Diagnosis and Treatment of Type 2 Diabetes chpt.15

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Diagnosis and Management of Type 2 Diabetes, 10th Edition, Ch 15, Pt1

Long-Term Complications: Macrovascular

Diagnosis_and_Management_of_Type_2_DiabetesSteve V. Edelman, MD

R. Henry, MD

The long-term, chronic complications of diabetes have the greatest impact on

the health of individuals with diabetes as well as on the health care

system. Diabetes and its associated vascular complications are the fourth

leading cause of death in the United States....

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Consequently, early detection and aggressive treatment of these

complications are essential to reduce associated morbidity and mortality.

Striving for tight metabolic control also has been proven to help delay the

onset and prevent the development of microvascular complications (diabetic

retinopathy, nephropathy, and neuropathy).

The DCCT, a multicenter, randomized clinical trial, investigated the effects

of intensive therapy vs. traditional therapy on the development and

progression of microvascular complications of Type 1 diabetes mellitus. The

aim of intensive therapy was to achieve and maintain near-normal blood

glucose values following a regimen of three or more daily insulin injections

or treatment with an insulin pump. In contrast, only one or two insulin

injections were used in conventional therapy. Patients were followed for a

mean of 6.5 years and assessed regularly for the presence or progression of

retinopathy, nephropathy, and neuropathy.

Intensive therapy proved to be highly effective in delaying the onset and

slowing the progression of the long-term complications being evaluated in

patients with Type 1 diabetes. Furthermore, similar benefits were observed

in the UKPDS in Type 2 diabetes. In response to the DCCT and UKPDS findings,

the ADA recommended striving for the best possible glycemic control in

patients with Type 1 and Type 2 diabetes with the following goals:

* Fasting and preprandial blood glucose level 80 mg/dL to 120 mg/dL

* PPG level <160 mg/dL

* A1c 7% (normal reference range = 4% to 6%) or three standard

deviations from the mean of the normal range.

Attempts to normalize glycemia and A1c should be balanced, however, with

minimizing weight gain and hypoglycemia and maintaining an acceptable

quality of life.

Macrovascular Disease

The incidence of the three major macrovascular diseases (coronary artery,

cerebrovascular, and peripheral vascular) is greater in individuals with

diabetes than in nondiabetic individuals, accounting for up to 80% of

mortality in adults with diabetes. Atherosclerosis develops at an earlier

age, accelerates more rapidly, and is more extensive in patients with

diabetes than in nondiabetics matched by age, weight, and sex.

Type 2 diabetes is a risk factor for macrovascular disease, as are

conditions that commonly coexist in patients with diabetes (hypertension,

dyslipidemia, and central obesity). Smoking and lack of exercise contribute

to an increased risk in both those with Type 2 diabetes and the nondiabetic

population. In addition, renal insufficiency can increase the risk of and

accelerate macrovascular disease in diabetic individuals with

microalbuminuria or gross proteinuria.

Weight control and exercise are safe and effective methods for modifying

macrovascular risk and should form the basis to which all other treatments

are added. The following treatments for hypertension and dyslipidemia should

be applied when appropriate.

Hypertension

Hypertension should be treated vigorously in all patients with diabetes to

limit and/or prevent the development and progression of atherosclerosis,

nephropathy, and retinopathy. Lowering elevated blood pressure is the most

important and immediate consideration, with a therapeutic goal of <130/80 mm

Hg if there is no evidence of protein in the urine. The goal for patients

with isolated systolic hypertension (180 mm Hg) is 160 mm Hg; further

reductions to 140 mm Hg are suggested if the treatment is well tolerated.

The goal for patients with renal insufficiency should be <120/80 mm Hg with

a mean blood pressure <93 mm Hg.

Treatment should be initiated with a no-salt added diet and weight loss (for

obese patients) combined with appropriate aerobic exercise. Because patients

with diabetes can be uniquely impacted by certain side effects of

antihypertensives, physicians must be familiar with the potential

complications with the various classes of antihypertensive drugs (Table

15.1).

In general, reductions in systolic or diastolic blood pressure of 5% to 10%

occur with most antihypertensives. The potential benefits of the commonly

prescribed antihypertensives are shown in Table 15.2. Treatment guidelines

include:

* One or more antihypertensive medications may be necessary to achieve

satisfactory blood pressure control.

