat, sprouting attachments between the internal surface of both the retina and the vitreous. Forces that result in traction to the fibrous tissue will result in hemorrhage with and without a retinal detachment.

Hyperglycemia has a direct effect on retinal cell death and subsequent retinal atrophy.²⁰⁵ Retinal glial cells lose their ability to maintain the blood-retinal barrier in a hyperglycemic environment, resulting in vascular leakage and proliferation.²⁰⁵

Genetic factors also play an important role in DR pathogenesis. Genes are expressed in the presence of chronic hyperglycemia, which can lead to

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severe DR. Familial clustering of severe retinopathy has been observed in clinical trials.²⁰⁶ Gene expression may occur independent of other risk factors for DR. Thus, genetic expression rather than the severity of hyperglycemia may be the most important risk factor for predicting likelihood of developing DR.

Prevention of Diabetic Retinopathy

Once retinal damage has occurred, restoration of vision is often difficult and stabilization becomes the primary interventional strategy. Panretinal photocoagulation, focal macular laser therapy, and vitrectomy are the main arsenals in the treatment of established DR. Each treatment modality carries risks, such as loss of night vision, cataract progression, glaucoma, loss of accommodation, and infection. No intervention is available for ischemic maculopathy. Therefore, modification of identifiable risk factors at the earliest stage of diabetes is indicated to prevent and delay the onset of retinopathy.

Modifiable risk factors associated with DR include hyperglycemia, hypertension, hyperlipidemia, anemia, obstructive sleep apnea, and smoking. The DCCT and the UKPDS demonstrated the important role of diabetes intensification in reducing retinopathy. In the DCCT, patients who had no retinopathy at baseline and were treated intensively had a 76% reduction in risk of developing DR.⁶ A subset of patients in the DCCT from both the intensively managed cohort and the conventional group had persistent A1C elevations of greater than 9% throughout the duration of the study. However, the conventional group had 2 times as many patients who developed DR as the intensively managed patients despite having similar A1C levels.⁴³ The lower rate of DR in intensively managed patients is due to the minimization of glycemic variation that occurs with multiple daily injections of insulin when compared with using only twice-daily insulin.⁴¹ T2DM patients in the UKPDS in the intensively managed cohort were able to reduce their A1C on average 1% when compared with conventionally managed patients. This 1% reduction in A1C was matched by a 25% reduction in microvascular complications (including fewer patients requiring photocoagulation for retinopathy).¹⁶¹ The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)²⁰⁷ showed that progression to such endpoints as DR was lowest in patients having A1C values 5.4% to 8.5% and highest in patients with A1Cs higher than 10.1%. More than 70% of these patients developed DR within 10 years.

As demonstrated by the EDIC study,¹⁰ early intervention and stabilization of blood glucose control results in a significant reduction in long-term risk of DR even if intensification deteriorates over time. Therefore, targeting A1C levels to as close to normal (4.9% to 5.1%) as safely possible appears to be appropriate to prevent progression to DR.

Normalization of BP also slows the progression of DR. In the UKPDS, the rate of progression of retinopathy was reduced by 34% and deterioration in

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visual acuity by 47% when the mean BP was lowered to 144/82 mm Hg.¹⁵⁹ The WESDR showed that progression to DR was highest in patients with baseline hypertension at the time of their initial diagnosis.²⁰⁷

Various trials have examined the possible benefits of ACE inhibitors on preventing and slowing the progression of DR in patients with and without hypertension. The EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes, for example, showed a 50% reduction in progression to retinopathy in those taking lisinopril.²⁰⁸

Like hypertension, hyperlipidemia may contribute to the progression of DR. Several studies have demonstrated the correlation between hyperlipidemia and the accumulation of retinal and macular hard exudates, which are associated with visual impairment.²⁰²^,²⁰⁹ Although these findings suggest that lipid lowering might reduce the rate of vision loss in patients with diabetes, prospective trials have not confirmed this hypothesis.

Anemia is also a risk factor for retinopathy,²¹⁰ and its treatment may help slow the progression of retinopathy.²¹¹

Two other risk factors that should not be overlooked in patients with diabetes are smoking and obstructive sleep apnea. Both are associated with worsening retinopathy and are amenable to treatment.²¹²

Patients with PDR have elevated levels of insulinlike growth factor 1 (IGF-1) in their serum and vitreous.²¹³ The IGF-1 induces retinal neovascularization through the hormonal activation of VEGF. Two studies (n = 585) evaluated the efficacy of monthly doses of a long-acting IGF-1 inhibitor (octreotide, sandostatin) on limiting the progression of pre existing DR, reducing the time to development of macular edema and the loss of visual acuity.²¹⁴ Although octreotide did not reduce the incidence of macular edema, the IGF-1 inhibitor did limit the clinically relevant progression of DR.²¹⁴

Screening Guidelines for Diabetic Retinopathy in Patients

DR must be detected and addressed early if the risk of visual loss is to be minimized. Current guidelines state that screening should begin in patients shortly after diagnosis of T2DM and 3 to 5 years after T1DM diagnosis; women with diabetes who are planning pregnancy should also have a comprehensive examination (Table 11-22). Researchers who retrospectively analyzed DCCT data, however, recommended starting annual eye examinations at diagnosis for T1DM and T2DM, noting that this might identify patients at greatest risk for rapid progression of retinopathy. After the initial examination, annual follow-up is essential, even if no retinopathy is found. If retinopathy is discovered, the frequency of visits should be adjusted according to the severity of findings and need for treatment. Some physicians prefer to delay eye referral until a newly diagnosed patient with T2DM is stabilized. Delaying referral for 3 to 6 months as diabetes is intensively managed often will improve visual acuity and retinal pathology. Patients with poor glycemic control may initially develop a reversible deterioration in their visual acuity once intensive

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management with insulin therapy is initiated. Frustration may mount as patients are informed that their eyes are free of disease yet they are unable to see clearly. Expensive glasses or contacts are prescribed, which will offer only temporary visual improvement as their A1C levels are lowered.

TABLE 11-22 Recommended Eye Examination Schedule for Patients with Diabetes

Diabetes Type	Recommended Initial Examination	Recommended Follow-up^a
T1DM	5 y after onset	Yearly
T2DM	At time of diagnosis	Yearly
Before pregnancy	Before conception or early in the first trimester	No DR to mild or moderate NPDR every 3 12 mo Severe NPDR or worse every 1 3 mo
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; DR, diabetic retinopathy; NPDR, nonproliferative diabetic retinopathy. ^aAbnormal findings may warrant more frequent follow-up. From Gardner TW, Antonetti DA, Barber AJ, et al. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002;(suppl):S253 S262 with permission.

Despite these well-established guidelines, the rate of annual retinal screening examinations for patients with diabetes is low ranging from 34% to 65%.²¹⁵ An ophthalmologist or optometrist fully trained in recognizing DR should provide these eye exams. Abnormal findings should result in either prompt treatment or timely referral for the management of DR. Any patient with persistent visual complaints should be referred more frequently.

Communication between the eye care team and the PCP is essential. Results of the eye examinations should be a part of the patient's permanent medical record. The PCP should provide the eye care specialist with the patient's current A1C and BP values.

Treatment of Diabetic Retinopathy

The use of aspirin and anticoagulant drugs is safe for patients with DR and does not increase the risk of vitreous hemorrhage. The Early Treatment of Diabetic Retinopathy Study (ETDRS)²¹⁶ found that the cumulative incidence of new vitreous hemorrhage was similar in patients taking either aspirin (650 mg per day) or placebo over a 4-year period.

Several new treatments are currently in advanced stages of clinical testing including PKC-beta inhibitors, inhibitors of VEGF, and intravitreal steroid injections. In a recently completed phase 3, double-blind, placebo-controlled clinical trial, ruboxistaurin (an aldose reductase inhibitor) was given to patients with moderately severe to very severe NPDR. Although ruboxistaurin

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32 mg reduced the risk of vision loss associated with DR, the drug did not prevent or delay the progression of the retinal disease.²¹⁷

Because none of the novel approaches has proven to have a significant effect on reducing progression of DR or the incidence of macular edema in patients with diabetes, glycemic control together with routine retinal examinations remains the cornerstone for preventing retinopathy.

