Staged diabetes management a systematic approach - part 8 pot

STAGED MANAGEMENT OF HYPERLIPIDEMIA AND DYSLIPIDEMIA 309• Review lifestyle modifications at each visit • Consider referral to a dietician • If smoker recommend tobacco cessation counseli

308 MACROVASCULAR DISEASE

of diabetes.31 The diagnosis of dyslipidemia in

individuals with diabetes includes one or more of

Note – different conversion factors are used for

cholesterol and triglyceride.

According to NCEP, diabetes is considered a

CHD risk equivalent Thus, the lipid goals for

individuals with diabetes are the same as for

in-dividuals with documented CHD For example,

the goal of therapy for LDL cholesterol is to

achieve a level <100 mg/dL (2.6 mmol/L) NCEP

has recognized that very low levels of HDL

(<40 mg/dL [1.1 mmol/L]) increase the risk of

CHD Conversely, high levels of HDL

choles-terol (>60 mg/dL [1.7 mmol/L]) are considered

cardioprotective

Note As with hypertension, the targets for

peo-ple with metabolic syndrome and dyslipidemia

should be the same as for those with diabetes.

While the evidence for these targets is sparse, there

is reason to believe that NCEP recommendations

will be equally beneficial for people with metabolic

syndrome.

Clinical manifestations of

hyperlipidemia/dyslipidemia

Generally there are no signs of hyperlipidemia or

dyslipidemia that would be readily recognized by

the patient The one exception is lipid deposits in

the eye that may be associated with changes in

vision Changes in vision, however, are also

asso-ciated with hyperglycemia and hypertension and

therefore careful evaluation to determine the cause

must be carried out Therefore, it is important to

maintain a program of careful surveillance using

periodic fasting lipid profile determination,

espe-cially in those individuals at highest risk Once

again the combination of type 2 diabetes and/or

metabolic syndrome, and obesity with a familyhistory of hyperlipidemia, present the highest-riskgroup in which hyperlipidemia or dyslipidemiamay be identified

Determining the starting treatment for dyslipidemia

While the discovery of lipid abnormalities in ple with hyperglycemia is common, its presenta-tion may be different from that found in patientswithout diabetes The key differences are:

peo-• elevated triglyceride level

• low HDL cholesterol level

• small dense LDL cholesterolThese differences require that a fractionatedlipid profile (total cholesterol, HDL cholesterol,and triglyceride) should be carried out The “cal-culated” LDL should then be determined (seeFigure 8.8)

As in the case of hypertension, treatment of lipidabnormalities usually will not require a change indiabetes therapy if the patient is maintaining HbA1cwithin 1.0 percentage point of the upper limit ofnormal In those patients with type 2 diabetes and/ormetabolic syndrome treated by medical nutritiontherapy only, some minor alterations in food plan(reduction in saturated fats) may be required withconcomitant weight management The selection ofpharmacologic agents to combat hyperlipidemiaand dyslipidemia raises additional considerations,since some lipid lowering drugs are known to ag-gravate blood glucose control

The current therapies are:

• lifestyle modification (Figure 8.7)

• HMG-CoA reductase inhibitors (statins)

• fibric acid derivatives

• bile acid sequestrants

• nicotinic acid (note: may raise blood glucoselevel)

• cholesterol absorption inhibitors

STAGED MANAGEMENT OF HYPERLIPIDEMIA AND DYSLIPIDEMIA 309

• Review lifestyle modifications at each visit

• Consider referral to a dietician

• If smoker recommend tobacco cessation counseling or programs, nicotine patch/gum or medications

MODIFICATIONS RECOMMENDATIONS

Diagnosed hypertension and/or dyslipidemia

Lipid Targets

LDL cholesterol 100 mg/dL

• With very high risk 70 mg/dL

• 30–40% reduction from baseline LDL HDL cholesterol 40 mg/dL Triglyceride  150 mg/dL

Blood Pressure Targets:

 130/80 mmHg in-office BP

 125/75 mmHg mean SMBP

LDL HDL TG BP

Weight reduction

Healthy eating plan

Sodium restriction

Physical activity

Alcohol consumption

Omega-3 Fatty Acids

Maintain normal body weight (BMI 25 kg/m 2 )

Eat a diet rich in etables, lean meats, low-fat dairy products; limit use of high fat snacks, desserts and fast food

fruits,veg-(DASH diet for hypertension) Reduce dietary sodium intake

to 2400 mg/day Encourage regular physical activity 30 minutes per day most days of the week; con- sider stress test if known CVD

Limit to no more than 2 drinks/day for men and 1 drink/day for women

With CHD, consume fatty fish and/or supplementation to achieve 1 g of EPA and DHA per day

Potential Effect: or minor or modest significant

_ _ _

_

Figure 8.7 Lifestyle Modifications

Treating hyperglycemia

Hyperlipidemia or dyslipidemia in the presence

of diabetes and/or metabolic syndrome requires

certain precautions In type 2 diabetes and/or

metabolic syndrome, if blood glucose is well

con-trolled by food planning and exercise alone then

no modifications in this therapy will be necessary

However, when blood glucose is high (HbA1c

>1.0 percentage point above normal) and there is

hyperlipidemia, lowering blood glucose is

impor-tant and may require moving to a pharmacological

diabetes regimen, e.g from food plan to oral agent

or insulin Similarly, in type 1 diabetes, if HbA1c

is not at target, more intensive blood glucose agement is necessary (see Chapter 6) In terms ofpriorities, the first step is to determine the severity

man-of the cholesterol level (see Table 8.2) Next, alterthe treatment for diabetes if the HbA1c >1.0 per-centage points above upper limit of normal

Selecting the appropriate therapy

Staged Diabetes Management recommends thefollowing strategy to select the appropriate start-ing therapy for dyslipidemia that is consistent withNCEP guidelines Begin by evaluating the LDL

310 MACROVASCULAR DISEASE

Table 8.2 Clinical Effectiveness of Lipid Lowering Agents

LDL Lowering Effect of Statins

-Simvastatin

Key:  up to 30%  up to 40%  up to 50%

 50%

Note: Statins lower triglycerides 15–25% and increase HDL5–15%

Clincial Effectiveness of Fibrates and Niacin

Triglyceride HDL LDL Fenofibrate 23–55% 10–20% 10–25%*

(160 mg/day) Gemfibrozil 20–31%

20–40%

6–12% 0–5%*

(600 mg bid) Niacin 15–30% 10–20%

(2000 mg/day)

*Treatment of patients with elevated triglycerides (TG) due to Type IV Hyperlipidemia may have increase in LDL cholesterol

Clincial Effectiveness of Bile Acid Sequestants and Cholesterol Absorption Inhibitors

LDL Triglyceride HDL Colesevelam** 15–20% 5–10%

15–20%

3–5% (3.8 g/day)

Ezetimibe 10–15% 1–3% (10 mg/day)

