Treatment of hypertension in patients with diabetes mellitus - PowerPoint Presentation

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Treatment of hypertension in patients with diabetes mellitus

This

topic will review the pathogenesis of hypertension in patients with diabetes mellitus and the three major treatment issues:

The evidence supporting benefit from the treatment of hypertension

The choice of antihypertensive drugs

The goal blood pressure

INTRODUCTION AND PREVALENCE

Hypertension is a common problem in

pts

with both type 1 and type 2

diabetes

PATHOGENESIS

 In addition to the development of diabetic nephropathy, at least three other factors have been proposed to contribute to hypertension in diabetes

:

Hyperinsulinemia

Extracellular

fluid volume

expansion

Increased

arterial

stiffness

Hyperinsulinemia 

This hypertensive response, although not noted in all studies, may be mediated by concurrent weight gain and by the

prohypertensive

effect of insulin.

Hyperinsulinemia

may be a link to explain the association between obesity and hypertension both in

nondiabetic

patients and those with type 2 diabetes, since insulin can increase sympathetic activity and promote renal sodium retention.

Volume expansion

 Sodium retention and volume expansion may be induced both by insulin and the hyperglycemia-induced increase in the filtered glucose load

The

excess filtered glucose is reabsorbed (as long as there is only moderate hyperglycemia) in the proximal tubule via a sodium-glucose

cotransporter

, resulting in a parallel rise in sodium

reabsorption

Thus, salt loading tends to raise the blood pressure, an effect that can be reversed by salt

restriction

Increased arterial stiffness

 Patients with diabetes have increased vascular stiffness, which is thought to be a consequence of increased protein

glycation

and, at a later stage,

atheromatous

diseas

The reduction in arterial

distensibility

, which is seen with both impaired glucose tolerance and overt diabetes, can contribute to the rise in systolic pressure and is associated with mortality risk

BENEFIT OF TREATMENT  

Early

treatment of hypertension is particularly important in diabetic patients both to prevent cardiovascular disease and to minimize progression of renal disease and diabetic retinopathy

Among patients with type 2 diabetes, the benefits of tight blood pressure control may be as great or greater than the benefit of strict

glycemic

control

nitial

therapy should include

nonpharmacologic

methods, such as weight reduction, increased consumption of fresh fruits, vegetables, and low-fat dairy products, exercise, salt restriction, and avoidance of smoking and excess alcohol ingestion.

Among

patients with a

SBP of

130 to 139 mmHg, or a diastolic pressure of 80 to 89 mmHg, initial therapy should consist of

nonpharmacologic

methods

If target blood pressure is not achieved after three months, treatment with pharmacological agents should be initiated.

Since hypertension places diabetic patients at high risk for cardiovascular complications, all diabetic patients with persistent blood pressures above 140/90 mmHg should be started on antihypertensive drug therapy

CHOICE OF ANTIHYPERTENSIVE DRUGS

ACE

inhibitors 

 — When antihypertensive drugs are used,

angiotensin

converting enzyme (ACE) inhibitors offer a number of advantages:

They lower the blood pressure, although no drug is likely to be sufficient as

monotherapy

.

They have no specific toxicity, except for cough and raising the plasma potassium concentration in patients with underlying

hyperkalemia

or renal

insufficiency

They have no adverse effects on lipid metabolism.

They may lower the plasma glucose concentration by increasing responsiveness to insulin.

A

possible effect of ACE inhibitors in reducing the incidence of new onset type 2 diabetes is discussed

elsewhere.

They protect against the progression of moderately increased

albuminuria

(formerly "

microalbuminuria

") and severely increased

albuminuria

(formerly "

macroalbuminuria

") due to type 1 and 2 diabetes and have been evaluated for primary prevention of diabetic nephropathy.

They may slow the progression of retinopathy.

Angiotensin II receptor blockers 

ARBs

appear to have the same benefits as ACE inhibitors described in the preceding section.

major

trials,

demonstrated

a clear benefit in terms of

renoprotection

with ARBs in patients with nephropathy due to type 2 disease

This

was also seen in early type 2 diabetes with normal kidney function and

normoalbuminuria

or moderately increased

albuminuria

in whom

an ACE inhibitor was at least as effective as an ARB

ACE inhibitor plus ARB 

  A separate issue is whether an ARB should be given with an ACE inhibitor

.

In the CALM trial of 199 hypertensive patients with type 2 diabetes with moderately increased

albuminuria

(formerly "

microalbuminuria

"), 

lisinopril

(20 mg/day) and 

candesartan

(16 mg/day) produced equivalent reductions in blood pressure that were significantly less than the response seen with combination therapy (14.1/10.7 and 16.7/10.4 versus 25.3/16.3) 

However, combination therapy was not compared to higher doses of either agent alone.