Macrovascular Complications

Case 6

Mr. Harvey is a 62-year-old African American diagnosed with T2DM 14 years ago. He has a 45-pack-year smoking history and a sedentary lifestyle. His father died of an acute MI at age 60. The patient admits to feeling tired and stressed out from working 16-hour days as a mortgage broker. Maybe this is why my sexual performance has started to decline recently. At first, I thought all the prescription medications I was taking might be causing me to feel so bad, so I just stopped taking everything 4 months ago, just to see if I would feel any different. Well, if anything, I'm feeling even worse! Now I can't even go up a flight of stairs without having to stop to catch my breath. My wife claims I'm just getting old. Maybe I should be taking some vitamins or antioxidants. What do you think, Doctor?

Mr. Harvey's pertinent physical and laboratory findings include:

Body mass index (BMI) = 37 kg per m²
BP = 162/94 mm Hg without any orthostatic changes
Funduscopic exam shows mild NPDR (last comprehensive eye exam was 2 years ago)
Heart exam: Irregular rapid rhythm with a rate of 104 to 110 beats per minute
A1C = 8.7%
Blood urea nitrogen (BUN) = 36 mg per dL
Serum creatinine = 1.5 mg per dL
Total cholesterol = 242 mg per dL
HDL-C = 32 mg per dL
TGs = 275 mg per dL
LDL-C = 145 mg per dL
Non-HDL-C (calculated) = 210 mg per dL
Serum iron level: reduced; serum transferrin level: reduced; serum ferritin level increased: 32 ng per mL (suggestive of anemia of chronic disease)
High-sensitivity C-reactive protein (hs-CRP) = 2.2 mg per L
Hemoglobin: 9.2 g per dL, hematocrit: 28.6 %
Electrocardiogram (ECG) = atrial fibrillation, rapid ventricular response, and evidence of left ventricular strain
GFR = 28 mL per minute per 1.73 m² (CKD stage 4)
Stool for occult blood: negative

Clearly one can see from this case the important role a PCP must have in managing patients with diabetes. Although referrals to specialists are certainly warranted, a urologist will not feel comfortable managing the patient's smoking habits. The cardiologist will most likely focus on the atrial fibrillation and status of the coronary arteries rather than on the patient's long-term renal status. However, this patient may have cardiac autonomic dysfunction and be at risk for silent ischemia. His multiple traditional cardiac risk factors include obesity, smoking, hypertension, hyperlipidemia, diabetes, and a positive family history of coronary artery disease. The elevated hs-CRP places this patient at immediate high risk for an acute myocardial event.²¹⁸ The nephrologist, although concerned about the reduced GFR, can prescribe ARBs, ACE inhibitors, and beta-blockers just as easily as PCPs who realize that lowering BP, improving lipids, and targeting improved glycemic control will slow the progression of CKD in this patient. If the patient experiences a rapid deterioration in his renal function after initiating an ARB or an ACE inhibitor, rather than continuing the drugs, one must discontinue the medications and perform a workup for renal artery stenosis.¹⁷² Evaluating for evidence of peripheral sensory and DAN is critical for delaying or preventing morbidity and mortality in patients such as Mr. Harvey. The foundation for improved care of Mr. Harvey remains intensification of his glycemic control. In short, because diabetes is such a multifactorial metabolic disease state, the comprehensive management of patients with diabetes begins and should remain with the PCP.

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Relationship between Hyperglycemia and Cardiovascular Disease

Diabetes is considered a cardiovascular risk-equivalent disease. The likelihood of dying of a first MI is the same for a patient with diabetes as for a nondiabetic who has previously survived one MI.²¹⁹ Postinfarction mortality is significantly higher in the presence of hyperglycemia compared with infarcts occurring when blood glucose levels are physiologic.²²⁰ Seventy-five percent to 80% of diabetes-related mortality is attributable to the three major forms of macrovascular complications, which include CHD, stroke [cerebrovascular accident (CVA)], and peripheral vascular disease (PVD).²²¹ Table 11-23 shows the predictors of cardiovascular mortality in patients with diabetes and Table 11-24 demonstrates the features commonly associated with CHD and diabetes.

Roughly 85% of acute strokes are atherothrombotic, and the rest are hemorrhagic (10% primary intracerebral hemorrhage and 5% subarachnoid hemorrhage). The risk of atherothrombotic stroke is two to three times higher in patients with diabetes, but the rates of hemorrhagic stroke and transient

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ischemic attacks are similar to those of the nondiabetic population.²²² Patients with diabetes are more prone to irreversible rather than reversible ischemic brain damage, and small lacunar infarcts are common. Stroke patients with diabetes have a higher death rate and a poorer neurologic outcome with more severe disability. Maintaining good glycemic 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.

TABLE 11-23 Predictors of Cardiovascular Mortality in Patients with Type 1 and Type 2 Diabetes

Type 1 Diabetes	Type 2 Diabetes
Overt nephropathy Hypertension Age Smoking Microalbuminuria Autonomic cardiac neuropathy	Presence of coronary artery disease Overt proteinuria Hemoglobin A_1c Hypertension
Adapted from Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. ABC of arterial and venous disease: vascular complications of diabetes. BMJ. 2000;320:1062 1066, with permission.

TABLE 11-24 Features of Coronary Heart Disease in Diabetic Patients

Atherosclerosis	Acute Myocardial Infarction	Revascularization
Prevalence of fatal and nonfatal coronary heart disease events 2 20 times higher than for nondiabetics of similar age Protective effect of female sex is lost. Plaque rupture leading to unstable angina and myocardial infarction is more common. Higher incidence of diffuse, multivessel disease Superimposed thrombosis more likely	In-hospital and 6-month mortality double that in nondiabetics Complications (e.g., arrhythmias, heart failure, death) more common Reperfusion rates after thrombolysis are similar to those of nondiabetics, but reocclusion and reinfarction rates are higher. Mortality reduced by insulin glucose infusion immediately after myocardial infarction	5-y survival rates after coronary artery bypass graft or percutaneous coronary angioplasty lower than for nondiabetics 5-y survival better after coronary artery bypass graft than percutaneous coronary angioplasty because of higher restenosis rates
Adapted from Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. ABC of arterial and venous disease: vascular complications of diabetes. BMJ. 2000;320:1062 1066, with permission.

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Atheromatous disease in the legs, as in the heart, tends to affect more distal vessels (e.g., the tibial arteries), producing multiple, diffuse lesions that are more challenging to bypass or dilate by angioplasty than are more proximal vessels with focal lesions.

Vascular disease and endothelial dysfunction appear to be accelerated in diabetes due to the multiple metabolic anomalies associated with hyperglycemia. Damaged endothelial cells produce lower levels of nitric oxide, thereby inhibiting vasodilation. Vascular smooth-muscle proliferation in association with higher circulating levels of plasminogen activator inhibitor-1 (PAI-1) leads to a state of hypercoagulation, increased thrombosis, and progressive atherogenesis. Inflammation within the endovascular environment is accelerated in the presence of hypertension, dyslipidemia, cigarette smoking, and direct endothelial cell damage from cytokines such as TNF and C-reactive protein.