** Colesevelam is recommended over colestipol and cholestyramine because of improved tolerability and positive effect on lipid panel

cholesterol and triglyceride level Lifestyle and

dietary modifications are the primary therapies

when both of the following conditions are met:

LDL <130 mg/dL (3.6 mmol/L) and triglyceride

<200 mg/dL (2.4 mmol/L) Both conditions are

and/or triglyceride ≥200 mg/dL (2.4 mmol/L)

pharmacologic therapy, along with lifestyle and

dietary modifications, is required to achieve lipid

targets Triglyceride levels ≥500 mg/dL (5.6

mmol/L) take precedence over an elevated LDL

level for the drug of first choice because of the

risk for chylomiconemia syndrome and

pancre-atitis Patients with severe hypertriglyceridemia

(>1000 mg/dL (11.3 mmol/L)) will require

ex-tremely low-fat diets, weight management, and

a fibrate

Lifestyle modification and dietary

interventions

Significant changes in lifestyle will be necessary

for all patients with dyslipidemia As with

hy-pertension, several areas of change are beneficial:

weight reduction, increased physical activity,

re-duction in alcohol intake, rere-duction in dietary fats,

and moderation in dietary sodium Many of these

are interlinked Clearly, alterations in diet and

physical activity level are important to emphasize

since they have an impact on lipids, hypertension,

of high-calorie and high-fat foods and drinks withlower-calorie substitutes is beneficial If this fails

to improve lipids, reduction in food intake is ten helpful A 10–20 per cent reduction in mealsize will lower total caloric intake by the sameamount If this fails to improve lipid levels, therestriction of food and drink should be attempted.This approach lists those foods, such as red meat,and drinks, such as whole fat milk, that are not ac-ceptable The goal should be caloric reduction bybetween 250 and 500 calories per day, which willresult in a 2–4 lb (1–2 kg) per month weight loss

of-If increased exercise of 30 minutes per day, threetimes per week, is added, the patient may lose up

to an additional 2 lb (1 kg) per month Reduction

in calories should be accompanied by modification

in both fat and sodium intake Since fat providesmore than double the calories of equivalent quan-tity of carbohydrate or protein, further reduction

in weight can be realized by replacing fat withcarbohydrate and protein

STAGED MANAGEMENT OF HYPERLIPIDEMIA AND DYSLIPIDEMIA 311

General recommendations include:

• fat at less than 30 per cent of total calories

• saturated fat less than seven per cent of total

calories

• fat limited to monounsaturated and

polyunsat-urated (avoid animal fats)

• meat limit to 6 ounces per day (avoid high-fat

products)

• dairy limit to low-fat variety

• eggs limit to 2–3 per week

• breads, whole-grain variety

• avoid alcohol if high triglyceride level

These recommended changes are for patients on

medical nutrition therapy as a solo therapy or as

part of the pharmacologic therapy

Medical nutrition therapy

adjust/maintain treatment

Improvement in the lipid levels should occur

within 3 months of initiation of treatment and

con-tinue until normal levels of total cholesterol and

LDL cholesterol are reached Continued

modifi-cation in diet and increase in activity level should

be encouraged to maintain improved lipid levels

If improvement is not occurring, consider

evalu-ation for adherence and introduction of

pharma-cologic therapy Refer to the Dyslipidemia Start

and Adjust DecisionPath to select the appropriate

drug therapy and then follow the specific

Ad-just/Maintain guide (see Figure 8.8)

Start drug treatment

The choice of drugs is based on the nature of the

lipid abnormality In general, however, treatment

for hyperglycemia takes precedence unless, as

already noted, the lipid abnormality is severe

Thus, the drug to be avoided initially is nicotinic

acid, which tends to aggravate blood glucose

control The one exception is the patient alreadytreated with insulin In this case, adjusting theinsulin dose will counteract the hyperglycemiceffect of nicotinic acid In all cases, the lipidtreatment should be targeted with the best drugfor the particular abnormality

Start all pharmacologic therapies at the

mmol/L), an HMG-CoA reductase inhibitor is ommended as long as the triglyceride level is

rec-<500 mg/dL (5.6 mmol/L) For triglyceride els≥500 mg/dL (5.6 mmol/L), independent of theLDL level, initiate fibric acid therapy If nicotinicacid is selected as the initial therapy, titrate thedose slowly to avoid flushing Initial patient con-tact should be weekly for 2–3 weeks to determinethe reaction to the drug therapy If an HMG-CoAreductase inhibitor is started, recheck liver profile

lev-in eight weeks Consider referral to a registered etitian and diabetes educator to reinforce lifestylechanges

di-Adjust/maintain drug treatment

At the four month visit cholesterol, LDL, HDL,and triglyceride levels are measured to identifyany current lipid abnormality (see Figure 8.8) Ifthe therapy has resulted in reaching the target, thepatient moves into the maintain phase Continue

to monitor the patient every 4–6 months After

1 year in the maintain phase, reduction in drugtherapy may be considered If the patient has notreached target, first determine whether the lipidabnormality is the same as before If it is thesame, assess overall adherence to the prescribedregimen This should address changes in lifestyle

as well as whether the medication dose and ing are followed Lifestyle changes should be re-flected in alteration in diet, activity level, weight,and blood glucose levels If the patient is on drugtherapy and adhering to regimen, increase the ini-tial drug until the maximum dose is reached Ifthe maximum dose is reached, consider addingthe next drug category If the first drug has been

tim-of some benefit, the second drug is added whilethe first drug is maintained at the current dose If

312 MACROVASCULAR DISEASE

Lipid Therapy/Start and Adjustment Guide

Statin

Fibric Acid

Nicotinic Acid (Niaspan) 500 mg/day 1000–2000 mg/day

Cholesterol Absorbtion Inhibitor

Bile acid sequestrants

Note: Monitor serum transaminase (AST/ALT) levels before and 8–12 weeks after starting a statin

or fibric acid; monitor periodically thereafter; discontinue therapy if AST or ALT 3 times upper

limit of normal (ULN)

NO

Patient with dyslipidemia

Consider statin therapy in all patients 35

years of age and with total cholesterol

T riglyceride 150 mg/dL

Titrate statin dose or add second agent,

rein-force food plan; see Lipid Therapy Selection

and Lifestyle Modifications

Figure 8.8 Dyslipidemia/Start and Adjust

the first drug was of no apparent benefit, replace

it with the next category drug

Note Should the patient develop a different lipid

abnormality or an additional abnormality follow

the change in therapy for dyslipidemia protocol

STAGED MANAGEMENT OF HYPERLIPIDEMIA AND DYSLIPIDEMIA 313

1 all lipid levels are normal;

2 continued elevated LDL;

3 LDL improved but now triglyceride is

ele-vated (>400 mg/dL [4.5 mmol/L]);

