Prevention of diabetes complications

clinical CORNERSTONE

aa DIABETES

m Vol. I No.3

Prevention of Diabetes Complications John A. Colwell,

MD,

PhD

Professor of Medicine Diabetes Center Medical University of South Carolina Charleston. South Carolina

Basic and cl;nical research findings have led to an increased understanding about diabetes and its complications. Therapeutic approaches are now based not only on predicted efects porn epidemiologic, correlative, or retrospective analyses, but oj?en on prospective intervention trials comparing a new form of therapy to the standard methods. M?hile this database may never be complete, partially due to the complexity and variability of the diabetic state, we now have excellent data that allow the development of aggressive new guidelines for care. Much of the materialpresented here reflects the views of the American Diabetes Association, as included in a recentpublication (1). These g&Mines are under review by a number of other organizations and will be subject to mod>cation for special situations. Thus, the terminology ‘&ideLines, ” rather than “standards of care, ” is chosen to indicate the flexibility necessary in developing such recommendations for general usage.

are closely related to chronic hyperglycemia, and that near-normalization of blood glucose by careful medical management will prevent or forestall the development of these complications (2). The same appears to be true for diabetic neuropathy. Generally, the earlier the intensive glycemic management starts in the course of the disease and the longer this approach is successfully achieved, the better are long-term results. This more recent information on the importance of glycemic regulation to delay the chronic microvascular and neuropathic complications may now be added to the older information that glycemic regulation will lead to a cessation of the acute symptoms of decompensated diabetes: polyuria, polydipsia, and, in some cases, ketoacidosis or hyperosmolar syndrome. In all of these respects, a very strong argument for intensive glycemic control may be made for people with type 1 and type 2 diabetes. Patients with diabetes also have an increased risk for major macrovascular complications that lead to substantial morbidity and increased costs

Ll

PEOPLE

WITH

DIABETE

Objectives These guidelines will provide physicians and other health care professionals with the means to set treatment goals, identify areas where increased attention is needed, assess the quality of treatment provided and modify it as needed, and define the criteria for referrals to specialists. For people with diabetes, these guidelines will also provide a means to assess the quality of medical care they receive, develop realistic expectations for their role in medical management, and compare their treatment outcomes to those suggested by the guidelines.

General Principles People with diabetes may develop a group of chronic complications that are primarily caused by prolonged hyperglycemia. It is now generally accepted that the so-called “microvascular” complications of diabetes (retinopathy and nephropathy)

58

clinicalCORNERSTONE

Clinical

Evaluation

Annual

Initial

DIABETES

q

a Vol. I No.3

+ Quarterly

H+PE

J

J

HT+WT

J

J

BP

J

J

Eye examination

J

Foot examination

J

J

Hb *,c

J

J

Lipids/lipoproteins

J

(4

Microalbumin

J

(4

(4

(4

Laboratory

Serum creatinine ECG (adults)

J plan

J

J

Diabetic education

J

J

Eye specialist referral

J

Management

Care guidelines apply to items in parentheses only if abnormal values. H = history; PE = physical examination; WT = weight; BP = blood pressure; Hb Ate = glycated hemoglobin; ECG = electrocardiogram.

HT = height;

ultimate effect will be a decrease in the many complications of diabetes mellitus, an increase in quality of life for the patients, and an overall decrease in medical expenses for the long-term consequences of diabetes.

and are the leading cause of mortality. Thus, diabetic patients have a two- to fourfold risk of dying from cardiovascular disease. Further, they have an increased prevalence of hypertension, atherogenic lipid/lipoprotein levels, obesity, and a collection of prothrombotic factors that contribute to vascular thromboses. To complicate the issue, the presence of more than one of these vascular risk factors appears to increase future vascular risk in an exponential way, rather than in an additive way. This information, coupled with the availability of newer tests and proven therapeutic strategies, has led to the development of a series of guidelines that stress the measurement of selected risk markers that must lead to definitive action, as indicated by abnormal findings. With this approach, the health professional will be able to monitor patients regularly, at reasonable cost, and will be able to take appropriate medical action based on solid information. The

Guidelines for Care A general therapeutic goal for people with diabetes is to achieve a nearly normal weight, a good quality of life, an exercise program, and a management plan that is mutually acceptable to the patient and the health care team. Costs should be reasonable. The generally accepted specific guidelines for care are shown in Table I.