Glucose can react extracellularly in nonenzymatic reactions. One pathologic mechanism shared with microvascular complications involves the glycosylation of protein within arterial wall matrix in a process that induces cross-linking of collagen within the vessel wall, reducing compliance. Direct glycation of LDL-C prolongs the half-life of these atherogenic lipoproteins, further increasing cardiovascular risk. Activation of the PKC-beta pathway in association with the oxidative stress induced by glycemic variability increases risk of cardiomyopathy.²²³^,²²⁴ Glycemic variability and oxidative stress appear to be the cornerstone for both microvascular and macrovascular pathogenesis.⁴¹

Why are some tissues (such as neurons or endothelial cells) prone to develop complications, whereas others (digestive cells) appear to be immune to the effects of prolonged exposure to hyperglycemia? The answer may lie in a cell's ability to assimilate the amount of glucose required as an energy source, before pumping any excess glucose to the outside of the cell. Neurons, nephrons, retinal cells, and endothelial cells are inefficient interstitial transporters of glucose. As glucose levels rise above 180 mg per dL in these at risk cells, reactive oxygen species (ROS) form within their mitochondria electron transport chain, triggering a cascade of events leading to microvascular and macrovascular disease.⁴⁰ The downstream targets of ROS formation include increased activity of protein kinase C (PKC), activation of nuclear factor (NF)- B, collagen synthesis, and cell death.²²⁵ Exposure to blood glucose levels above 180 mg per dL for just 4 hours can cause the downstream effects of ROS to persist for up to 7 days, even if the blood glucose levels are quickly normalized.²²⁶ One can easily understand the biological link between the extremely high incidence of cardiovascular disease and hyperglycemia.

As with microvascular disease, improvement in glycemic control can significantly lower the risk of macrovascular complications. The UKPDS demonstrated that each 1% reduction in A1C was associated with a corresponding 14% reduction in the risk of MIs.⁹ There was no A1C threshold that targeted the optimal macrovascular risk reduction. Thus, lowering the A1C as close to normal as possible is certainly a desirable target.

Patients with T1DM who were intensively managed on average for 6.5 years in the DCCT then followed for 17 years once the study concluded had a significantly

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lower rate of cardiovascular events than those patients treated with conventional therapy.²²⁷ Intensive insulin management in T1DM patients reduced the risk of nonfatal MI, stroke, or death from CVD by 57% and the risk of any CVD event by 42% compared with conventionally treated DCCT patients. Associated with the prolonged improvement in the A1C, intensively managed patients had lower A1C levels as well as lower incidences of microalbuminuria and albuminuria, both of which are associated with CVD. Other studies have demonstrated that intensive therapy reduced the progression of atherosclerosis, measured by carotid intima-media thickness,²²⁸ as well as the prevalence of coronary artery calcification.²²⁹ The mechanisms responsible for the improvement in outcomes and for the prolonged effects on early intervention remain uncertain. Some investigators feel that metabolic memory results in long-term beneficial effects on macrovascular risk reduction in intensively managed patients with T1DM. Regardless of the protective mechanism associated with improved glycemic control, the risk reduction achieved by initiating intensive therapy in T1DM patients as soon as the diagnosis is made is compelling. Risk reduction achieved with other proven interventions such as lowering cholesterol and BP are far less than those attained by intensively managing patients with diabetes.

Risk reduction for macrovascular disease involves targeting treatment at each one of the metabolic abnormalities that coexist with hyperglycemia.¹²

Global Risk Assessment

The use of a mathematical model to predict the likelihood of developing long-term diabetes-associated complications would help the physician target specific treatment targets, which should lower the risk. In addition, global risk assessment models could be useful in educating patients regarding the importance of fine-tuning metabolic therapy or maintaining adherence to a prescribed treatment plan. Risk factor assessment may target two different populations. Patients who have already suffered a diabetes-related complication, such as a stroke or acute MI, should be evaluated to determine which interventions may be prescribed to prevent the occurrence of a secondary event. Primary prevention strategies are used to delay or avoid an initial event from occurring in high-risk patients, that is, an acute MI, stroke, lower extremity amputation, and so forth.

Although the precise definition of CHD varies according to which endpoints are evaluated during any given clinical trial, the major disease states include unstable angina, acute MI, revascularization, and coronary death.²³⁰ Patients who are at low risk for developing CHD meet the following clinical parameters²³¹:

Serum total cholesterol: 160 to 199 mg per dL
LDL-C: 100 to 129 mg per dL
HDL-C: 45 mg per dL or higher in men and 55 mg per dL or higher in women
BP: lower than 120 mm Hg systolic and lower than 80 mm Hg diastolic
Nonsmoker
No diabetes mellitus

Patients with T1DM and T2DM have a higher overall risk for CHD. T2DM patients are of particular concern because so commonly these individuals

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present with both advancing age and multiple other risk factors such as hypertension and hyperlipidemia. Therefore, identification of these high-risk patients should allow physicians to focus attention on treating as many individual risk factors to target while vigorously pursuing healthy lifestyle and behavioral interventions to reduce macrovascular disease.

The major and independent risk factors for CHD are cigarette smoking of any amount, elevated BP, elevated serum total cholesterol and LDL-C, low serum HDL-C, diabetes mellitus, and advancing age. Other factors are associated with increased risk for CHD (Table 11-25). Preventive efforts should target each major risk factor. Any major risk factor, if left untreated for many years, has the potential to produce CHD. Nonetheless, an assessment of total

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(global) risk based on the summation of all major risk factors can be clinically useful for three purposes: (a) identification of high-risk patients who deserve immediate attention and intervention, (b) motivation of patients to adhere to risk-reduction therapies, and (c) modification of intensity of risk-reduction efforts based on the total risk estimate.

TABLE 11-25 Risk Factors for Cardiovascular Disease

Major Risk Factors

Predisposing Risk Factors

Smoking
Hypertension
Elevated LDL-C, low HDL-C
Diabetes
Advancing age

Obesity^a
BMI categories

18.5 24.9 kg/m² Normal
25 29 kg/m² Overweight
>30.0 kg/m² Obesity

Abdominal obesity (defined as a waist circumference >40 inches in men and 35 inches in women)
Physical inactivity^a
Family history of premature coronary heart disease
Ethnic characteristics
Psychosocial factors^b
Elevated serum triglycerides
Small LDL-C particles
Elevated serum homocysteine^c
Elevated serum lipoprotein (a)
Prothrombotic factors (e.g., fibrinogen, PAI-1)
Inflammatory markers (e.g., CRP)

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; PAI-1, plasminogen activator inhibitor-1; CRP, C-reactive protein.
^aThese risk factors are defined as major risk factor by the American Heart Association.
^bHostility, depression, and social isolation have been shown to have predictive value (King KB. Psychologic and social aspects of cardiovascular disease. Ann Behav Med. 1997;19:264 270).
^cAlthough elevated homocysteine levels are associated with higher risk of coronary heart disease (CHD), reduction of homocysteine levels has not been proven to lower the risk of CHD. However, homocysteine levels may be lowered with folic acid as well as vitamins B₆ and B₁₂. Measuring homocystine levels should be performed only in high-risk individuals (Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999;99:178 182).
Adapted from Grundy SM, Pasternak R, Greenland P, Smith S, Fuster V. Assessment of cardiovascular risk by use of multiple risk-factor assessment equations. Circulation. 1999;100:1481 1492, with permission.

Traditionally, Framingham scores have been used to estimate cardiovascular risk. However, Framingham scores estimate risk for persons without clinical manifestations of CHD.²³² The Adult Treatment Panel III places patients with diabetes in a category of CHD risk equivalents in which risk equates to that of persons with established CHD.²³³ A more detailed evaluation of cardiac risk coupled with an aggressive attempt at risk modification or reduction should be a part of every diabetes workup.

Several risk engines are useful in assessing the likelihood of developing heart disease and strokes. The UKPDS Risk Engine (available for downloading at: http://www.dtu.ox.ac.uk/index.html?maindoc=/riskengine/download.html) provides risk estimates and 95% confidence intervals in patients with T2DM not known to have heart disease. A patient's risk for heart disease and stroke can be calculated for any given duration of T2DM based on current age, sex, ethnicity, smoking status, presence or absence of atrial fibrillation, and levels of A1C, systolic BP, total cholesterol, and HDL-C.