4 both LDL and triglyceride are abnormal

If the LDL abnormality remains the principal

concern, HMG-CoA reductase inhibitor should be

increased until the maximum dose is reached At

this point, if there is still insufficient improvement,

a bile acid sequestrant or cholesterol absorption

inhibitor (ezetimibe) should be added If there

is still no improvement, nicotinic acid may be

considered; however, blood glucose must be

mon-itored and modification of the diabetes regimen

may be required If the LDL is being managed

and triglyceride levels are now abnormal, fibric

acid is added at starting dose When both LDL

and triglyceride levels are high, the LDL lowering

drug should be increased and fibric acid initiated

Continue this until the maximum dose is reached

or normal levels are restored In the event that the

therapies are not succeeding, consider referral to

a specialist in lipid disorders

Initial triglyceride abnormality

If the patient originally had an elevated

triglyc-eride level, at the four month follow-up one of

the following conditions might be present:

1 continued elevated triglyceride;

2 triglyceride level improved but now has

ele-vated LDL as well;

3 abnormal LDL and triglyceride;

4 all values normal

If the triglyceride abnormality remains the

prin-cipal concern, fibric acid should be increased until

the maximum dose is reached At that point, if

there is still insufficient improvement, add

nico-tinic acid (however, blood glucose should be

fol-lowed and medications adjusted) If the

triglyc-eride level is being managed and LDL is now

abnormal, HMG-CoA reductase is added at imum dose Whenever HMG-CoA reductase andfibric acid are used together, the risk of myopa-thy is increased Ask the patient to report mus-cle weakness or tenderness When both LDL andtriglyceride levels are high, the triglyceride low-ering drug should be increased and HMG-CoAreductase initiated Continue this until the maxi-mum dose is reached for both agents or normallevels are restored

min-Note In the event that the therapies are not succeeding, consider referral to a lipid specialist.

Initial LDL/triglyceride abnormality

If there originally was an elevated LDL and mal triglyceride level, at the four month follow-upone of the following conditions might be present:

abnor-1 continued elevated LDL/triglyceride;

2 LDL improved but now has elevated

triglyc-eride (>400 mg/dL or 4.5 mmol/L) as well;

3 triglyceride level improved, LDL still mal;

abnor-4 all values are normal

Maintain the current therapy when there is provement If there is no improvement, continue

im-to adjust the drug until the maximum dose isreached Change the category of drug if the initialtherapy fails

Selecting the appropriate therapy for hypertension and dyslipidemiaMany of the drug therapies and all of the dietarychanges benefit more than one of the abnormali-ties Medical nutrition therapy for hypertension isidentical to that for diabetes or insulin resistance.Further modifications of fat intake due to dys-lipidemia would benefit both hyperglycemia andhypertension Reduction in blood glucose levels tonear normal will contribute to improved lipid lev-els, independent of the type of therapy (medicalnutrition, oral agent, or insulin)

314 MACROVASCULAR DISEASE

Additional therapeutic options for prevention and

treatment of cardiovascular disease

Recently, adjunctive therapies have been

intro-duced for the primary and secondary prevention

of CVD in individuals with diabetes (and for

peo-ple with metabolic syndrome as well) Some of

these therapies are highly recommended as part

of Staged Diabetes Management (i.e aspirin

ther-apy) based on evidence from numerous clinical

studies, while others are less well investigated and

accepted (i.e folate supplementation) Ultimately,

it is up to the provider to weigh the possible

benefits and risks before initiating any of these

therapies

Aspirin therapy

Numerous primary and secondary prevention

tri-als have demonstrated the ability of aspirin

ther-apy to offer significant protection from myocardial

infarction, stroke, and mortality due to

cardio-vascular events.32 Aspirin blocks the synthesis of

thromboxane, a potent vasoconstrictor and

stim-ulator of platelet aggregation Because of the

overwhelming evidence in support of using

as-pirin therapy to prevent cardiovascular events,

SDM recommends aspirin therapy for all

in-dividuals greater than 30 years of age While

no current studies in individuals with diabetes

and/or metabolic syndrome have established the

appropriate dose for primary or secondary

pre-vention of CVD, SDM recommends a daily

dose of 325 mg of aspirin Enteric-coated tablets

should be considered to minimize gastrointestinal

side effects Consider lower-dose aspirin therapy

(81–162 mgqd) if patient experiences minor

gas-trointestinal upset (stomach pain, heartburn,

nau-sea/vomiting) Contraindications for aspirin

ther-apy include anticoagulant therther-apy (warfarin) or

other antiplatelet therapy (ticlopidine), allergy to

salicylates, severe liver disease, and bleeding

dis-orders

Hormone replacement therapyHormone replacement therapy, which includes es-trogen or combined progestin and estrogen, iscommonly used to ameliorate conditions associ-ated with menopause (hot flashes, vaginal dryness,and osteoporosis) Several observational clini-cal studies have shown a strong association be-tween hormone replacement therapy and reducedmorbidity and mortality due to CVD in post-menopausal women This would appear to be

of clinical importance to women with diabetesbecause they experience a significantly higherrate of CVD than women without the disease.However, in two large randomized clinical tri-als (Heart and Estrogen/Progestin ReplacementStudy and Women’s Health Initiative) no long-term cardiovascular benefit was demonstrated insubgroup analysis of women in these studies withdiabetes.33,34 Thus, SDM recommends that thedecision to initiate hormone replacement therapyfor post-menopausal women should not be based

on purported protection against CVD and must

be weighed against the modest increased risk ofendometrial carcinoma and breast cancer foundassociated with long-term estrogen supplementa-tion Contraindications for hormone therapy re-placement include pregnancy, known or suspectedbreast cancer, known or suspected estrogen depen-dent neoplasia, abnormal vaginal bleeding, throm-bophlebitis, or thromboembolic disease

Nutritional therapies for cardiovascular disease

Antioxidant supplementation

Vitamins C and E and β-carotene serve as tioxidants in the body by scavenging free radicalsthat are responsible for catalyzing the oxidation ofmany cellular components While the relationship

an-REFERENCES 315

between antioxidant therapy and coronary heart

disease is not clearly delineated, it is thought to

involve the inhibition of oxidation of LDL-C

Ox-idation of LDL-C appears to be required before it

can be taken up by macrophages in the arterial

wall, leading to atheroma People with diabetes

have enhanced susceptibility to LDL-C oxidation,

which may be one of the factors explaining the

increased risk of CVD in these individuals Since

large placebo controlled studies have failed to

demonstrate the CVD benefit of high-dose

vita-min E,18 SDM recommends that patients avoid

special supplements of vitamin E; rather, a daily

multivitamin should be considered

Folate supplementation

Folate, and to a lesser extent vitamins B6 and B12,

have been suggested to be effective in preventing

CVD because of their ability to lower

homocys-teine levels Homocyshomocys-teine is an amino acid that

is formed by the metabolism of methionine in

the liver Folate, vitamin B6, and vitamin B12

are critical for the metabolic conversion of

ho-mocysteine into other amino acids and have been

shown to be effective at reducing homocysteine

levels Elevated homocysteine levels have been

shown to be an independent risk factor for

coro-nary artery disease.35 Currently, SDM does not

recommend determining homocysteine levels on

a routine basis Determining homocysteine levels

should be considered primarily for patients with

established CVD in the absence of other risk

fac-tors If homocysteine levels are elevated (above

normal laboratory reference range), folate

supple-mentation of 0.4–1 mg per day is recommended

Folate supplementation is not recommended for

the prevention of CVD unless elevated teine levels have been documented Homocysteinelevels should be determined after 8–12 weeks offolate supplementation to ascertain the effective-ness of therapy