Goals for Therapy Care guidelines are defined to focus on examinations that might lead to preventive action to forestall complications. To succeed, the health professional must have specific goals of therapy that have

59

clinicalCORNERSTONE

s DIABETES

m Vol. I No.3

-

Goal

Action

Before meals

80-120 mg/dL

2140 mg/dL

Bedtime

loo-140

X60 mg/dL

Glucose

mg/dL

57%

28%

<130/85 mm Hg

>130/85 mm Hg

<30 mgl24 h

230 mgl24 h

Cholesterol

<200 mg/dL

2200 mg/dL

Triglycerides

5200 mg/dL

2250 mg/dL

LDL-C

4130” mg/dL

2130 mg/dL

HDL-c

>35 mg/dL (M)

135 mg/dL (M)

>45 mg/dL (F)

145 mg/dL (F)

Hb *,c BP Urine microalbumin Lipids

*Low-density lipoprotein cholesterol (LDL-C) goal is ~100 mg/dL in those with coronary heart disease, peripheral vascular disease, or stroke. Some authorities recommend a goal ~100 mg/dL for all people with diabetes. Hb AIc = glycated hemoglobin; BP = blood pressure; HDL-C = high-density liproprotein cholesterol; M = male; F = female.

seven areas to develop as realistic targets. Each of these areas plays a key role in influencing the severity, rate of development, and outcomes of the major complications of diabetes. Rather than deal with these areas in great depth, we have chosen to emphasize issues that are of clinical importance and may not be fully realized by many health care professionals. It has been necessary to be brief; however, our goal is to introduce some new concepts that might be useful in improving patient care for many people with diabetes.

been shown by controlled trials to produce optimal results. Goals of therapy for glycemic regulation, blood pressure (BP) control, management of urinary albumin excretion, and lipid therapy that fit these criteria are shown in Table II.

Approaches to Comprehensive Therapy for Diabetes and Its Complications By applying these guidelines and setting specific goals for therapy, definitive action may be taken to produce beneficial long-term effects in individuals with diabetes. Each of these approaches is supported by solid, large-scale, prospective, clinical trial data, and it is accepted that evidence of this nature gives the strongest support for long-term clinical management. A somewhat different perspective on these issues is given in Table III, where goals, actions, and effects are presented that will predictably improve quality of life and eventually reduce medical costs for people with diabetes.

GLYCEMIC REGULATION: HEMOGLOBIN A,, Glycemic regulation is the key to slowing progression of microvascular complications (1). In crosssectional and retrospective studies, it has long been clear that poor glycemic control (ie, high glycated hemoglobin Aic [Hb A,J levels) correlates with retinopathy, nephropathy, neuropathy, and (in some studies) with cardiovascular disease. The Diabetes Control and Complications Trial (DCCT) and other smaller prospective studies have clearly shown that

AJOR AREAS In the next section of this chapter, we have chosen

60

clinicalCORNERSTONE

____-

q

DIABETES

q

Actions

Long-term

Laser therapy

Prevent blindness

Blood pressure each visit Yearly lipid profile

Antihypertensives Lipid therapy

1 CVA incidence $ MIS, CV deaths

Kidney

Yearly microalbumin

ACE1

1 ESRD 1 Dialysis + transplants

Legs

Examine feet and check pulses every visit Sensory test: Neuropathy

Bypass Foot care

1 Amputations

Quarterly Hb Ate

Intensive glycemic management

1 Vascular + neuropathic complications

Organ

Short-term

Eyes

Yearly examination eye specialist

Heart, brain

Patient

Goals

by

CVA = cardiovascular accident; MIS = myocardial infarctions; ACE1 = angiotensin-converting end-stage renal disease; Hb Aic = glycated hemoglobin.

intensive glycemic management will slow progression of retinopathy, nephropathy, and neuropathy (2). When such therapy produces Hb Arc levels in the 7% to 8% range (4% to 6% is normal), the risk reduction is impressive. However, it should also be recognized that any reduction of Hb Ate to a lower level will reduce risk for microvascular disease progression. There is no threshold below which benefit is lacking. Since it can take time to determine and affect the level of Hb A,,, the health care professional can take action based on results of self-monitored blood glucose levels. When accurately done, these levels correlate well with Hb Ale levels (3).

Vol. I No.3

Effects

enzyme inhibitor;

ESRD =

The goal for Hb A,, is 7% or less, and action to lower Hb A,, should be taken if it is 2 8%, although further risk reduction of progression of retinopathy is achieved by lowering Hb Aic to the normal range of 4% to 6%. This is

Important Points o Hb Ale estimates the mean blood glucose over the previous 6 to 8 weeks; o Hb Ale should be measured quarterly in all diabetic patients. If frequent changes in therapy are under way, it may be measured every 6 to 8 weeks; o Hb Aic may be drawn in the fasting or nonfasting state; o Measuring Hb A,, is preferable to measuring total glycated hemoglobin, which estimates glucose attached to Hb A,,, b, and c. I-lb Aic has become the gold standard for most interventional trials, such as the DCCT, a Usual normal ranges are 4% to 6% for Hb A,, and 6% to 8% for total glycated hemoglobin;

often difficult to achieve without severe hypoglycemia; e Methodologies for measuring glycated hemoglobin in your laboratory and determining normal ranges may differ from standards (learn these differences!); e If Hb Ale and home glucose monitoring values do not agree, use the Hb A,, values; cb Some laboratories measure fructosamine, which estimates the concentration of glycated proteins in serum. These proteins have a shorter half-life than hemoglobin, and levels can be useful in