As risk factors are identified, patients should be informed about the importance of treating these risk factors as safely as possible to targeted goals. Patients may complain about the additional expenses they might incur as they attempt to modify risk factors related to hypertension, hyperlipidemia, and anemia. However, diabetes is a complicated metabolic disorder. Physicians and patients cannot focus on simply managing blood glucose levels. Successful proactive diabetes management within the primary care environment requires that patients be adequately screened for diabetes-related complications and appropriately treated to the designated target. Patients will soon come to the realization that using two oral agents, a basal insulin, three antihypertensive agents, two medications for reducing lipid levels, aspirin, and possibly folic acid supplements may be required each day to maintain a safe metabolic environment. Patients using insulin pumps or multiple daily injections may need to use three additional injections of pramlintide daily to improve glycemic control, while monitoring their glucose levels eight times daily. Pump patients who use the sensor augmented system may experience fewer wide glycemic excursions, thereby limiting the expression of free radicals.

One of the most detailed and patient-friendly global risk engines, Diabetes PHD (Personal Health Decisions), can be accessed as a link through the ADA Web site (https://www.diabetes.org/phd/profile/start.jsp). Diabetes PHD can be used to explore the effects of a wide variety of healthcare interventions (both behavioral and pharmacologic) on 30-year risk of developing a heart attack, stroke, kidney disease, lower extremity amputation, and DR. Information that needs to be uploaded into the site includes a detailed health history (MI, stroke, angina, bypass surgery, angioplasty, heart failure, retinopathy, albuminuria,

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CKD or ESRD, diabetic neuropathy, neuropathic ulcer), age, ethnicity, sex, height, weight, lipid levels, smoking history, BP reading, dates of last eye exam, frequency and intensity of exercise, frequency of office visits, A1C, foot exam, presence and level of proteinuria, list of medications, length of time patient has used aspirin, family history of diabetes and/or CVD, and a list of all current medications related to managing diabetes, hypertension, and hyperlipidemia. Diabetes PHD, as powered by a health modeling program known as Archimedes, then calculates the patient's risk of developing microvascular and macrovascular complications over the next 30 years (Fig. 11-13).

At first, high-risk patients may look at the graphic profiles with fear and trepidation as if consulting with a tarot card reader. The healthcare provider can then recalculate the data that was input to demonstrate for the patient the reduction in risk that could be expected if he or she stops smoking, loses

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weight, lowers the BP and lipid levels, and improves the glycemic control (A1Cs). The results lay the foundation for explaining the importance of targeting individual metabolic risk factors for treatment while demonstrating to the patient that managing diabetes requires more effort than simply controlling blood glucose levels.

Figure 11-13 Diabetes PHD (Personal Health Decisions) Risk Engine. By inputting information regarding a patient's lifestyle, medication use, laboratory results, and vital statistics, the Diabetes PHD risk engine can be used to predict risk of heart attack, stroke, chronic kidney disease, amputation, and diabetic neuropathy over a 30-year period. Health factors and lab data can also be reset to demonstrate to each patient the changes in risk analysis that will be anticipated with improvement or deterioration in the metabolic parameters. (Diabetes PHD available at: https://www.diabetes.org/phd/profile/start.jsp.)

Reducing Macrovascular Risk in Patients with Diabetes

Targeting Hypertension in Diabetes Patients

Hypertension Fast Facts

Patients with borderline hypertension (systolic BP of 130 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg) should be given lifestyle/behavioral therapy alone for a maximum of 3 months. If the BP treatment targets are not achieved, drugs that block the renin-angiotensin system should be incorporated into the treatment regimen
Patients with clinical hypertension (systolic BP 140 mm Hg or diastolic BP 90 mm Hg) should receive drug therapy in addition to lifestyle/behavioral therapy.
Initial drug therapy for hypertensive patients should be with a drug class that has been proven to reduce CVD events in patients with diabetes (ACE inhibitors, ARBs, beta-blockers, diuretics, CCBs).
All patients with diabetes and hypertension should be treated with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. If needed to achieve BP targets, a thiazide diuretic should be added.
If ACE inhibitors or ARBs are used, one should monitor renal function and serum potassium levels.
A rise in serum creatinine in patients using an ARB or ACE inhibitor could be suggestive of renal artery stenosis, which can occur in up to 70% of patients with T2DM.
Multiple drug therapy (two or more agents at proper doses) is generally required to successfully reduce the BP to target.
Although there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements:
- For patients with T1DM with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy.
- For patients with T2DM, hypertension, and microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria.
- For those with T2DM, hypertension, macroalbuminuria (>300 mg per day), and renal insufficiency, an ARB should be strongly considered.

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In elderly hypertensive patients, BP should be lowered gradually to avoid complications.
Patients not achieving target BP on three drugs, including a diuretic, and patients with a significant renal disease should be referred to a physician experienced in the care of patients with hypertension.

BP reduction in patients with diabetes improves long-term outcomes. The HOT study²³⁴ reported a 51% reduction in cardiac events in the diabetes subpopulation (n = 1,501) who were able to intensively reduce their diastolic BP to lower than 80 mm Hg. The UKPDS reported significant reductions in all diabetes-related endpoints, deaths, stroke, and microvascular complications when the BP in diabetic subjects was intensively lowered to 144/82 mm Hg versus 154/87 mm Hg.⁹

Hypertension must be treated vigorously in all patients with diabetes to limit and/or prevent the progression of both macrovascular and microvascular complications.²³⁵ The BP target for a patient without evidence of microalbuminuria is less than 130/80 mm Hg.²³⁶ Patients with isolated systolic hypertension (systolic BP > 180 mm Hg) should be treated to a target of 160 mm Hg initially and then to 140 mm Hg if the treatment is well tolerated.²³⁷ Patients with renal insufficiency should have their BP lowered to 125/75 mm Hg.¹⁸⁸

As a general rule, reductions in systolic or diastolic BP of 5% to 10% occur with most single antihypertensive agents. Therefore, more than one drug is often needed to treat patients with diabetes and hypertension to target. Often the addition of a small or moderate dose of a second drug offers better control with fewer side effects than using full doses of the first agent of choice. Table 11-26 lists the antihypertensive drug classes, commonly seen class complications, and their beneficial effects on diabetes risk reduction.

First-line Drugs for Hypertension

The first-line drug class for managing hypertension in patients with diabetes is ACE inhibitors. Calcium antagonists or low-dose thiazide diuretics can be added if the BP goal of less than 130/85 mm Hg is not achieved with ACE inhibitor monotherapy. Calcium antagonists and thiazide diuretics have been show to reduce cardiovascular events and progression of renal disease while being metabolically neutral in their effects on glucose control and lipid profiles.²³⁸^,²³⁹ The combination of ACE inhibitors with either a calcium antagonist or a thiazide diuretic can reduce proteinuria.²⁴⁰ Between 3% and 33% of patients using ACE inhibitors may develop a progressive dry hacking cough. This nonrelenting class side effect is more commonly observed in Asian patients.²⁴¹ Stopping the ACE inhibitor usually resolves the dry cough and irritated throat symptoms within 2 weeks.

Although ARBs are better tolerated than ACE inhibitors, the efficacy of ARBs in reducing macrovascular complications is still open to debate. ARBs

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can be used as a first-line antihypertensive agent in patients unable to tolerate ACE inhibitors. The Diabetics Exposed to Telmisartan And Enalapril (DETAIL) study²⁴² confirmed that the ACE inhibitor enalapril maleate (Vasotec) and the ARB telmisartan (Micardis) had equivalent renoprotective effects. The CALM study¹⁷ suggests combining ACE inhibitor plus ARB reduces both BP and urinary albumin levels better than if either agent were to be used as monotherapy.