Calcium channel blockers 

 Somewhat similar considerations (efficacy and lack of adverse effects of lipid or carbohydrate metabolism) apply to the

nondihydropyridine

calcium channel blockers ( 

diltiazem

and 

verapamil

)

However, an ACE inhibitor is still preferred as initial therapy, in part because it appears to be superior to

verapamil

for the primary prevention of diabetic nephropathy among hypertensive patients with type 2

diabetes

Two

major hypertension trials, HOT and

Syst-Eur

, found no evidence of a deleterious effect from a long-acting

dihydropyridine

in diabetic patients

In addition,

amlodipine

was associated with similar rates of coronary mortality and nonfatal myocardial infarction as 

chlorthalidone

and 

lisinopril

in the much larger ALLHAT trial of patients with hypertension and risk factors for cardiovascular disease

However, a 

higher 

rate of heart failure among diabetic patients was observed with

amlodipine

compared with

chlorthalidone

(relative risk 1.42, 95% CI 1.23-1.64), a finding also observed among patients without

diabetes

Similar results in terms of safety and efficacy were reported in a 2004 meta-analysis of 14 studies that evaluated calcium channel blockers in hypertensive diabetic patients

[

A separate question is the role of calcium channel blockers in combination

therapy

Amlodipine

may provide better protection against cardiovascular events than low-dose 

hydrochlorothiazide

when

both are used in combination with an ACE inhibitor

Beta blockers 

 Although there are concerns about masking of hypoglycemic symptoms and possible exacerbation of peripheral artery disease, beta blockers are effective therapy for hypertension in diabetic patients

.

In the UKPDS study of patients with type 2 diabetes, 

atenolol

was as effective as 

captopril

in terms of both blood pressure lowering and protection against

microvascular

disease

Carvedilol

is a combined nonselective beta- and alpha-1 adrenergic antagonist that improves survival in patients with heart failure and may have certain advantages compared to other beta blockers in patients with

diabetes

The

Atherosclerosis Risk In Communities study (ARIC) study found that, among hypertensive patients who did not have diabetes, beta blocker therapy (but not 

carvedilol

) was associated with a 28 percent increased risk of developing type 2 diabetes compared to no antihypertensive therapy; this relationship was not seen with

thiazides

, calcium channel blockers, or ACE inhibitors 

alpha blockers

Although

not widely used as primary therapy in diabetes because of side effects such as orthostatic hypotension, peripheral alpha blockers (such as 

doxazosin

) are as effective in lowering blood pressure as ACE inhibitors and calcium channel blockers and have a more favorable metabolic profile

SUMMARY AND RECOMMENDATIONS

The

prevalence and time of development of hypertension in patients with diabetes mellitus varies with the type of diabetes.

Among patients with type 1 diabetes, the incidence of hypertension rises from 5 percent at 10 years' duration, to 33 percent at 20 years, and 70 percent at 40 years.

The

blood pressure typically begins to rise within the normal range at or within a few years after the onset of moderately increased

albuminuria

(formerly "

microalbuminuria

") and increases progressively as the renal disease progresses.

Among patients with type 2 diabetes, as many as 40 percent are hypertensive at the time of diagnosis and, in approximately one-half of these patients, the elevation in blood pressure occurred 

before 

the onset of moderately increased

albuminuria

.

Choice of antihypertensive agents

An ACE inhibitor or ARB is clearly preferred as initial therapy in any hypertensive diabetic patient who has moderately increased

albuminuria

(formerly "

microalbuminuria

") or severely increased

albuminuria

(formerly "

macroalbuminuria

") in an attempt to slow renal disease progression

.

Most experts will also begin with an ACE inhibitor or ARB in hypertensive diabetic patients without

proteinuria

. This is unlikely to occur in patients with type 1 diabetes in whom moderately increased

albuminuria

typically precedes

hypertension

Goal blood pressure 

Major

guidelines, published before the ACCORD BP trial, suggested that the goal blood pressure in patients with diabetes mellitus is less than 130/80 mmHg

.

However, there are no convincing data supporting this approach, with the possible exception of patients with diabetic nephropathy and

proteinuria

in whom weak evidence suggests that such a goal may slow the rate of progression of the

nephropathy

We recommend a goal blood pressure of less than 140/90 mmHg compared with higher pressures in all patients ( 

Grade 1B 

).

We suggest (a weaker recommendation) an attempt to lower the systolic pressure below 130 to 135 mmHg (preferably less than 130 mmHg) if it can be achieved without producing significant side effects ( 

Grade 2B 

).

We recommend a goal blood pressure of less than 130/80 mmHg compared with higher pressures in patients with diabetic nephropathy and

proteinuria

(500 mg/day or more) ( 

Grade 1B 

).

For patients who fulfill the entry criteria in ACCORD BP (type 2 diabetes plus either cardiovascular disease or at least two additional risk factors for cardiovascular disease), the authors and reviewers of this topic suggest that the risks and burdens of aiming for a goal systolic pressure of less than 120 mmHg (more side effects, extra patient visits, and increased cost) plus the lack of experience of almost all physicians in attaining such a goal may be too great a burden to achieve the small reduction in stroke that may be attained (absolute benefit 1 in 89 patients at five years).

However

, such a goal may be considered in highly motivated patients who would accept more aggressive antihypertensive therapy to further reduce their risk of stroke.