clinicalCORNERSTONE

0

o

o

e

m DIABETES

q

Vol. I No. 3

selected cases where short-term (1 to 2 weeks) evaluation of glycemic control is needed. One example is during pregnancy. However, levels may be abnormal in uremia and in states where altered serum proteins occur; An accurate, short, turnaround (lOminute) Hb Ale method by finger-stick is now available and can be measured in the office on the DCA 2000TM (Bayer Corporation, Elkhart, Ind.). Results correlate extremely well with the best laboratory methods, as long as rigorous quality control methods are followed; Severe hypoglycemia is the main limiting factor in type 1 diabetic patients as levels of Hb Ale approach the normal range (4% to 6%); While obese type 2 diabetic patients are less susceptible to severe hypoglycemia than are type 1 patients, they often have mild symptoms of hypoglycemia as levels of Hb Ate approach the normal range; Intensive glycemic regulation usually requires a team approach for type 1 diabetes and often requires multiple antidiabetic agents used concomitantly in type 2 diabetes.

strategy. This is the top priority in diabetes care. Further, there is evidence that the triglyceride level is an independent risk factor for CHD in diabetes. The Helsinki Trial showed a trend towards a reduction of cardiovascular deaths with long-term triglyceride lowering with gemfibrozil therapy in diabetes. Thus, goals for lipid therapy are aggressive in diabetes, and, fortunately, may be achieved with pharmacologic, dietary, and glycemic control therapy (1,4).

Important 0

0

0

0

0

0

0

0

LIPlDS/LIPOPROTEINS Coronary heart disease (CHD) is the major contributor to mortality in diabetes. Low-density lipoprotein cholesterol (LDL-C) and triglycerides are major contributors. Lipid profiles must be measured, at least on an annual basis, and more often if they are abnormal and therapy is instituted. It is now clear, in diabetic as well as nondiabetic individuals, that lowering of LDL-C and serum cholesterol is associated with a major reduction in risk of heart attack, even as a primary prevention

e

0

0

62

Points

Hyperlipidemia is unusual in type 1 diabetic patients who are well managed on insulin; In the presence of significant albuminuria from diabetic renal disease, lipids in type 1 diabetic patients may change to an atherogenic profile: elevated cholesterol, LDL-C, triglycerides, and low high-density lipoprotein cholesterol (HDL-C); At least 30% to 40% of people with type 2 diabetes have lipid levels indicating the need for therapy; The most common pattern in type 2 diabetes is elevated triglycerides and low HDL-C, with normal or slightly elevated cholesterol and LDL-C; This altered lipid profile responds suboptimally to intensive glycemic regulation, and supplementation with lipid-lowering agents may be needed; If hypertriglyceridemia is the problem, substituting monounsaturated fats for polyunsaturated fats in a low-saturated-fat diet may be helpful; Metformin and troglitazone provide modest action to lower plasma triglyceride levels; Because people with diabetes are at high risk for cardiovascular disease, LDL-C levels should be ~130 mg/dL and below 100 mg/dL, if possible. Triglyceride levels should be ~200 mg/dL; Compositional changes in lipoproteins may accelerate atherosclerosis in diabetes; these include glycation, oxidation, and small, dense LDL-C particles; These compositional changes may be present even though plasma lipid concentrations are normal; Interventional trial data indicate that aggressive LDL-C lowering with statins and normalization

clinicalCORNERSTONE

of triglycerides with gemfibrozil will prevent myocardial infarctions (MIS) and vascular deaths. In problem cases, combination therapy may be needed, with recognition of an increased risk for liver and/or muscle enzyme elevation; o Lipoproteins, especially triglycerides in the verylow-density lipoprotein fractions, are correlated with an increased tendency for thrombosis in diabetes. Two mechanisms are through increased plasma levels of plasminogen activator inhibitor (PAI-1) and potentiation of platelet aggregation and thromboxane release; o In postmenopausal women with elevated serum cholesterol levels, estrogen replacement may lower cholesterol and LDL-C and raise HDL-C levels. Estrogen therapy will also lower elevated PAI- levels in postmenopausal women.

normal levels as do nondiabetic individuals (5). The major issues at this point are: (a) At what BP level should antihypertensive therapy be started? and (b) What are the agents of choice for people with diabetes?

Important Points

l

DlABETES

.

Vol. I No.3

diabetes in type 1 patients; If a patient has hypertension, centripetal obesity, insulin resistance, hypertriglyceridemia, and low HDL-C (syndrome X), there is an increased risk for cardiovascular disease and type 2 diabetes. Aggressive cardiovascular risk-factor control is indicated; Angiotensin-converting enzyme inhibitor (ACEI) therapy is the first-choice antihypertensive agent in people with type 1 diabetes. Begin therapy when microalbuminuria and/or BP of 130/85 mm Hg is detected; In the kidney it is intraglomerular hypertension, not necessarily associated with systemic hypertension, that is specifically addressed by ACE1 therapy; In type 1 diabetes, hypertension may become fixed. This occurs at a relatively late stage and often is associated with progression of retinopathy and renal failure; In type 2 diabetes, hypertension is frequently of multifactorial origin. Such “type 2” issues as arteriolar nephrosclerosis and renal artery stenosis must be considered; Any agent (or combination) that returns BP to normal ranges is protective against future vascular events; In addition to ACEI, other first-line agents for people with diabetes are calcium channel blockers and a-receptor blockers. These agents are often effective either alone or in combination and have no significant effect on glucose or lipids; Other effective agents are low-dose thiazides (25 mg/d or less) and cardioselective P-blockers. These are often very useful in low doses as adjuncts to other antihypertensive agents. They do carry a small risk of increasing hyperlipidemia, and P-blockers can cause hypoglycemia unawareness; Endocrine causes of hypertension are rare but occasionally found in diabetic patients. Pheochromocytoma may produce glucose intolerance or exacerbate diabetes by a-receptor-mediated inhibition of insulin secretion. Aldosteronism may impair glucose tolerance by contributing to potassium depletion; Hyperglycemia will occur if intravenous diazoxide is used as an emergency agent. This