TABLE 11-26 Antihypertensive Agent Useful in Patients with Diabetes

Drug Class	Possible Complications	Effects on Coronary Rates	Effects on Progression of Renal Disease	Effects on Stroke
Angiotensin-converting enzyme (ACE) inhibitors	Up to 33% develop cough (especially high incidence in Asian population)^a Proteinuria can occur in presence of renal artery stenosis	Beneficial	Beneficial	Beneficial
Angiotensin II receptor blocker (ARB)	Same renal-protective effects as ACE; macrovascular protective outcomes are less clear. Do not cause cough May cause hyperkalemia	Unknown	Beneficial	Unknown
Beta-blockers (noncardioselective)	Cardiac failure Impaired insulin release with hyperglycemia Blunts patient response to hypoglycemia, resulting in possible hypoglycemic unawareness Sexual dysfunction Fatigue Depression Cold hands Reduced exercise performance. May result in inability to raise heart rate in response to exercise. Patients will develop dyspnea on exertion Worsening of asthma Delayed recovery from hyperglycemia	Beneficial	Beneficial	Beneficial
Beta-blockers (cardioselective)	Hypoglycemic unawareness Hyperlipidemia Sexual dysfunction Cardioselectivity may be lost with high dosing	Beneficial	Beneficial	Beneficial
Alpha-blockers	Orthostatic hypotension Drug interaction with drugs commonly used by men for sexual dysfunction (PDE-5 inhibitors). May cause severe hypotension	Controversial	Unknown	Unknown
Calcium channel blockers (CCBs)	Ankle edema Constipation Hot flashes Heart block Possible negative inotropic effect dependent on agent used	Controversial	Controversial	Beneficial
Thiazide diuretics	Hypokalemia, hypochloremic metabolic acidosis Hyperglycemia Dyslipidemia Sexual dysfunction	Beneficial	Unknown	Beneficial
ACE, angiotensin-converting enzyme; PDE-5, phosphodiesterase-5. ^aWorld Health Organization. International Diabetes Federation. Diabetes Action Now: An Initiative of the World Health Organization and International Diabetes Federation. Geneva, Switzerland: World Health Organization; 2004. Adapted from American Diabetes Association. Clinical Practice Recommendations 2007. Diabetes Care. 2007;30(Suppl 1):S15 S16.

In the UKPDS, the ACE inhibitor captopril was equally efficacious as the beta-blocker atenolol in reducing microvascular and cardiovascular complications in patients with T2DM. Patients with renal artery stenosis may develop a decline in renal function when using ACE inhibitors or ARBs.¹²⁶

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ACE inhibitors have been shown be cardioprotective in addition to their beneficial effects on kidney function. The HOPE trial studied more than 3,500 subjects age older than 55 years with diabetes with a documented previous cardiovascular event. Patients were randomized to receive either ramipril 10 mg per day or placebo and vitamin E plus placebo. Within 4.5 years, the ramipril-treated group had a 22% reduction in MI, a 33% reduction in stroke, a 37% reduction in any cardiovascular event, and a 24% reduction in the development of overt nephropathy when compared with the placebo group.¹⁶³ These benefits occurred despite minor (<3 mm Hg) reduction in BP, suggesting the possibility that ACE inhibitors have benefits for patients independent of BP reduction. Patients using ACE inhibitors should be monitored for hyperkalemia every 3 to 6 months.²⁴³

Although beta-blockers reduce cardiovascular events and slow renal disease progression, their side effect profile is less advantageous than with ACE inhibitors or ARBs. Sexual dysfunction may discourage patient adherence. However, beta-blockers should be used as an alternative to ACE inhibitors in patients with diabetes and established CHD, those who have had an MI, and those who develop angioedema or hyperkalemia in response to ACE inhibitors.

Second-line Drugs for Hypertension

Although ACE inhibitors or ARBs are considered first-tier antihypertensive therapy in patients with diabetes, the choice of secondary agents requires treatment individualization. The National Kidney Foundation recommends adding either a thiazide diuretic or a long-acting CCB to the antihypertensive regimen if the BP target has not been achieved.²⁴⁴ Using long-acting CCBs (verapamil HCl or diltiazem HCl) can help reduce proteinuria, whereas dihydropyridine CCBs have no such effect²⁴⁵ (Table 11-27). In the recently completed International Verapamil Study (INVEST) of more than 22,000 people with CAD and hypertension, the non-DCCB verapamil demonstrated a similar reduction in cardiovascular mortality to a beta-blocker. Moreover, this relationship held true in the diabetic subgroup.²⁴⁶

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a large randomized trial of different initial BP pharmacologic therapies, found no large differences between initial therapy with a chlorthalidone, amlodipine, and lisinopril. Diuretics appeared slightly more effective than other agents, particularly for reducing heart failure.²⁴⁷

Prescribing Ambulatory Blood Pressure Monitoring for Patients with Diabetes

Home blood pressure monitoring (HBPM) should be considered as a means of assessing hypertensive treatment in patients with diabetes. Although the ADA

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makes no mention of HBPM in the published Standards of Medical Care for Patients With Diabetes Mellitus, ²³⁶^,²⁴⁸ many potential benefits may be gained from encouraging patients to monitor their own BP readings:

TABLE 11-27 Calcium Channel Antagonists

Calcium Channel Blocker Class	Dose (mg/d)	Doses per Day
Dihydropyridine calcium antagonists
Amlodipine (Norvasc)	2.5 20	1
Felodipine (Plendil)	2.5 20	1
Isradipine (DynaCirc, DynaCirc CR)	2 20	1 2
Nicardipine (Cardene SR)	60 90	2
Nifedipine (Adalat CC, Procardia XL)	30 120	1
Nisoldipine (Sular)	20 60	1
Nondihydropyridine calcium antagonists
Diltiazem (Cardizem CD, Cardizem SR, Dilacor, Tiazac)	120 360	1 2
Verapamil (Calan SR, Isoptin SR)	90 480	2
Verapamil (Covera HS, Verelan)	120 480	1

Adequate BP control across the drug-dosing interval during awake hours can be determined. If the BP tends to rise above the designated treatment target after supper, alterations in the drug dose or interval should be considered. Perhaps addition of another therapeutic agent may be necessary to allow targeted BP control throughout the day.
HBPM can evaluate the effectiveness of increasing or decreasing doses of antihypertensive drugs during titration.
Patients are able to check and record their BP when they become symptomatic, such as light headed, to document possible side effects such as orthostatic hypotension.
HBPM can increase compliance to pharmacologic and behavioral interventions. Because hypertension lacks signs and symptoms, checking BPs at home increases patients' awareness regarding the importance of participating in their own medical care and becoming an active member of the decision-making team.

When initiating HBPM, patients are instructed to

Use the automated BP monitoring devices whenever possible.
Understand their BP target goals and that their BPs will tend to fluctuate.

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Bring the BP meter in at each visit so that they can be tested against the standard office equipment.
Check and record the BP first thing in the morning while sitting on the bed and at night before retiring. To develop a good testing routine, the clinician should suggest monitoring on Monday, Wednesday, and Sunday weekly.
BP can be checked as scheduled or whenever the patient becomes symptomatic.

A sample HBPM form is shown in Figure 11-14.

Figure 11-14 Sample Home Blood Pressure Monitoring Form.

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Summary: Treating Hypertension to Target Can Reduce Long-term Diabetes-related Complications

In summary, there is strong epidemiologic evidence linking hypertension in diabetes with adverse macrovascular and microvascular outcomes. Long-term complications can be reduced by lowering the target BP in patients with diabetes to less than 130/80 mm Hg. Patients with diabetes and proteinuria should have their BP target lowered to less than 120/75 mm Hg as tolerated. Attaining these BP goals will often require combination therapy with ACE inhibitors selected as the anchoring drug. Patients with microalbuminuria or clinical nephropathy can initiate therapy for hypertension with either an ACE inhibitor or an ARB, because both classes have similar efficacy on BP control and slow the progression of kidney disease. Beta-blockers should be considered for patients at high risk for CHD as well as for patients who have had a prior MI.

Treatment decisions regarding hypertension management should be individualized based on the clinical characteristics of the patient, coexisting disease states, patients' personal preferences, and cost considerations.