homocys-Fish oil therapy

Omega-3 fatty acids that are found in fish oilhave been shown to be an effective alternative

to fibrates and niacin for treating eridemia Omega-3 fatty acids reduce triglyceridelevels by decreasing the production of VLDLtriglycerides in the liver A meta-analysis of 26clinical studies demonstrated that fish oil effec-tively lowers triglyceride levels by up to 30 percent with no significant change in HbA1c.36 Fatty(non-farm raised) fish are high in the omega-3fatty acids eicosapentaenoic acid (EPA) and do-cosahexaenoic acid (DHA) The American HeartAssociation recommends that patients withoutdocumented CHD eat fatty fish (lake trout, seasalmon, albacore tuna) at least twice per week be-cause sufficient epidemiological and clinical dataexist to support their role in reducing the risk ofcardiovascular disease.37 It is important to con-sider that certain fatty fish may have high levels

hypertriglyc-of mercury and other contaminants In patientswith documented CHD, increased consumption

of fatty fish and/or supplementation in order toachieve 1 g of EPA and DHA/day is recom-mended In patients with isolated hypertriglyc-

eridemia (>200–400 mg/dL or 2.3–4.5 mmol/L),

further supplementation of EPA and DHA to2–4 g/day may be considered to lower triglyceridelevels

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9 Microvascular Complications

Detection and treatment of diabetic nephropathy

Recent evidence suggest that renal disease may

precede diabetes, or it may occur as a result of

per-sistent hyperglycemia Generally termed diabetic

nephropathy, to distinguish it from other forms

of nephropathy (such as IgA nephropathy), it is

a serious co-morbidity of diabetes mellitus and is

the leading cause of end-stage renal disease The

purpose of this section is to clarify the

relation-ship between diabetic nephropathy, blood glucose,

and blood pressure In addition, the current

stan-dards of care for assessing, diagnosing, and

treat-ing diabetic nephropathy are outlined The key

points are:

• screening and early detection of diabetic

nephropathy is critical

• management of hypertension and

hyper-glycemia will dramatically slow the onset and

progression of diabetic nephropathy

The interrelationship between the progression of

diabetic nephropathy and hypertension has been

known for many years.1,2 Hyperglycemia and, to

a lesser extent, dyslipidemia have been identified

as risk factors for diabetic nephropathy and have

been implicated in its pathogenesis.3,4 Therefore,

treatment to prevent or slow the progression ofdiabetic nephropathy is based on the management

of hyperglycemia, hypertension, and dyslipidemia.Chapters 4–6 provide DecisionPaths for manage-ment of type 2 and type 1 diabetes in detail.Chapter 8 discusses the treatment of hypertensionand dyslipidemia for individuals with diabetes ormetabolic syndrome

The current impact of diabetic nephropathy

As many as one million people with diabetes

in the United States may have kidney disease.Nephropathy is a serious complication of dia-betes and is the leading cause of end-stage renaldisease (ESRD) More than 40 per cent of in-dividuals with type 1 diabetes (∼300 000) willprogress to overt diabetic nephropathy within

20 years of diagnosis.5 It is quite rare for dividuals with type 1 diabetes to develop overtdiabetic nephropathy within five years of diagno-sis, during what is often referred to as the “silent”period Approximately 10 per cent of people withtype 2 diabetes (∼800 000) develop overt diabetic

in-Staged Diabetes Management: A Systematic Approach (Revised Second Edition) R.S Mazze, E.S Strock, G.D Simonson and R.M Bergenstal

 2006 Matrex ISBN: 0-470-86576-X

320 MICROVASCULAR COMPLICATIONS

nephropathy; however, studies indicate that when

the duration of diabetes exceeds 25 years, the

percentage of individuals with type 2 diabetes

that develop overt nephropathy is the same as

that with type 1 diabetes.5 Most individuals

di-agnosed with overt nephropathy will proceed to

ESRD and require dialysis (or a kidney

trans-plant) In the United States 45 per cent of

pa-tients with ESRD have diabetes, and, of these,

approximately 60 per cent have type 2 diabetes

and 40 per cent have type 1 diabetes.14 The

in-cidence of diabetic ESRD has risen exponentially

over the past decade, primarily due to the

increas-ing number of individuals with type 2 diabetes

progressing to ESRD Not surprisingly, groups

at highest risk for diabetes also have the

high-est prevalence of ESRD African-Americans and

American Indians are at particular risk They have

a three-fold greater chance of developing ESRD

compared with Caucasians.14

Pathogenesis and stages

of diabetic nephropathy

Diabetic nephropathy results from the

forma-tion of lesions in the kidney The underlying

pathogenesis of diabetic nephropathy is still not

clearly understood, but involves a combination

of HTN, hyperglycemia, and proteinuria Diabetic

nephropathy is characterized by distinct

morpho-logic and biochemical changes in the kidney that

coincide with the onset and progression of renal

disease Enlargement of the mesangium, a

mem-brane composed of mesangial cells and

extracel-lular matrix supporting the glomerular capillary

loops, is one of the most prominent morphologic

changes Elevated glucose levels have been shown

to increase the production of collagen, fibronectin,

and laminin in the mesangial extracellular

ma-trix, resulting in a significant thickening of the

mesangial basement membrane.6,7 This

thicken-ing compresses the glomerular capillaries, alterthicken-ing

intraglomerular hemodynamics Other changes

in-clude a dramatic loss in capillary surface area and

decreased levels of heparin sulfate in the

extracel-lular matrix

Diabetic nephropathy progresses through tinct stages characterized by the amount of albu-min “spilled” into the urine The earliest stage,incipient diabetic nephropathy, is characterized bylow levels of albumin in the urine (referred to

dis-as microalbuminuria) Studies have shown thatmicroalbuminuria is the best predictor of the pro-gression to the next stage, called overt diabeticnephropathy.8 Not only does albumin serve as amarker of the progression of diabetic nephropathy,but it appears to directly damage the glomerulus.The progression from incipient to overt diabeticnephropathy normally takes many years Approx-imately 80 per cent of patients with microal-buminuria progress to overt diabetic nephropa-thy (proteinuria) Overt diabetic nephropathy ischaracterized by macroalbuminuria, which can bedetected with the standard urinalysis “dipstick”test for proteinuria As diabetic nephropathy pro-gresses, renal insufficiency ensues, leading to el-evated serum creatinine levels Normally, renalfailure or ESRD develops in 3–15 years afterthe development of overt diabetic nephropathy.End-stage renal disease is marked by severe pro-teinuria and azotemia, a condition caused by highlevels of urea and creatinine in the bloodstream