HYPERTENSION Hypertension is clearly a major contributor to renal failure, strokes, and retinopathy and also contributes to coronary artery disease, congestive heart failure, and peripheral vascular disease. Intervention trials are numerous, and it appears that people with diabetes respond to lowering of BP to

l

I

For people with diabetes, begin antihypertensive therapy when BP reaches 130/G mm Hg instead of 140/90 mm Hg; Hypertension often precedes diabetes in type 2 patients and, if present, almost always follows

63

clinicalCORNERSTONE

m DIABETES

w Vol. I No.3

-

. ..---.

-~...~.-

~~

levels (ie, 5.5 mg/L) from ACE1 therapy. Renal consultation may be needed if serum creatinine levels continue to rise in spite of ACE1 therapy and glycemic regulation.

agent is a potent inhibitor of insulin release. The effect is probably mediated via a-adrenergic receptors; o Diabetic patients with long-standing hypertension may develop autonomic neuropathy and postural hypotension. In this case, midodrine (ProAmatineTM), a recently approved a-receptor agonist, may avoid severe hypotension but must be used under careful monitoring.

Important

Points

Detection of microalbuminuria is critical; Usual dipstick methods for detecting protein miss microalbuminuria; Quantitate urine albumin yearly by a 24-hour specimen or by an albumin-creatinine ratio, preferably in first-voided urine. If this is not available, a random specimen may be used; Albumin values: mg/24 h (or mg/g creatinine) Microalbuminuria > 30 Macroalbuminuria > 300 Albuminuria is present in 30% to 40% of people with type 2 diabetes and may be present before diagnosis of the disease is made; Albuminuria is a predictor of cardiovascular events in type 1 and 2 patients, and predicts potential renal failure in type 1 patients; An atherogenic lipid/lipoprotein profile (elevated cholesterol, LDL-C, triglycerides, and low HDLC) typically accompanies albuminuria in diabetes (treat this!); If macroalbuminuria is present, follow serum creatinine levels (or creatinine clearance) at least yearly to monitor renal insufficiency; Intensive glycemic regulation in type 1 diabetes will delay or prevent the appearance of microalbuminuria and will delay progression of microalbuminuria to macroalbuminuria; Progression to renal failure in people with type 1 diabetes may be slowed down by ACE1 therapy, intensive glycemic regulation, and excellent BP control; The database on the two preceding points in type 2 diabetes is less conclusive, but most experts recommend intensive glycemic management, ACE1 therapy, and use of other antihypertensives, as indicated in type 1 patients; Maximum benefit is provided by aggressive treatment of hypertension, starting with ACE1 therapy in type 1 diabetes when BP reaches 2130/85 mm Hg;

Iiu A relatively new area of great importance is microalbuminuria. Many studies now have shown that the repeated excretion of small amounts of albumin (microalbuminuria) is a predictor of eventual renal failure in type 1 diabetic patients and of cardiovascular events in type 1 and 2 diabetic patients (6-9). Further, progression of microalbuminuria and renal failure may be prevented or slowed by ACE1 therapy in type 1 diabetes (6). Progression of microalbuminuria may also be slowed by intensive glycemic regulation in type 1 patients (2). BP regulation, by combined therapy if necessary, is critical. A practical point is that the routine urine laboratory

dipstick is not sensitive enough to pick up most cases of microalbuminuria (24-hour urine albumin range of 30 mg to 300 mg). There are now some sensitive dipsticks that will detect microalbuminuria, and these may receive wider use in the future for screening in a cost-effective way. If microalbuminuria is found (or macroalbuminuria > 300 mg/24 h), follow serum creatinine levels (or creatinine clearance) at least yearly to monitor progression of renal insufficiency. Serum potassium should be monitored regularly, since it may rise to high

64

.-___

clinicalCORNERSTONE

If persistent cough limits ACE1 therapy, an angiotensin receptor blocking agent may be substituted.