Management of Dyslipidemia

Hyperlipidemia Fast Facts

Lifestyle modification focusing on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increased physical activity has been shown to improve the lipid profile in patients with diabetes.
In diabetic individuals without overt CHD:
- The primary goal is an LDL-C lower than 100 mg per dL.
- For those older than 40 years, statin therapy to achieve an LDL-C reduction of 30% to 40% regardless of baseline LDL levels is recommended.
- For those younger than 40 years but at increased risk due to other cardiovascular risk factors who do not achieve lipid goals with lifestyle modifications alone, the addition of pharmacologic therapy is appropriate.
In diabetic individuals with overt CHD:
- All patients should be treated with a statin to achieve an LDL-C reduction of 30% to 40%.
- A lower LDL-C goal of less than 70 mg per dL, using a high dose of a statin, is an option.
One should lower TGs to less than 150 mg per dL and raise HDL-C to greater than 40 mg per dL in men and greater than 50 mg per dL in women.
Lowering TGs and increasing HDL cholesterol with a fibrate is associated with a reduction in cardiovascular events in patients with clinical CHD, low HDL-C, and near-normal levels of LDL-C.
Combination therapy using statins and other lipid-lowering agents may be necessary to achieve lipid targets but has not been evaluated in outcomes studies for either CHD event reduction or safety.

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Statin therapy is contraindicated in pregnancy.
Glitazones appear to be the best agents for managing isolated low levels of HDL-C in patients with T2DM.

Lipid abnormalities that accelerate atherosclerosis and increase CHD risk are more common in patients with T2DM than in nondiabetic subjects. Combined with central obesity, dyslipidemia has become a major cause of morbidity and mortality in T2DM.

Ninety-seven percent of adults with diabetes have at least one lipid abnormality,²⁴⁹ with the primary characteristic being elevated TGs and low HDL-C levels. In patients with diabetes, the LDL-C is usually not significantly different from what is seen in nondiabetic patients. However, patients with T2DM typically have a smaller, denser LDL particle, which increases lipoprotein atherogenicity even if the absolute concentration of the LDL-C is not elevated.²⁵⁰

The best predictor of CHD in patients with T2DM, especially women, is the atherogenic dyslipidemia associated with high TGs and decreased HDL-C levels.²⁵¹^,²⁵²

Lipoprotein Production and Packaging

The principal components of foods that humans ingest are protein, fat, fatty acids, carbohydrates, and fiber. After passing through the stomach, nutrients are either absorbed from the intestines or excreted from the colon. Most dietary fat consists of TGs, which for an average-sized, active individual consuming 2,000 cal per day contains 30% fat or 66 g of TGs and 250 mg of cholesterol. The cholesterol and TGs are stored in the liver as a future energy source.

When fatty acids are ingested, they pass through the intestinal cells where they are packaged into chylomicrons. The chylomicrons consist of 86% TG fat, 9% phospholipids, 3% cholesterol, and 2% protein²⁵³ as they circulate within the plasma. The chylomicrons essentially act as pizza delivery men bringing nutrients to the adipose tissue and skeletal muscle cells. Once the chylomicrons enter the adipose tissue capillaries and muscle cells, they encounter lipoprotein lipase, an enzyme that hydrolyzes the TG fat, producing a chylomicron remnant. The chylomicron remnant is then delivered to the liver. Within the liver, the chylomicrons are repackaged as lipoprotein particles, differing in their size, density, and atherogenicity.

The small, dense LDL particles are atherogenic, whereas the large, buoyant LDLs are not. Embedded within the wall of the LDL particles are apolipoproteins (Apo A and Apo B). Several Apo B molecules are embedded within the walls of LDL particles, with a higher concentration of Apo B in small, dense LDL particles (Fig. 11-15). Apo A molecules are located within the walls of HDL particles.

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Figure 11-15 Two Patients with Similar Low-density Lipoprotein Cholesterol (LDL-C) Values but with Different Cardiovascular Risk. Patient A has large, buoyant LDL-C that contains lower levels of atherogenic Apo B. Patient B has a higher calculated non-HDL-C value than patient A. This imparts a 19% higher risk in men and 11% higher risk in women of having a fatal cardiac event due to the more atherogenic clinical profile associated with apolipoprotein B. Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol.

A strong correlation exists between cardiac risk, a high concentration of circulating small, dense LDL particles, and levels of Apo B.²⁵⁴ An inexpensive and efficient way to predict cardiac risk is to calculate the non-HDL-C value. The non-HDL-C contains all known and potential atherogenic lipid particles, has been shown to be a stronger predictor of cardiac death than LDL-C concentration, and correlates well with the patient's severity of obesity and visceral adiposity.²⁵⁵

The calculation of the non-HDL-C is made simply by subtracting the HDL-C level from the patient's total cholesterol. Thus, if the total cholesterol is 200 mg per dL and the HDL is 30 mg per dL, the non-HDL-C is 170 mg per dL. In general, the non-HDL-C should be less than 30 mg per dL higher than the patient's acceptable LDL-C level. All patients with diabetes should have a

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targeted LDL-C of less than 100 mg per dL. Therefore, a non-HDL-C of 124 mg per dL would indicate a lower risk of cardiovascular death when compared with a non-HDL-C of 198 mg per dL. A 30 mg per dL rise in non-HDL-C corresponds to a 19% increase risk of cardiovascular mortality in men and an 11% higher risk in women²⁵⁵ (Fig. 11-15). Lipid management in patients with diabetes should be determined based on the calculation of the non-HDL-C when the TG level exceeds 200 mg per dL.²⁵⁶ The target non-HDL-C level is less than 130 mg per dL in these individuals.²⁴⁸

Pharmacologic agents are necessary when lifestyle interventions fail to achieve the targeted lipid levels. However, some experts advocate the use of statins for all patients with T2DM and patients who have had T1DM for more than 10 years. These opinions are based on several large randomized placebo-controlled clinical trials that have demonstrated improved survival rates in patients taking statins regardless of their baseline LDL-C levels. The Heart Protection Study²⁵⁷ demonstrated that in individuals with diabetes older than 40 years with a total cholesterol >135 mg per dL, LDL reduction of ~30% from baseline with the statin simvastatin was associated with an approximately 25% reduction in the first-event rate for major coronary artery events independent of baseline LDL, pre-existing vascular disease, type or duration of diabetes, or adequacy of glycemic control. In the Heart Protection Study, approximately 600 patients with T1DM had a proportionately similar, but not statistically significant, reduction in risk compared with patients with T2DM. Similarly, in the CARDS study,¹⁵ patients with T2DM randomized to 10 mg atorvastatin daily had a significant reduction in cardiovascular events, including stroke.

Combination therapy, with a statin and a fibrate or statin and niacin, may be efficacious for patients needing treatment for all three lipid fractions, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis. The risk of rhabdomyolysis seems to be lower when statins are combined with fenofibrate than gemfibrozil. There is also a risk of a rise in plasma creatinine, particularly with fenofibrate.²⁵⁸

Statins are the drug class of choice when elevated LDL-C is the primary lipoprotein abnormality. These agents reduce cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methlyglutaryl coenzyme A (HMG-CoA) reductase, which controls the rate of cholesterol synthesis. Statins are useful as monotherapy or in combination therapy with bile acid sequestrants and ezetimibe (which reduces the absorption of cholesterol from the gut). Statins, on average, reduce LDL-C 30% from baseline. The drugs should be taken at bedtime because cholesterol synthesis occurs while sleeping.

Bile acid sequestrants-binders [colestipol (Colestid), cholestyramine (Questran)] must be taken 1 hour before or 4 hours after other oral medication so there is no interference with absorption. These drugs also cause constipation and can exacerbate gastroparesis. The bile acid binders can also worsen hypertriglyceridemia.

Nicotinic acid is very effective at improving HDL-C and TG levels. However, glucose intolerance may worsen in patients with T2DM. The most common

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side effect associated with the use of niacin, hot flashes, can be reduced by advising the patient to take the drug with the dose of aspirin at dinner.