At this point renal replacement therapies (dialysis)are begun and kidney transplantation is consid-ered Although, at this juncture, dialysis and/orkidney transplants are the only solutions for dia-betic nephropathy, they are not ideal because ofthe associated high mortality of patients undergo-ing these therapies

Hyperglycemia and diabetic nephropathy

The Diabetes Control and Complications Trial3showed that the maintenance of near euglycemia

in type 1 diabetes drastically reduces the quency and severity of kidney disease Intensivemetabolic control resulted in a 39 per cent riskreduction in microalbuminuria in the primary pre-vention cohort and a 54 per cent risk reduction

fre-DETECTION AND TREATMENT OF DIABETIC NEPHROPATHY 321

in the occurrence of macroalbuminuria in the

sec-ondary intervention cohort (participants with

mi-croalbuminuria at the start of the study) A similar

reduction in risk was found in the United

King-dom Prospective Diabetes Study for type 2

dia-betes patients undergoing intensive management.9

Other studies have also shown the predictive

na-ture of elevated glucose levels, making it one of

the major risk factors for microalbuminuria and

macroalbuminuria.7,10Thus, maintenance of

near-normal blood glucose levels clearly is imperative

for the prevention of diabetic nephropathy or to

slow the progression of the disease

Hypertension, dyslipidemia,

and diabetic nephropathy

The causes of hypertension in individuals with

type 1 diabetes are generally different from those

in patients with type 2 diabetes In type 1

dia-betes, hypertension is often associated with

un-derlying renal disease In type 2 diabetes,

obe-sity and insulin resistance (even in the absence

of renal disease) are thought to be the critical

link Nevertheless, hypertension has been a

prin-cipal factor for both the onset and progression

of diabetic kidney disease in both type 1 and

type 2 diabetes Research by the

Microalbumin-uria Collaborative Study Group11 indicates that

increases in blood pressure occur concurrent with

rising urinary albumin levels This takes place

even when albumin levels are within the

nor-mal range (albumin/creatinine ratio <30 mg/g,

<30 mg albumin/24 hours, or albumin excretion

rate <20 µg/min) Hypertension may play a role

in the pathogenesis of diabetic nephropathy, thus

aggressive treatment of hypertension is critical for

its prevention

Dyslipidemia is often associated with

albumin-uria in diabetes Elevated levels of total

choles-terol, and LDL, triglycerides, and reduced HDL

levels, appear to be risk factors for the

de-velopment of diabetic nephropathy The precise

role of dyslipidemia in the onset and

progres-sion of diabetic nephropathy is not fully

under-stood However, treatment of dyslipidemia is an

important facet of care for those with diabeticnephropathy

Renal disease, type 2 diabetes, and metabolic syndrome

Does renal disease precede diabetes? Increasinglythis question is being asked by researchers inter-ested in determining the etiology of renal failure

in persons with type 2 diabetes Thought to be

a consequence of diabetes, renal disease is nowconsidered to be part of a metabolic syndromethat encompasses several inter-related disorders:hypertension, dyslipidemia, hyperglycemia, andobesity Does it matter whether renal disease is

a consequence of, co-morbidity with, or sor to diabetes? The answer is that it matters only

precur-if clinical decisions rely on the sequence of orders The SDM approach is, in the presence

dis-of any dis-of these co-morbidities, to screen for theothers

Diabetic nephropathy practice guidelines

The standards of care for kidney disease and pertension in type 1 and type 2 diabetes differslightly from those for individuals without di-abetes These standards are summarized in thepractice guidelines (see Figure 9.1) and in thissection

hy-Common clinical manifestations

While there are no specific clinical signs of derlying kidney disease, there are risk factors thatshould invoke a concern for diabetic nephropathy.Poor glycemic control, hypertension, retinopathy,elevated LDL cholesterol, and duration of diabetesgreater than 5 years are all predictors of diabeticnephropathy

• Albumin to Creatinine Ratio: Every 6–12 months

• Serum creatinine and blood urea nitrogen (BUN) annually in patients with albuminuria

• Estimate glomerular filtration rate (GFR)

• When GFR ⬍60, consider consult with Endocrinologist, Diabetologist, or Nephrologist.

Microalbuminuria Random albumin-to-creatinine ratio (A/C ratio) 30–300 mg albumin/gram creatinine

(preferred method) on at least 2 out of 3 occasions Albumin-specific dipstick may be used for screening; verify all positive dipstick results with A/C ratio

Macroalbuminuria Albumin-to-creatinine ratio ⬎300 mg albumin/gram creatinine or protein dipstick

positive Note: Total protein-to-creatinine ratio is acceptable when albumin-to-creatinine ratio ⬎500-1,000 mg/gm

Targets

Monitoring

Follow-up

Screening Albumin-to-Creatinine Ratio (A/C ratio); type 1 diabetes:After 5 years diagnosis,then

yearly; type 2 diabetes:At diagnosis, then yearly

• Hypertension BP ⬎130/80 mmHg

• HbAlc ⬎7%

• Sibling with chronic kidney disease

• Smoking

• Duration of diabetes ⬎5 years

• Family history of hypertension and/or dyslipidemia

Risk Factors

• American Indian or Alaska Native; African American; Asian; Native Hawaiian

or other Pacific Islander; Hispanic

Figure 9.1 Kidney Disease Practice Guidelines

Screening and diagnosis of diabetic

nephropathy

In general, the diagnosis of diabetic nephropathy

relies on persistent elevated albumin levels in the

urine Abnormal glomerular filtration rate (GFR)

is another indicator, but this information is often

not available All newly diagnosed patients with

diabetes should initially be screened for

microal-buminuria using the albumin/creatinine ratio (A/C

ratio) (see Figure 9.2) Clinicians need to be

cog-nizant of and evaluate for potential contamination

or conditions at the time of specimen collection

that can affect albumin levels in the urine These

include urinary tract infections, poor glycemiccontrol, fever, blood in the urine, congestive heartfailure, extreme hypertension, and vaginal fluidcontamination Any of these situations or condi-tions can increase albumin levels The dipstick testfor proteinuria is inadequate for making a diagno-sis of incipient diabetic nephropathy, character-ized by microalbuminuria, because the test is notsensitive enough to detect low levels of albumin.Thus, all negative protein dipsticks must be fol-lowed by a laboratory test for microalbuminuria.Staged Diabetes Management recommends that

a random urine sample be used for albuminuriascreening because of sensitivity, convenience to