q Vol. I No.3 -__I_-

Patients will have some degree of retinopathy after 15 Years of postpubertal diabetes; The rate of progression of retinopathy is slowed by intensive glycemic control and by excellent Bp control. The earlier these measures are started in the course of diabetes, the more effective they are; People with type 2 diabetes also acquire retinopathy, and it proceeds as a function of the known duration of the disease. Because many people with type 2 diabetes are diagnosed late in the course of the disease, about 20% to 25% of patients may have retinopathy at the time of diagnosis. For this reason, all type 2 diabetic patients should be referred yearly to an eye specialist for examination upon diagnosis of the disease; Limited studies have shown that regular exarninations using a nonmydriatic camera will produce photographs that may be read locally and lead to improved access to eye care; Maculopathy consists of edema and/or lipid exudates, usually in the perimacular area; if extensive, this may limit central vision. Maculopathy may coexist with proliferative diabetic retinopathy. Controlled clinical studies have clearly defined indications for laser treatment of maculopathy to preserve vision; Because the lipid exudates seen in maculopathy have their origin in circulating blood and/or lipids, aggressive lipid-lowering strategies, including excellent glycemic control, are usually indicated.

HY E-I-I Diabetes is the leading cause of blindness among adults in the United States. Blindness and visual loss can be prevented by regular examinations for cataracts, maculopathy, retinopathy, and other lesions (10). Studies have shown that an examination by a physician with an ophthalmoscope through nondilated pupils will often miss important lesions. Such examinations, preferably through dilated pupils, should be done at least annually in the primary care physician’s office. Diabetic

patients (except type 1 patients in the first 5 years after diagnosis) should have yearly examinations, with pupillary dilation, by a recognized eye specialist. Controlled studies have clearly found that properly timed laser or other therapy will prevent progression of maculopathy and proliferative diabetic retinopathy and will preserve vision.

Important

Y DlABETES

a

Points

Lower extremity amputation is one of the most devastating complications of diabetes, causing disability in over 50,000 Americans every year. The American Diabetes Association (ADA) estimates that up to 85% of nontraumatic lower extremity amputations in the United States can be avoided every year. Keep the following ADA recommendations in mind when examining patients (11):

@ Retinopathy may be mild or undetectable prior to puberty and in the first 5 years of onset of type 1 diabetes. Therefore, yearly examinations may be delayed until after this period in these patients; g There may be extensive changes in the ocular fundus with minimal or no visual symptoms; e Decrease in visual acuity is often due to blood glucose fluctuations, especially with prolonged hyperglycemia. Refraction should be delayed until at least a few months of good diabetes control has been maintained; @ Retinopathy progresses with increasing duration of diabetes. In type 1 diabetes, close to 100% of

Inspect Feet e Examine the feet of all patients at each visit; e An annual comprehensive foot examination should include vascular and neurologic assessments.

65

clinical CORNERSTONE

II DIABETES

P Vol. I No.3

7. Use an emery board to shape toenails like the ends of your toes.

1. Wash your feet daily. 2. Dry your feet well, especially between the toes.

8. Change daily into soft, well-fitting 3. Lubricate

your skin daily with a moisturizing

socks or stockings.

lotion. 9. Wear shoes that fit well and are comfortable.

4. Inspect your feet daily to check for cuts, blisters, or calluses.

10. Examine your shoes daily for foreign bodies.

5. Use a line emery board to keep calluses at a minimum.

11. Never walk barefoot.

6. Trim toenails very carefully, with no skin trauma.

12. Consider visits to a podiatrist on a regular basis.

*You may wish to photocopy this table as a handout for patients.

Think Risk

Important Points One of the most common foreign bodies found in a foot with a nonhealing wound is an insulin needle. People with diabetes should be instructed not to bend or break off needles; Sensory testing with a monofilament is recommended; monofilaments may be obtained from the Center for Specialized Diabetic Foot Care, PO Box 373,405 Hayden St., Belzoni, MS 39038 or call l-800-543-9055; Patients should be enrolled in a smokingcessation program.

The “Big Four” for amputation are: 1. Neuropathy 2. Peripheral vascular disease 3. Anatomic deformity 4. Previous ulcer

ASPIFUN THERAPY People with diabetes are at an increased risk for vascular thromboses. For instance, MI is three to four times more common in people with diabetes than in age- and sex-matched control subjects. This risk is magnified by the addition of other vascular risk factors, including hypertension, hyperlipidemia, and cigarette smoking.

Think Skin Integrity e Lubricate dry skin to prevent cracking; o Treat web spaces with powder, lamb’s wool, or elasto-gel pads between the toes; 0 Ask a professional to trim toenails; e Keep calluses to a minimum to avoid pressure, fissures, or infection; o Avoid keratolytic foot creams.

Think Shoes and Socks B The best time to purchase shoes is late in the day when the feet are slightly swollen; e Since 1993, the Medicare therapeutic footwear provision pays 80% of “reasonable and allowable costs”; e A useful handout for patients is provided in Table IV.

Premenopausal diabetic women lose the cardiovascular risk protection afforded to premenopausal nondiabetic women. Most strokes are thrombotic in diabetic individuals.