* Adding a second drug to small or moderate doses of the first drug

often results in better control with fewer side effects than using full

doses of the first agent.

DCMS17_Edelman_Tab15-1DCMS17_Edelman_Tab15-2

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors and now the ARBs commonly are the first choices for therapy

because they are effective and have a low incidence of side effects. They

are useful in diabetic patients with and without nephropathy. In the UKPDS,

the ACE inhibitor captopril was equally efficacious as the beta-blocker

atenolol in reducing microvascular and CV complications of Type 2 diabetes.

They have no negative impact on carbohydrate or lipid metabolism, can slow

the rate of progression of proteinuria in diabetic nephropathy, reduce the

decline in renal function, and prevent progression of retinopathy. Caution

should be used in patients with peripheral occlusive disease because renal

artery stenosis may be present, which could lead to renal decline with ACE

inhibitors.

ACE inhibitors have now been shown to be cardioprotective in addition to

having beneficial effects on the diabetic kidney. The Heart Outcomes

Prevention Evaluation (HOPE) trial studied more than 3500 subjects with

diabetes who had documentation of previous CV events and were over 55 years

of age. Subjects were randomized to either ramipril (10 mg/day) or placebo

and vitamin E or placebo. Within 4.5 years, the ramipril-treated group

experienced a 22% reduction in MI, a 33% reduction in stroke, a 37%

reduction in any CV event, and a 24% reduction in the development of overt

nephropathy when compared with the placebo group. These benefits occurred

despite minor reductions in blood pressure, raising the possibility that ACE

inhibitors have benefits for diabetic patients independent of blood pressure

lowering. In summary, the HOPE study is a landmark study confirming the

results of multiple smaller and less-powered studies demonstrating the

cardiac and renal protective effects of ACE inhibitors in subjects with

diabetes. Based on the results of these studies, ACE inhibitors should be

considered as first-line therapy in diabetics with mild to-moderate

hypertension and/or microalbuminuria or macroalbuminuria.

Serum potassium should be monitored during therapy with ACE inhibitors in

patients with suspected hyporeninemic hypoaldosteronism (Type IV renal

tubular acidosis) to prevent severe hyperkalemia.

Angiotensin II Receptor Blockers

Like the ACE inhibitors, ARBs have been shown to slow the progression of

albuminuria and to be protective in diabetic nephropathy. There is some

evidence from the Candesartan and Lisinopril Microalbuminuria study that

combining an ACE inhibitor and an ARB reduces blood pressure and urinary

albumin levels more than either agent alone.

â-Blockers

â-Blockers are being used more frequently as antihypertensive agents

following the beneficial effects reported with atenolol in the UKPDS.

Besides equal efficacy to the ACE inhibitor captopril, atenolol did not

cause an increased incidence of hypoglycemic episodes. However, it is

probably prudent to avoid â-blockers in patients with a history of severe

hypoglycemia or hypoglycemic unawareness. The potential to blunt

counterregulatory responses or prolong hypoglycemia needs to be weighed

against the clear-cut benefits of â-blockers to reduce mortality in diabetic

patients with recent MI. Selective â-blockers may be more beneficial than

the nonselective â-blockers and have a lower incidence of side effects.

á-Blockers

Adrenergic blockers have been associated with improved insulin sensitivity

and modest decreases in LDL cholesterol, but no long-term randomized studies

have been conducted examining renal or CV outcomes. Orthostatic hypotension

can occur, so caution should be used in patients with diabetic autonomic

neuropathy.

Calcium Channel Blockers

There are three subclasses of CCBs: the dihydropyridine group (DCCBs) and

the benzothiazepines and phenylalkylamines (NDCCBs). The DCCBs are a

heterogenous class of compounds with significant pharmacologic differences

and a primary vasodilatory effect. Due to conflicting evidence, it is

unclear whether the DCCBs reduce CV events or progression of nephropathy.

They may protect against stroke but appear to be less effective than ACE

inhibitors in reducing CV events. An increase in CV mortality has been

reported with the short-acting DCCB nifedipine. Short-acting DCCBs are not

approved for and should not be used to treat hypertension in diabetic

patients.

Use of the NDCCBs has been associated with decreased proteinuria in

short-term studies of patients with overt diabetic nephropathy.

Next Week: Use of Diuretics and Dyslipidemia

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