DETECTION AND TREATMENT OF DIABETIC NEPHROPATHY 323

Patient with type 1 or type 2

Type 1: Screen 5 years

Type 2: Screen at diagnosis

and annually thereafter

Repeat screen twice more

within 2 months, rule out UTI

Repeat screening annually

YES

NO

At least 2 of 3 A/C

ratios ⬎30 mg/g

Repeat screening annually

after diagnosis; annually thereafter

Figure 9.2 Screening for Kidney Disease

the patient and ease of sample collection To

ac-count for variability in the concentration of solutes

and in the time of specimen collection, all random

urine collection tests for albuminuria should be

adjusted with urine creatinine Because of

inher-ent day-to-day variability in urine albumin levels,

diagnosis requires that at least two out of three

tests be positive in order to make the diagnosis of

microalbuminuria Twenty-four hour urine

collec-tion used to be considered the “gold standard” for

albuminuria screening This test may be used for

screening and diagnosis of albuminuria, but due

to patient inconvenience and concerns over

accu-racy of sample collection (i.e missed collection)

it is neither recommended nor required

In many cases, the presence of incipient or overt

diabetic nephropathy is associated with underlying

hypertension (see Figure 9.2) The increase in

blood pressure is a response to the renal disease

but may also be part of the pathogenesis of

dia-betic nephropathy The majority of patients have

no symptoms, but occasionally headache, ness, or blurred vision is reported Risk factors forhypertension include obesity, visceral adiposity,insulin resistance manifested as hyperinsulinemia,hyperlipidemia, family history of hypertension,lack of exercise, smoking, and age greater than 50.African-Americans and Hispanics form particulargroups at high risk for hypertension As part ofgood diabetes management, blood pressure needs

dizzi-to be monidizzi-tored at every visit Any evidence ofhypertension should be treated aggressively

Glomerular filtration rate. The tion of the glomerular filtration rate (GFR) is analternative and complementary diagnostic mea-surement of kidney function While not a rou-tine test, GFR is often used in clinical studies

determina-to detect and monidetermina-tor the progression of diabeticnephropathy At the time of diagnosis of type 1diabetes, the GFR is normally elevated because ofglucose-induced hyperfiltration, osmotic effects,and increased blood pressure The GFR of newlydiagnosed patients with type 2 diabetes is variable.Glomerular filtration rate is measured by follow-ing the urinary clearance of radioactively labeledcompounds Normal reduction in GFR in the gen-eral population is less than 0.03 ml/min/month; anacceptable limit in patients with diabetes is lessthan 0.2 ml/min/month

Estimations of GFR are increasingly ing available on lab reports or easily determinedusing online calculators Two currently avail-able methods to estimate GFR are shown inTable 9.1 Chronic kidney disease is defined as

becom-GFR <60 mL/min/1.73 m2 for at least 3 months

Creatinine clearance. The determination ofcreatinine clearance provides a means to test kid-ney function and is considered an indicator ofGFR Creatinine is generated in muscle fromthe spontaneous cyclization of creatine into cre-atinine, which is subsequently released into thebloodstream and excreted via the kidneys Thisendogenous source of creatinine is directly pro-portionate to muscle mass and varies with ageand sex However, in the absence of renal disease,the clearance of creatinine is relatively constant in

324 MICROVASCULAR COMPLICATIONS

• Increase ACEI or ARB

to maximum tolerated dose

• Obtain A/C ratio every

6-12 months

Obtain serum creatinine

annually and estimate GFR

NO Continue with current therapy, follow-up with annual A/C ratio and eGFR

• ⬍125/75 mmHg SMBP

• HbA1c ⬍7%

• Stabilization or improvement in albumin/creatinine (A/C) ratio

Initiate Treatment

• Start ACEI or ARB

• Obtain baseline potassium,

serum creatinine and

estimate GFR

• Follow-up potasium at two

weeks; see Hypertension

Drug Therapy and

nephrologist; see Stages

of Chronic Kidney Disease

Patient with macroalbuminuria (A/C ratio ⬎300 mg/g)

eGFR ⬍30 ml/min/

1.73m 2 ?

Targets

• ⬍130/80 mmHg in-office BP

• ⬍125/75 mmHg SMBP

• HbA1c ⬍7%

• Stabilization or improvement in Albumin/Creatinine (A/C) ratio

• Start or increase ACEI or ARB to maximum tolerated dose

• Obtain serum creatinine and estimate glomerular filtration rate; see

NO

NO

eGFR 30 to 59 ml/min/

1.73m2? Continue current regimen,treat to targets shown

above; obtain annual A/C ratio, serum creatinine and eGFR Moderate decrease in GFR

(Stage 3 Chronic Kidney Disease); consider referral to

nephrologist; see Stages of Chronic Kidney Disease

Treatment

• Start or maintain ACEI or ARB and achieve maximum tolerated dose, monitor potassium levels

• Treat to BP and HbA1c targets shown above

• Referral to dietician to initiate low protein diet (⬍0.8 gm protein/kg/day)

Monitoring and Follow-up

• Proteinuria and edema Serum creatinine with eGFR every 6–12 months

• Monitor for anemia annually

• Access for bone disease

YES

Macroalbuminuria Microalbuminuria

Estimation of Glomerular Filtration Rate (eGFR)

Repeat A/C ratio within

3–6 months

YES

Figure 9.3 Microalbuminuria and Macroalbuminuria Screening, Diagnosis and Treatment

any one individual Creatinine clearance is

calcu-lated from measurements of creatinine in the urine

or serum For males under age 40, the normal

reference interval for urine creatinine clearance

is 90–140 mL/min/1.73 m2; for females under

age 40, it is 80–125 mL/min/1.73 m2.13

Crea-tinine clearance decreases by 5–8 per cent

ev-ery decade after age 40 Often, only the serum

(or plasma) creatinine level is measured The

normal reference interval for serum (or plasma)

creatinine is 0.8–1.5 mg/dL (70–130µmol/L) In

contrast to the GFR, at the time of diagnosis of

type 1 diabetes, the serum creatinine levels are

often quite low (∼0.8 mg/dL or 70 µmol/L)

be-cause of glomerular hyperfiltration Patients with

incipient or overt diabetic nephropathy usuallymaintain serum creatinine levels in the normalreference range As the diabetic nephropathy pro-gresses to end-stage renal failure, there is acorresponding rise in the serum creatinine to

>2.0 mg/dL (180 µmol/L) This increase

contin-ues to >10 mg/dL (880µmol/L), signaling a totalshutdown of kidney function

Treatment of diabetic nephropathy

Diabetic nephropathy cannot be cured However,evidence has been accumulating that the onset

of diabetic nephropathy can be delayed and its

DETECTION AND TREATMENT OF DIABETIC NEPHROPATHY 325

Table 9.1 Estimation of Glomerular Filtration Rate (eGFR)

(186 × [serum creatinine in mg/dL]-1.154 × [age in years]-0.203 ×

[0.742 if female] × [1.21 if African American]= estimated GFR

*This abbreviated MDRD equation does not require Blood Urea

Nitrogen (BUN) or albumin level

Levey et al Ann Intern Med 1999; 130:461-470.