66

clinicalCORNERSTONE

Important

Points (12)

s DIABETES

q

Vol. I No.3

@Albuminuria (micro or macro) @Lipids: Cholesterol >200 mg/dL LDL-C >130 mg/dL HDL-C ~40 mg/dL Triglycerides >250 mg/dL 4. The following are not candidates for aspirin therapy: o Type 1 diabetic patients and nonobese type 2 diabetic patients without any cardiovascular risk factors except diabetes; o People with aspirin allergy, bleeding tendency, anticoagulant therapy, recent GI bleeding, and clinically active hepatic disease.

o Meta-analyses of trials examining the use of aspirin after a heart attack or stroke have conclusively shown that aspirin therapy affords a risk reduction of about 25% as a secondary prevention strategy; o In one mixed primary and secondary prevention trial in diabetic individuals (The Early Treatment of Diabetic Retinopathy Study, or ETDRS), aspirin therapy was associated with a significantly decreased risk for heart attack in the first 5 years of the study; o In the US Physician’s Study, a primary prevention trial, aspirin use was associated with a significant risk reduction for MI in nondiabetic and diabetic physicians; o The ETDRS showed that aspirin therapy did not increase the risk of retinal or vitreous bleeding; 0 The risk of gastrointestinal (GI) or cerebral bleeding is lowered by using low-dose aspirin therapy; e Enteric-coated aspirin is associated with few upper GI side effects. Also, it produces a sustained, low blood aspirin level, which is needed to acetylate the cycle-oxygenase enzyme in the platelets. This inhibits thromboxane synthesis and platelet aggregation.

SUMMARY AND CONCLUSIONS Intensive glycemic regulation occupies the central stage in the care of people with diabetes. Hyperglycemia defines the disease, and careful correction will prevent or forestall microvascular and neuropathic complications. However, evidence has accumulated that there is a long period before the diagnosis of type 2 diabetes that is not usually marked by elevated blood glucose levels but during which vascular damage occurs. Thus vascular damage in diabetes must be viewed as being multifactorial, and guidelines for care that focus on glycemia to the exclusion of other factors are likely to be inadequate. In this chapter, we have emphasized this multifactorial etiology and have cited evidence that supports specific action steps to take. Since total glucose exposure (duration of elevated blood glucose level) is clearly a critical factor, it is important to stress glycemic regulation as early as elevated glucose levels are recognized, perhaps even at the stage of impaired fasting glucose, as recently defined by an international Expert Committee (14). The availability of newly approved drugs now allows a rapid change in management if therapy does not produce a normal glycated hemoglobin level. The health care professional and patient are now equipped to move rapidly and directly to attain the best possible glucose control in a short period. It must be recognized, however, that this approach will not provide complete vascular protection for many patients. In fact, one can develop a strong argument that factors other than

Recommendations (13) 1. Use enteric-coated aspirin in low doses of 81 to 325 mgld; 2. Use aspirin therapy as a secondary prevention strategy in diabetic individuals who have evidence of large-vessel disease. This includes diabetic patients with a history of MI, vascular bypass procedure, stroke or transient ischemic attack, peripheral vascular disease, claudication, and/or angina; 3. Use aspirin therapy as a primary prevention strategy in high-risk patients with type 1 or type 2 diabetes. This includes diabetic subjects with: o A family history of CHD 0 Cigarette smoking 0 Hypertension l Obesity (>120% desirable weight); body mass index (BMI) >28 kg/m2 in women, >27.3 kg/m2 in men

67

clinical CORNERSTONE

m DIABE IXS

B Vol. I No. 3

elevated plasma glucose are more critical for survival for people with diabetes. Thus, as noted, marked risk reductions in major macrovascular complications of diabetes have been achieved in prospective clinical trials with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for LDLC, with ACE1 in the case of renal failure in type 1 diabetes, with low-dose aspirin therapy to prevent vascular death and/or MI, with antihypertensive therapy to prevent strokes, and with laser therapy to prevent blindness. In all cases, these major studies have included people with diabetes who did not receive intensive glycemic control as part of the intervention trial design. Further, it may be predicted that modification of other vascular risk factors that are now under intensive investigation in diabetes will also successfully modify the course of the disease. For instance, elevated plasma homocysteine levels have been shown to magnify vascular risk, but these levels may be made normal by supplementation with folic acid, and vitamins B, and B,,. Additionally, the fibrinolytic system is altered in diabetes, primarily due to elevated plasma levels of an inhibitor of fibrinolysis-PAI-1. Levels of the factor are reduced by weight reduction, some drugs, and by estrogens in postmenopausal women. In addition, studies may well show that the use of antioxidants may modify the course of atherosclerosis in diabetes, and drugs that affect qualitative (ie, small, dense LDL-C particles) rather than quantitative changes in lipoproteins that promote atherosclerosis may be shown to be effective in preventing large-vessel complications.