Fibric acid derivatives (gemfibrozil, fenofibrate) may be combined with a statin in patients with mixed hyperlipidemia disorders. Three and 6 weeks after starting combination therapy, creatinine phosphokinase (CPK) and alanine aminotransferase (ALT) levels should be monitored and the lipid levels repeated at 6 weeks. Once a stable dose is maintained and the CPK and ALT are below three times the upper limit of normal, frequent monitoring becomes unnecessary.

When hypertriglyceridemia is the primary lipid abnormality (TG levels >200 mg per dL with or without low HDL levels), a fibric acid derivative is the drug of choice. Gemfibrozil reduces TG levels, usually with small decreases in HDL-C. Fenofibrate is a fenofibric acid derivative that may lower LDL-C in addition to reducing TG values and increasing HDL-C levels.

Isolated low HDL-C levels are very difficult to treat. Perhaps the best medications to increase HDL-C in T2DM are the glitazones, which raise HDL-C up to 20%.²⁵⁹ The PROactive study²⁶⁰ demonstrated that pioglitazone reduced the

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risk of nonfatal heart attacks, strokes, and deaths by an additional 16% in patients with T2DM who were already taking drugs such as statins, fibrates, ACE inhibitors, beta-blockers, and aspirin. Patients who used pioglitazone increased their HDL-C by 9% and reduced their TGs by 13% when compared with patients using placebo. Of interest is the fact that this study involved 5,238 high-risk patients in 19 European countries with a history of having had an acute MI, coronary bypass surgery, or stroke. Therefore, high-risk patients can gain additional protection from secondary MIs and stroke while on pioglitazone.

TABLE 11-28 Recommendations for Lipid Targets in Adult Patients with Diabetes^a

Parameter	Target	Comment
LDL-C	<100 mg/dL	A lower LDL cholesterol goal of <70 mg/dL is recommended for patients with overt CHD. For those older than 40 years, statin therapy to achieve an LDL reduction of 30% 40% regardless of baseline LDL levels is recommended. Patients < age 40 should use statins if lifestyle intervention does not result in targeted lipid levels.
Triglycerides	<150 mg/dL	Lowering triglycerides and increasing HDL cholesterol with a fibrate is associated with a reduction in cardiovascular events in patients with clinical CVD, low HDL, and near-normal levels of LDL.
HDL-C	>40 mg	For women, it has been suggested that the HDL goal be increased by 10 mg/dL.
LDL-C, low-density lipoprotein cholesterol; CHD, coronary heart disease; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol.
^aCurrent NCEP/ATP III guidelines suggest that in patients with triglycerides 200 mg/dL, the non-HDL cholesterol (total cholesterol minus HDL) be utilized. The goal is 130 mg/dL. (Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of The Third Report of The National Cholesterol Education Program [NCEP] Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III]. JAMA. 2001;285:2486 2497.) From American Diabetes Association. Standards of medical care in diabetes 2006. Diabetes Care. 2006;29:S4 42, with permission.

The ADA clinical practice recommendations for lipid management in adults appear in Table 11-28. Patients with dyslipidemias should have their treatment prioritized based on the protocols listed in Table 11-29.

TABLE 11-29 Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults

First priority: lower LDL-C

Lifestyle intervention
Preferred drug class: statins
Secondary drug classes: bile acid-binding resin (cholestyramine, colesevelam, colestipol), cholesterol absorption inhibitor (ezetimibe), fenofibrate, and niacin

Second priority: raise HDL-C

Lifestyle intervention
Nicotinic acid or fibrates (gemfibrozil, fenofibrate)

Third priority: lower triglycerides^a

Lifestyle intervention
Glycemic control
Fibric acid derivatives, niacin, high-dose statins (in patients with elevated LDL-C)

Treating patients with combined hyperlipidemia

First improve glycemic control and use a high-dose statin
Second choice: improved glycemic control plus statin plus fibric acid derivative^b
Third choice: Improved glycemic control plus statin plus nicotinic acid

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
^aPatients with triglyceride levels >400 mg/dL may require insulin in addition to monotherapy or combination therapy lipid-lowering agents.
^bbGemfibrozil causes a two- to sixfold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or the pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared with gemfibrozil/statin coadministration. (Reference: Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145 156.)

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Screening for Asymptomatic Coronary Heart Disease in Diabetes

The overall prevalence of CHD in patients with diabetes is as high as 55%, compared with 2% to 4% in the general population.²⁶¹ In addition, diabetes is now considered a CHD risk-equivalent disease, meaning that the incidence of a primary MI event over 7 years in asymptomatic patients with T2DM was found to be equivalent to a group of nondiabetic patients who had already experienced an MI.²¹⁹ Many patients with diabetes may be victims of silent ischemia in which they develop objective evidence of myocardial injury in the absence of chest discomfort or other anginal equivalents such as exertional dyspnea. The mortality rate associated with silent ischemia is 50% compared with only 35% of patients who experience chest pain associated with a myocardial infarction.²⁶² The perception of chest discomfort should prompt patients to seek emergent medical care for their condition, which would improve the likelihood of their survival. Patients with silent ischemia are more likely to present to their physician with atypical symptoms, some of which may be chronic in nature, as those shown in Table 11-30. Objective measures of myocardial injury include ECG abnormalities, myocardial perfusion defects, or reversible wall-motion abnormalities. Silent ischemia can be identified by graded exercise stress testing, myocardial perfusion imaging, and echocardiography. The different techniques have all reported various percentages of asymptomatic diabetic patients who have evidence of silent ischemia. For example, single-photon emission computed tomography (SPECT) studies report abnormalities of myocardial perfusion in up to 30% of asymptomatic patients with diabetes.²⁶³

The best means to screen for and diagnose silent ischemia in patients with diabetes remains controversial. Exercise stress testing does not often detect single vessel disease and may not be a sensitive indicator of myocardial disease

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if the patient is unable to reach 85% of the maximum predicted heart rate. Obese patients who have neuropathy, PVD, and limited exercise tolerance can rarely achieve the targeted heart rate. Stress echocardiography can detect regional wall-motion abnormalities during exercise-induced ischemia. However, patients with limited exercise tolerance as well as technical imaging issues related to obesity may limit the utility of this procedure to screen for silent ischemia.

TABLE 11-30 Clinical Manifestations of Silent Ischemia

Fatigue
Hemoptysis
Edema
Cough
Arrhythmia
Shortness of breath
Nausea
Diaphoresis
Confusion

Measuring coronary artery calcification by electron beam computed tomography (EBCT) has been proposed as a method to screen for silent ischemia. However, the degree of atherosclerosis measured by coronary artery calcium may not necessarily correlate with the actual coronary stenosis or severity of silent ischemia.²⁶³

SPECT imaging has become the preferred method for assessing myocardial ischemia in patients with diabetes. SPECT imaging has an 86% sensitivity in patients with greater than 50% stenosis and a 90% sensitivity when the stenosis exceeds 70%.²⁶⁴

Pharmacologic stress imaging using adenosine, dipyridamole (a coronary vasodilator), or dobutamine (which increases myocardial oxygen demand) can substitute for exercise stress testing as a means to detect CHD in patients with diabetes.

The ADA recommends screening for cardiac disease in asymptomatic patients when two or more of the following risk factors are present²⁴⁸:

Total cholesterol 240 mg per dL or higher, LDL-C 160 mg per dL or higher, or HDL-C 35 mg per dL or lower
BP higher than 140/90 mm Hg
Smoking
Family history of premature CHD
Presence of microalbuminuria or macroalbuminuria

In the DIAD study, SPECT imaging was performed on 522 asymptomatic patients with T2DM to assess the prevalence and clinical predictors of silent myocardial ischemia as well as to assess the adequacy of the ADA screening guidelines for asymptomatic patients.²⁶⁴ The DIAD study demonstrated that using the ADA guidelines as a screening tool for identifying high-risk patients for CHD failed to identify many disease-laden patients. In fact, just as many low-risk patients had evidence of CHD as high-risk patients. Those patients with cardiac autonomic neuropathy appeared to be at highest risk for silent ischemia. Evidence-based guidelines for surveillance of asymptomatic CHD in patients with T2DM have not been published.