[140 - age in years] × weight in kg/[72 × serum creatinine]= estimated GFR in ml/min/1.73m2

Note= multiply result by 0.85 for women Example: 65 year old woman weighing 70 kg and serum creatinine of 1.3 mg/dL

[140-65] × 70/[72 x 1.3] × 0.85= 48 ml/min/1.73m2

Cockcroft and Gault Nephron 1976; 16:31-41.

progression retarded Near-normal glycemic

con-trol and the aggressive treatment of

hyperten-sion are the two most important treatment

op-tions available for the management of diabetic

nephropathy Chapters 4–6 provide guidelines

for achieving and maintaining metabolic control

in individuals with diabetes The maintenance

of near euglycemia (HbA1c within one

percent-age point of the upper limit of normal) is of

paramount importance for those diagnosed with

diabetic nephropathy

Serum creatinine levels are an important

consid-eration in diabetes oral agent selection Table 9.2

provides guidelines for selecting the appropriate

oral agent

treatment of hypertension is essential in

de-laying the onset and slowing the progression

of diabetic nephropathy Practice guidelines

and DecisionPaths, located in Chapter 8, have

been formulated for the assessment, diagnosis,

and treatment of hypertension Briefly, tension management begins with appropriatemedical nutrition therapy along with changes

hyper-in lifestyle Specific dietary changes hyper-includereduction of sodium in the diet by limiting theuse of processed foods, and limiting alcoholintake Lifestyle changes include increasedactivity/exercise and smoking cessation Mon-itoring blood pressure at home and at work(SMBP) may provide necessary interim data

to determine how well lifestyle changes areworking

If medical nutrition therapy is not sufficientfor blood pressure control, mono-drug therapywith an angiotensin converting enzyme (ACE) in-hibitor or angiotensin II receptor blocker (ARB)should be initiated Both ACE inhibitors and ARBblockers have been shown in large prospectiveclinical research studies to slow the progression

of nephropathy.15 – 17 If patients experience sideeffects (cough) while taking an ACE inhibitor,consider switching to an angiotensin II receptorblocker If ACE inhibitor or ARB therapy alone

Table 9.2 Oral agent selection in the presence of diabetic nephropathy

> 2.0 mg/dL (>180µmol/L) Meglitinide or thiazolidinedione

1.4–2.0 mg/dL (120–180 µmol/L) α-glucosidase inhibitor, meglitinide, sulfonylurea, or thiazolidinedione

< 1.4 mg/dL (<120µmol/L) All oral agents

326 MICROVASCULAR COMPLICATIONS

is not sufficient to reduce blood pressure, other

anti-hypertensive drugs, including calcium

chan-nel blockers, β-blockers, diuretics, or α-blockers

should be added (see Chapter 8) It is

impor-tant to note that the recently published

Anti-hypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT)18

demon-strated that no significant differences were noted

between the diuretic chlorthalidione and ACE

in-hibitor lisinopril in incidence of ESRD Thus,

thiazide diuretics should be considered in

com-bination with ACE inhibitor/ARB therapy or if

contraindications preclude the use of these two

classes of antihypertensive medications Recently,

small studies testing the effect of dual

block-ade of the renin–angiotensin system have been

conducted to look at potential benefits of

us-ing an ACE inhibitor and ARB in

combina-tion

Treatment of dyslipidemia. Dyslipidemia is

often associated with incipient diabetic

nephropa-thy In particular, elevated LDL and

triglyc-eride levels are predictors of microalbuminuria

Dyslipidemia should be treated aggressively (see

Chapter 8) Recommendations call for increased

physical activity and less than 30 per cent of

to-tal caloric intake from fat (<10 per cent saturated

fat) If food plan, exercise, and lifestyle

modifi-cations are not sufficient to achieve near-normal

lipid levels, pharmacologic agents that improve

lipid levels should be initiated HMG-CoA

reduc-tase inhibitors, fibric acid derivatives (fenofibrate

and gemfibrozil), and bile acid binding resins

(colestipol and cholestyramine) are all viable apeutic options for the treatment of dyslipidemia

ther-in the presence of diabetes Nicotther-inic acid should

be used with caution because of its tendency toaggravate blood glucose control

Modifications in dietary protein. Diets low

in protein have been shown to have renalprotective effects and to slow the progression

of overt diabetic nephropathy (macroalbuminuria)

in animal studies and in human studies withsmall cohorts To date, no conclusive evidencehas shown that low-protein diets slow the pro-gression from incipient diabetic nephropathy (mi-croalbuminuria) to overt diabetic nephropathy It

is hypothesized that excess protein in the dietcauses glomerular hyperfiltration, renal vasodi-latation, and changes in intraglomerular pressure,all of which are associated with proteinuria TheAmerican Diabetes Association12 recommends aprotein dietary intake of 0.8 g/kg body weight perday, or∼10 per cent of total caloric intake, for in-dividuals with macroalbuminuria (overt nephropa-thy) Further reduction of protein intake to 0.6g/kg body weight per day may be considered forpatients with rapidly declining GFRs Preliminaryevidence suggests that the protein source, plantversus animal, may play an important role in theobserved renal protective effect of a low-proteindiet Vegetable protein may be more beneficial andanimal protein more harmful More studies are re-quired before any conclusions can be drawn

Detection and treatment of eye complications

Retinopathy, cataracts, and glaucoma are serious

complications of diabetes Diabetic retinopathy is

the leading cause of non-injury-related blindness

in the United States and is responsible for reduced

visual acuity The purpose of this section is to

detail the relationship between diabetic eye

com-plications and hyperglycemia, outline the current

standards of care for assessing, diagnosing, and

treating diabetic retinopathy, and set the criteria

and timelines for referring patients to eye-care

specialists The key points are:

• screening and early detection of diabeticretinopathy are critical

• when properly detected and treated, ment of hyperglycemia and hypertension (and

manage-to a lesser extent dyslipidemia) will ically slow the onset and progression of dia-betic retinopathy

dramat-The progression of diabetic retinopathy as a sequence of hyperglycemia in type 1 diabetes has

con-DETECTION AND TREATMENT OF EYE COMPLICATIONS 327

been established for several years.1,2 The

associ-ation of hypertension and diabetic retinopathy in

type 2 diabetes was shown in the United

King-dom Prospective Diabetes Study.15Patients in the

“tight” hypertension control cohort had a 34 per

cent reduction in progression of diabetic

retinopa-thy versus the “less tight” hypertension control

group The association of dyslipidemia with the

pathogenesis of diabetic retinopathy remains

un-clear, but is thought to be a risk factor for its

development Current diabetes care to prevent the

onset of diabetic retinopathy, or to slow its

pro-gression, is based primarily on early detection

through routine screening and intensive

manage-ment of hyperglycemia and hypertension

Staged Diabetes Management addresses these

issues by providing a systematic approach to

the prevention, detection, and initial management

of diabetic retinopathy along with DecisionPaths

with guidelines for referral of patients with

dia-betic retinopathy to eye-care specialists

The current impact of diabetes

related eye complications

Diabetes is the leading cause of legal blindness

(best corrected visual acuity of 20/200 or worse in

the better eye) in people age 20–74 3

Approxi-mately 12 per cent of all individuals with type 1

di-abetes with duration of didi-abetes more than 30 years

are legally blind, and an overwhelming majority

of individuals with type 2 diabetes with duration

of disease more than 15 years have some type of

diabetes related eye complication.2 Retinopathy,

cataracts, and glaucoma comprise the three primary

diabetes related eye complications Alone, or in

combination, they may all lead to legal blindness

Of principal concern for patients with diabetes is

retinopathy, characterized by changes in the

vas-cularization of the retina Diabetic retinopathy is

either totally or at least partially responsible for

approximately 85 per cent of legal blindness

(suf-ficiently impaired vision to make driving and other

routine activities impossible) in these individuals

Glaucoma and cataracts are the primary causes of

legal blindness in individuals with type 2 diabetes,

with diabetic retinopathy becoming a greater cern as the mean age of diagnosis is occurring at ayounger age

con-Types of eye complication diabetic retinopathy

Diabetic retinopathy is the major ocular tion associated with diabetes The pathogenesis ofdiabetic retinopathy is still unclear Persistent hy-perglycemia has been implicated in the onset andprogression of diabetic retinopathy, but the preciserole of elevated glucose has yet to be elucidated.Diabetic retinopathy actually encompasses a range

complica-of retinal abnormalities that have been staged inaccordance to the severity of retinal damage.The first stage is early nonproliferative diabeticretinopathy (NPDR) and is characterized by reti-nal microaneurysms, dot and blot hemorrhages,hard lipid exudates, and macular edema The nextstage is called moderate to severe NPDR and ischaracterized by cotton wool spots (soft exudatesindicating localized arteriolar closing), venous ab-normalities, and intraretinal microvascular abnor-malities (dilated capillaries in ischemic areas ofthe retina)

The most severe stage is called proliferativediabetic retinopathy (PDR) This stage is charac-terized by the development of neovascularization.The new blood vessels that develop to supplyblood flow to the retina are fragile and subject

to rupture New blood vessels are classified intotwo distinct categories based on the site of forma-tion New vessels on the disk (NVD), located onthe optic nerve head, and new vessels elsewhere(NVE) are at a greater risk of rupture The extentand location of the new vessels and the presence

of preretinal or vitreous hemorrhages determinethe severity of proliferative retinopathy Extensive

NVD (>1/3 disk diameter) and/or NVE with

ac-companying vitreous bleeding is considered highrisk for visual loss

The various mechanisms of vision ment associated with diabetic retinopathy are wellestablished Central vision impairment usuallyinvolves macular edema, a condition in which theretina swells due to the leakage of tissue fluid

impair-328 MICROVASCULAR COMPLICATIONS

and lipoproteins from abnormal retinal

vascula-ture Macular edema accounts for a significant

amount of vision impairment in the diabetes

pop-ulation Vision impairment can also result when

strands of fibrous tissue accompanying

neovascu-larization cause a distortion of the retina If the

formation of new vessels continues unabated, the

strands of fibrous tissue begin to produce

trac-tional forces, eventually leading to tractrac-tional

reti-nal detachment Vision is lost if tractioreti-nal retireti-nal

detachment involves the macula Partial loss of

vision may occur if the detachment occurs at the

retinal periphery Another cause of visual

impair-ment is formation of new blood vessels,

charac-teristic of proliferative diabetic retinopathy This

may result in vitreous hemorrhage The gel-like

vitreous becomes cloudy with the resultant

vi-sual impairment proportionate to the severity of

hemorrhage

Cataracts

Cataracts result from the opacification of the

crys-talline lens The opacification of the lens results in

diminished visual acuity Surgery is generally

re-quired to correct this condition Cataracts in

indi-viduals with or without diabetes (senile cataracts)

are morphologically similar, but recent evidence

suggests that they differ biochemically Research

suggests that high glucose levels induce

nonenzy-matic glycation and browning of lens crystallins

(by the same mechanism responsible for

glycosy-lation of hemoglobin), leading to opacification of

the lens in the senile-like diabetic cataract.4,5

Se-nile cataracts in individuals without diabetes do

not contain aberrantly glycated lens crystallins

Moreover, increased lens sorbitol, from the

con-version of glucose into sorbitol by aldose

re-ductase, has been implicated in the formation of

cataracts in animal models of diabetes.6 Whether

sorbitol plays a role in the formation of cataracts

in humans is still unresolved A second type of

cataract, called “snowflake” occasionally develops

in untreated or poorly controlled patients with type

1 diabetes These cataracts may disappear once

near-normal glycemic control is established

Glaucoma

Two forms of glaucoma (primary and secondary)occur most often in individuals with diabetes Pri-mary open angle glaucoma is characterized by el-evated intraocular pressure that may lead to opticnerve damage and subsequent loss of visual fieldand central vision Diabetes has often been noted

as a risk factor for primary open angle glaucoma,but the relationship has not been corroborated inall studies Neovascular glaucoma (rubeosis) is asecondary form of glaucoma resulting in the de-velopment of abnormal new vessels on the iris thatobstruct the outflow channels of the eye, causing

an increase in intraocular pressure This form ofglaucoma is often painful and results in loss ofthe eye It is associated with severe abnormal is-chemia and proliferative retinopathy

Hyperglycemia and diabetic retinopathy

Intensive metabolic control (HbA1c∼7 per cent)

in the nine year Diabetes Control and tions Trial7 resulted in a 76 per cent reduction

Complica-in the risk of developComplica-ing retComplica-inopathy Complica-in patientswith type 1 diabetes and slowed the progression

of retinopathy The earlier Kroc Study8,9 ing conventional insulin therapy with intensive in-sulin therapy showed no significant improvement

compar-in slowcompar-ing the progression of nonproliferative abetic retinopathy over a 1–2 year period Thisobservation was also noted during the first twoyears of the Diabetes Control and ComplicationsTrial, reinforcing the concept that long-term, notshort-term, near normalization of blood glucose

di-is critical for slowing the progression of diabeticretinopathy The United Kingdom Prospective Di-abetes Study Group10demonstrated the benefit ofimproved glycemic control in reducing the risk ofdiabetic retinopathy in individuals with type 2 dia-betes In addition, epidemiologic data are stronglysupportive of a positive correlation between bloodglucose level and risk of diabetic retinopathy inpatients with type 2 diabetes Thus, maintenance

of normal blood glucose levels is imperative for