professionals and the public are recognizing that a chronic disease like diabetes requires a multifactorial approach to risk markers and is best managed by a multiple-team-member approach in various aspects of preventive care. In addition, many centers and communities have developed strategic plans to address diabetes and its complications from a variety of directions, using a public- or community-oriented approach rather than the traditional physician-patient, one-to-one-relationship. 1. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 1998;21(suppl l):S23-S35. 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl JMed. 1993;329:977-986. 3. American Diabetes Association. Tests of glycemia in diabetes [position statement]. Diabetes Care. 1998;21(suppl l):S69-S71. 4. American Diabetes Association. Management of dyslipidemia in diabetes [position statement]. Diabetes Care. 1998;21(suppl l):S36-S39. 5. American Diabetes Association. Treatment of hypertension in diabetes [consensus statement]. Diabetes Care. 1998;21(suppl l):S4-S55. 6. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329: 1456-1462. 7. Gall MA, Borch-Johnson K, Hongaard P, et al. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;4:1303-1309. 8. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin dependent diabetes. Arch Intern Med. 1997;157:1413-1418. 9. American Diabetes Association. Diabetic nephropathy [position statement]. Diabetes Care. 1998; 2l(suppl l):S50-s53. 10. American Diabetes Association. Screening for diabetic retinopathy [position statement]. Diabetes Care. 1998;21(suppl l):S47-S49. 11. American Diabetes Association. Foot care in patients with diabetes [position statement]. Diabetes Care. 1997;2O(suppl l):S31-S32. 12. American Diabetes Association. Aspirin therapy in diabetes mellitus [technical review]. Diabetes Care. 1997;20:1767-1771. 13. Colwell JA. Aspirin therapy in diabetes mellitus [position statement]. Diabetes Care. 1998;21:S45-S46. 14. American Diabetes Association Report of the Expert Committee on the Diagnoses and Classification of Diabetes Mellitus [Committee Report]. Diabetes Care. 1998;21:55-519.

Implementation It is estimated that there are at least 16 million people with diabetes in the United States, about 30% of whom are not aware of having the disease. The majority of diabetic individuals are cared for by primary care physicians. However, lack of time and fiscal constraints often make implementation of guidelines difficult and burdensome for the health care provider. Nevertheless, it is becoming increasingly apparent that early preventive approaches will pay great dividends in the long run if proven techniques are followed. Health care

68

clinical CORNERSTONE

ADVISORY

BOARD

COLWELL The combination of hyperglycemia and hypertriglyceridemia is critical. An elevated plasma triglyceride level has been shown to be a risk factor for coronary artery disease that should be modified. In the nondiabetic, it is usually a patient with chylomicronemia or a type IV dyslipidemia. If you look at it in the diabetic population, there is very good correlative evidence that hypertriglyceridemia is an independent risk factor for CHD. The real issue is whether or not modification is going to prevent coronary events. The data are confounded by an association with low HDL and the thrombotic process. Particularly in diabetes, hypertriglyceridemia affects platelet function and fibrinolytic activity to promote thrombosis.

ADVISORY

= VOI. I ~0.3

BOARD

Do angiotensin II receptor blockers actually decrease glomerular hypertension? In the diabetic patient in whom an angiotensin II receptor blocker is substituted for an ACE inhibitor because of the development of a persistent cough, are there data to indicate they work just as well?

BOARD

Are the therapies directed at the sugar, triglycerides, or both?

COLWELL Obviously, the ACE inhibitor data are much stronger; there have been few prospective longterm trials with the receptor blockers. In shortterm studies, receptor blockers have lowered micro- and even macroalbuminuria, and they do seem to obviate the problem of cough, which a lot of patients have. So, ACE inhibitors are first-line therapy, with the receptor blockers as second-line; if there is a complication-particularly coughone would use the receptor blockers.

COLWELL Therapy is directed at glucose and triglycerides. Some of the newer fibrates, such as fenofibrate, lower triglycerides specifically within diabetic patients without much effect on glucose or LDL. Studies are now looking at whether this approach will modify angiographic events. ADVISORY

DIABETES

consumption. But some patients with diabetes are carbohydrate sensitive, and the more you push the carbohydrates, the higher their triglycerides go, particularly if they are secreting a fair amount of insulin. For the hypertriglyceridemic diabetic who is hyperinsulinemic, it may be best to reduce carbohydrates drastically. This, of course, could increase the percentage of protein and fat in the diet. But you can maintain a low-saturated fat diet with monounsaturated fats; the most ready source is olive oil. Using this approach, you can end up with higher total fat consumption, so it is important to work with a dietitian to keep the weight at least constant.

Please elaborate on the importance of managing hypertriglyceridemia in patients with insulin resistance.

ADVISORY

.

BOARD

Could you explain why it might be preferable to use monounsaturated fats to lower triglycerides?

ADVISORY

COLWELL When lowering triglycerides, the usual strategy is to liberalize carbohydrate intake and cut total fat

If a patient has a normal Hb Ale and is selfmanaging well, would you still say that 4 times a year follow-up is necessary with regard to the parameters in Table I?

69

BOARD

clinicalCORNERSTONE

.