Current evidence suggests that noninvasive tests can improve assessment of future CHD risk. There is, however, no current evidence that such testing in asymptomatic patients with risk factors improves outcomes or leads to better utilization of treatments.²⁶⁵ The ADA recommends that high-risk patients should be evaluated by a cardiologist to determine the most effective way to screen patients for silent ischemia and to assist in the modification of all significant risk factors.

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Summary

The microvascular and macrovascular complications of diabetes can result in a reduction in lifespan and create disabilities affecting every aspect of a patient's daily living. From simply walking to the store to reading the newspaper, to having an intimate relationship with one's spouse, or eating a meal at a granddaughter's birthday party, the effect of long-term hyperglycemia can be life altering. Many of the macrovascular complications of diabetes are silent. Patients are unable to feel the devastation caused by hypertension or hyperlipidemia. Because silent myocardial ischemia is painless and free of symptoms, patients are often shocked to learn that a resting ECG shows evidence of an old MI. The general symptom of progressive fatigue might be interpreted as simply getting older by some patients and physicians rather than as a direct result of the anemia of CKD or the reduced cardiac output from CHF.

Although diabetes can cause devastating complications, physicians now know that they can prevent or slow the progression of microvascular and macrovascular disease. By intensively managing newly diagnosed patients with diabetes for at least 6.5 years as shown in the EDIC study,¹⁰ long-term outcomes for microvascular and macrovascular complications are improved even if glycemic control worsens. Physicians must insist that patients achieve the lowest and safest possible A1C levels possible while assuring them that their efforts at treatment intensification will pay off in the future. Coaching patients to physiologically manage their diabetes is time intensive. However, the standards of care for diabetes management have been well publicized. Many patients and their family members are familiar with the meaning of treating to target. Those patients who may not be as well informed come to their PCP for the best possible care for their chronic disease states. Physicians must not let their patients or patients' families down by providing anything less than a comprehensive, personalized, and modernized approach to diabetes care.

Table 11-31 summarizes the impact of microvascular and macrovascular diabetes-related complications.

As a PCP, one should concentrate efforts on identifying patients at risk for complications while providing timely and appropriate screening for metabolic abnormalities that may fuel these complications. Once early complications are identified, interventions can be used to delay the progression of end-stage disease. One must also remember that managing patients with diabetes requires much more than just adjusting insulin or oral agents. Physicians must treat patients to their appropriate BP and lipid targets and make certain that they use aspirin. Behavioral and lifestyle interventions must be continually enforced.

Finally, when seeing diabetes patients, clinicians should remember that the patients are doing their best to manage this very complicated disease. By checking their blood glucose level four to eight times daily; interpreting their blood glucose results; determining their preprandial dose of insulin based

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on their meal carbohydrate content and postmeal activity level; and taking a statin, two or three antihypertensive drugs, aspirin, and folic acid, these patients should be given a great deal of credit. Patients' nonadherence may simply result from a lack of understanding on how to self-manage their own disease state.

Very rarely do patients die of diabetes; they die as a result of prolonged exposure to hyperglycemia. Therefore, the focus should be on screening all patients for diabetes-related complications. Once the complication is diagnosed,

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interventions should be prescribed that will either reverse or delay the progression of these destructive and often silent pathologic disease states.

TABLE 11-31 Summary of Diabetes-related Complications

Cardiovascular

Heart disease and stroke account for 65% of deaths in people with diabetes.
Adults with diabetes have heart disease death rates 2 to 4 times greater than those without diabetes.
Diabetes is a cardiac risk equivalent. Likelihood of mortality from initial heart attack is identical to that in an adult without diabetes who survived a primary MI but died as a result of the secondary event.
The risk of stroke is 2 to 4 times higher and the risk of death from stroke is 2 to 8 times higher among people with diabetes.
The severity of the stroke is directly related to the degree of hyperglycemia at the time of the event.
Death from cardiovascular disease in women has increased 23% over the past 30 y compared with a 27% decrease in women without diabetes.
Deaths from heart disease in men with diabetes have decreased only 13% versus a 36% decrease in men without diabetes.
Lower extremity peripheral arterial disease is twice as high among individuals with diagnosed diabetes. These conditions disproportionately affect the elderly, non-Hispanic blacks, and Mexican Americans.

Neuropathy

Present in 60% to 70% of patients.
30% of people with diabetes >40 y are insensate in their feet.
Neuropathy is the leading cause of nontraumatic lower extremity amputation in the United States.
In 2002, 82,000 nontraumatic lower-limb amputations were performed in people with diabetes, costing >$37,000 per patient.
Autonomic neuropathy can cause sexual dysfunction (in both men and women), loss of bladder control, diarrhea, bloating, syncope, loss of temperature control, dehydration, and silent MI.

Retinopathy

Diabetes is the leading cause of blindness in the United States.
12,000 to 24,000 new cases of blindness each year are due to diabetes in adults ages 20 to 74.
Hispanics are at particularly high risk for vision loss.

Nephropathy

Diabetes accounts for 44% of new cases of ESRD in the United States.
In 2002, 44,000 patients with diabetes began dialysis or sought kidney transplantation as a result of ESRD.
In 2002, 154,000 patients with diabetes were being dialyzed.
Dialysis costs exceed $57,200 per patient per year.
High-risk patients for ESRD include African Americans (>5 times the risk for whites), Native Americans (>6 times), and Hispanic Americans (>4 times).

Complications of Pregnancy

Poorly controlled diabetes prior to conception and during the first trimester results in birth defects (macrosomia, cardiac anomalies) in 5% to 10% of fetuses and is responsible for spontaneous abortions in 20% of pregnancies.
Patients with gestational diabetes are at higher risk of developing type 2 diabetes in the future.
Babies born to mothers with gestational diabetes weighing <2.5 kg or >4 kg are at higher risk of developing type 2 diabetes as adolescents.
Patients with preexisting retinopathy or neuropathy may experience a significant deterioration from baseline with their pregnancy.

Periodontal Disease

Twice as likely to occur in adults with diabetes.
May be severe in diabetes, resulting in loss of the attachment of teeth to the gums.

MI, myocardial infarction; ESRD, end-stage renal disease.
From American Diabetes Association. Complications of Diabetes Web site. http://www.diabetes.org/diabetes-statistics/complications.jsp. Accessed December 10, 2005; and Gregg EW, Sorlie P, Paulose-Ram R, et al. Prevalence of lower extremity disease in the U.S. adult population >40 years of age with and without diabetes. 1999 2000 National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:1591 1597.

Intensification may be met with resistance at both the patient and professional levels. Physicians might think that allowing a patient to try lifestyle intervention for a little while longer to reduce the baseline A1C of 8.5% to normal might encourage a patient to better understand the diabetes disease state. Unfortunately, while waiting for patients to come to

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terms with their diabetes, their aldose reductase and PKC-beta pathways are firing up. AGEs are forming, increasing oxidative stress in sensitive tissues. Irreversible complications are beginning to take hold. The opportunities to intervene, reverse, or delay these pathologic events are vanishing along with the patient's normal endothelial cell and beta-cell functioning. As sorbitol levels increase within the retina and peripheral neurons, the previously asymptomatic patient is noted to have mild DR. Complaints of night-time paresthesias and difficulty with balance may follow. The atherosclerosis developing within the renal arteries results in elevated production of renin, which ultimately will raise BP. Angiotensin II release by the kidneys results in hypertension. Endothelial cell damage is accelerated in the presence of atherogenic dyslipidemia, cigarette smoking, elevated levels of C-reactive protein, and vascular inflammation. As higher levels of large, buoyant LDL-C lipoproteins laden with Apo-B subunits take hold within injured blood vessel walls and become oxidized, plaque formation is accelerated. At this time, patients are told by their doctors that their diabetes is out of control and that they must get a grip on their lives and on their diets. The terrified patient promises the doctor that he or she will get it right this time. Leaving the house for the first jog in 15 years, the patient suffers a fatal MI.

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