DIABETES

I Vol. I No.3

COLWELL If the Hb A,, is under good control and the patient is doing home glucose monitoring, probably once or twice a year is fine. The same idea applies to visits to the ophthalmologist. Patients with stable retinopathy who are under good diabetic control do not necessarily have to be seen on a yearly basis, which also saves a lot of expense. ADVISORY

intracellular potassium in pancreatic beta cells, which resulted in impaired insulin secretion. Such depletion can be avoided via the use of lowdosage thiazide diuretic therapy and, if needed, potassium supplementation, ADVISORY

BOARD

You made the important point that the methodology for measuring glycated Hb varies depending on the laboratory. What kinds of differences should doctors be aware of?

COLWELL P-Blockers are thought to have the potential for impairing insulin secretion because, by blocking P-receptors in the pancreas, they can cause the a-receptors-inhibitors of insulin secretionto dominate. In addition, there is concern that P-blockers may increase the risk of hypoglycemia in diabetic patients by inhibiting glucose release from the liver, as well as by masking some of the symptoms of hypoglycemia. Balancing these potential risks are the potential benefits offered by P-blocker use in patients with coronary artery disease, particularly in preventing another MI in post-MI patients. My personal feeling is that the use of low-dose, cardioselective P-blockers is beneficial in diabetic patients; these agents seem free of any adverse effects on glucose tolerance, lipids, and the development or recognition of hypoglycemia.

COLWELL The main message is that total glycated Hbs tend to run about 2% higher regarding the range of normal. The range of normal is about 6% to 8% with glycated Hb versus 4% to 6% for Hb Arc. So if guidelines indicate that you need to take action with an A, glycated Hb > 8%, doctors should be aware that that really means Hb A,,, it does not mean total glycated Hb. ADVISORY

BOARD

A possible association between P-blocker use and impaired insulin secretion was also a concern when managing the hypertensive diabetic patient. Is this still true?

BOARD

In the management of hypertension in the diabetic patient, the use of thiazide diuretics was somewhat frowned upon in the past. Is this still the case and what were the reasons for the concern? COLWELL Provided the dosage of thiazide is low (ie, 12.5 to 25 mg/day of hydrochlorothiazide), most diabetologists tend to support its use in the treatment of hypertension, particularly as adjunctive or secondline therapy. At this low dosage, there does not appear to be a negative impact on blood lipids or glucose tolerance. Early studies suggested that diuretic use was associated with the depletion of

ADVISORY

BOARD

In Table II you discussed the target BP as being 430/85 mm Hg. If you’ve gotten a patient down to that level, would you try to go even lower? COLWELL I have a goal of getting the diastolic down to 30 mm Hg. I think that 85 mm Hg just represents a

70

clinicalCORNERSTONE

consensus view, but most people are being more aggressive, starting earlier, and aiming for 130&O or 120/80 mm Hg, if you can achieve that without hypotensive symptoms. ADVISORY

ADVISORY

n

DIABETES

a Vol. I No.3

BOARD

In the diabetic patient started on an ACE inhibitor for microalbuminuria, but who is normotensive, what therapeutic endpoint should you strive to achieve?

BOARD

You cited the statistic that microalbuminuria can be present in up to 30% to 40% of type 2 diabetics at the time of diagnosis. In light of this, do you believe that patients identified at high risk for the development of diabetes (ie, history of gestational diabetes, strong family history of diabetes, morbid obesity) should be screened for this abnormality? COLWELL It’s controversial, because this gets into issues of cost control. It is important to emphasize microalbuminuria testing because a regular dipstick is set too high-it picks up 2300 mg/24 hours. It will be above the microalbumin range (20 to 30 mg/24 hours). This is important, since microalbuminuria predicts eventual renal insufficiency and dialysis, particularly in type 1. In type 2 diabetes, microalbuminuria seems to be more a predictor of cardiovascular events and death than of renal failure. Essentially, microalbuminuria is a marker of glomerular capillary endothelial damage. If you get an endothelial leak, you will find micro amounts of albumin in the urine. To confirm the test as a true positive, one ought to do it at least 2 or 3 times (including a 24-hour algorithm) to rule out the possibility that it is not just due to infection, exercise, or some other variable. If it is confirmed, one would prescribe ACE inhibitor therapy right away, even in type 2 diabetes patients who may not even be hypertensive. The real problem is that urinary microalbumin isn’t being measured as often as it should be by primary care physicians.

COLWELL The suggested goal is a 250% drop in urinary albumin when you remeasure. It is fairly empirical, but a 50% drop is generally accepted as evidence of effective therapy. ADVISORY

BOARD

Assume that you’ve maxed out your ACE inhibitor in that same patient. Would you add a calcium blocker? COLWELL Probably not based on the urinary albumin. However, if the blood pressure isn’t controlled, I might add a calcium channel blocker. If the pressure is running 140/90 or even 130/85 mm Hg, my choice of a second drug would likely be a low-dose thiazide, merely to treat pressure as opposed to albumin. ADVISORY

BOARD

You discussed monofilaments for testing neuropathy in the feet. Does Specialized Diabetic Foot Care offer them for free, or is there a fee? COLWELL You can get one monofilament for free by calling the toll-free number, l-800-543-9055. After that, you pay a fee of $10 each. Pharmaceutical companies that now dispense monofilaments are Bayer, Who-McNeil, and Hoechst Marion Roussel.