Arterial Disease

Arterial Disease

In type 2 diabetes there is evidence of increased arterial stiffness. This phenomenon may explain why the BP elevation is predominantly of systolic nature in these patients. Diastolic BP is usually also elevated, but often to a

lesser extent unless overt renal damage is present. The hypothesis that large vessel disease produces systolic elevation of BP, which in turn increases albu- minuria and provokes renal damage, is intriguing. BP reduction may reduce albuminuria but could also potentially provoke ischemia in other organs, e.g. the brain or the heart. Treatment therefore may often be difficult and stepwise reduction is recommended. These limitations clearly support the concept of early antihypertensive treatment in these individuals, e.g. in patients with microalbuminuria long before too severe hypertension.

Of note, patients with essential hypertension do show insulin resistance and/or hyperinsulinemia. Since insulin resistance is also a mechanism involved in the pathogenesis of type 2 diabetes, insulin resistance may also contribute to BP elevation in diabetes. Indeed, elevated BP is found early in the course of type 2 diabetes right from the time of diagnosis, where insulin resistance probably is an important phenomenon.

There are other abnormalities that may be involved in the genesis of hypertension in diabetes, such as increased sympathetic nervous activity pro- ducing increased vascular reactivity. This may also be related to obesity. How-

Table 2. How antihypertensive agents may be combined in diabetes b -Blockers

Yes (diuretics often required)

ACE inhibition Yes (diuretics

Yes (theoretically interesting or angiotensin

Yes

often required) combination, results promising) receptor blockers

Ca blockers 1 Yes (diuretics

Yes (often used; often required)

Yes (rarely used) Yes (rarely used)

also with diuretics) Diuretics

ACE inhibition Careful clinical metabolic and BP monitoring always required, including control of serum electrolytes and

b -Blockers

b -Blockers + diretics

serum creatinine of GFR index (combination therapy used in more than 50% of patients). 1 Some results suggest cardiovascular long-term effect less favorable than with ACE inhibition in type 2

diabetes.

ever, since these phenomena may not point clearly to specific modalities of treatment, they will not be further discussed.

Treatment of BP Elevation

Mechanisms of BP Elevation and Choice of Therapy in Nephropathy Based upon the known mechanisms operating in the genesis of hyperten-

sion, some interesting concepts regarding selection of antihypertensive treat- ment are evolving in diabetes. The abnormalities in renal function, where hyperfusion, hyperfiltration and increased glomerular pressure may be impor- tant mediators, favor the use of ACE inhibitors, since these agents tend to reduce efferent glomerular resistance. This effect, operating by reducing glomerular pressure, may even to some extent be independent of systemic hypertension or systemic BP level. The sodium retention evident in both type

2 and type 1 diabetes supports the use of diuretics and sodium restriction in antihypertensive programs in diabetes. The early cardiac hyperfunction in microalbuminuric patients may suggest the use of cardioselective b-blockers to reduce this hyperfunction. Obviously, the generalized BP reduction seen with all these agents may be of prime importance, but these mechanisms could also favor the use of combined treatment: ACE inhibitors, diuretics and

possibly b 1 -blockers (or other agents) in diabetic patients (table 2). Calcium blockers reduce BP, and may be important in therapy although some, but decreasing, controversy exists.

Table 3. Diabetes-related side effects and favorable effects related to antihypertensive treatment in diabetics (mainly type 1 diabetes)

Calcium blockers Angiotensin or loop)

Diuretics (thiazide Noncardio-

Cardioselective

ACE inhibitors

Triple treatment:

selective

b -blockers

diuretic b 1 -blockers/ receptor

blockers Glucose intolerance Yes, type 2, but

b -blockers

ACE inhibitors

Limited or no change No No related strongly

No problem

No problem

No side effects

Insulin sensitivity (with small dosages) to hypokalemia)

not changed clinically

Hypoglycemic No

Limited or no change No No masking

Yes, mainly

A problem, but

Not seen

in type 1

limited, seen in

(with small dosages)

diabetes

few patients

Unfavorable lipid Yes, but not with

No No profits

Likely

Limited or

No side effects

small doses

nonexisting

Other unfavorable May cause

Foot edema seen No effects

Less physical

Less physical

Coughing and

Limited (with

sodium depletion exercise

exercise capacity drug-related side small dosages)

in few patients

capacity

effects (uncommon)

No potentiation Under (apart from BP

Favorable effects Elimination of

Reduction of

Reduction of

Elimination

Probably also

of peripheral investigation reduction)

edema

cardiovascular cardiovascular

sodium excess

combination of

morbidity/

morbidity/

and possibly

favorable effects

restoration of

(stable GFR?)

Normalization Normalization

glomerular

of cardiac

of cardiac

pressure gradients

arrhythmias?

arrhythmias?

Related to BP Yes abnormal

Effect on Not well

Not well

Yes, but relatively Very consistent

Addition of ACE

reduction albuminuria

documented

documented

few studies exist

finding

inhibition reduces

abnormal albuminuria Reducing fall rate

Not documented Ungoing of GFR

Not documented

GFR stable on

documented

this program

studies

Obviously, from a theoretical point of view, potential additional beneficial effect should be considered (table 3). For example, ACE inhibitors may as

suggested specifically reduce the localized increased pressures seen in these patients, as originally observed in animal studies. The presence of edema of course favors the use of diuretics. It is suggested that arrhythmias may play

a role in the early mortality, especially in type 2 diabetic patients, and the observation that in trials in patients at risk b-blockers are especially effective

in diabetic patients points to additional beneficial effects of b-blockers in the management of hypertension in diabetics where cardial disease and silent myocardial infarctions are not uncommon. Importantly, in heart failure b-

blockers are increasingly being used according to new trials, e.g. the Merit HF Study.

Clearly, side effects are important and these are usually dose related. For example, the well-known diabetogenic effect of diuretics may be dose dependent with sufficient BP reduction with small doses that are not diabetogenic. Potas- sium loss is important but can readily be restored by potassium supplemen- tation or by the use of ACE inhibition. Also small doses of diuretics may Clearly, side effects are important and these are usually dose related. For example, the well-known diabetogenic effect of diuretics may be dose dependent with sufficient BP reduction with small doses that are not diabetogenic. Potas- sium loss is important but can readily be restored by potassium supplemen- tation or by the use of ACE inhibition. Also small doses of diuretics may

blockers but is only of minor importance with cardioselective b-blockers and the phenomenon is not important in type 2 diabetics that may especially benefit from cardioprotection by b-blockers. Most ACE inhibitors do certainly not possess any diabetogenic effects, rather they are neutral. Thus there is no negative effect on glucose metabolism or lipid homeostasis; a positive effect has in fact been observed in some studies. This positive or rather neutral pattern may therefore favor the use of ACE inhibitors in diabetic patients. Importantly, no increased frequency of hypoglycemia is seen in clinical practice. Coughing as a side effect is surprisingly rare in diabetic patients, possibly due to diabetic neuropathic changes. The new angiotensin II receptor antagonists could be considered in this situation, also with other side effects caused by ACE inhibitors.

Problems of Optimized Glycemic Control During Antihypertensive Treatment In recent years it has become increasingly clear that good glycemic control

is of clear importance in the prevention and postponement of diabetic renal disease. As documented in the DCCT, good glycemic control can reduce the number of patients that develop advancing renal disease. Improved metabolic control seems also to protect against deterioration in renal function in patients with microalbuminuria. However, it is important to stress that it is quite often difficult to obtain good metabolic control, especially in patients with incipient or overt renal disease. There are no formalized long-term trials with a sufficient number of patients on the effect of optimized diabetes care in patients with overt renal disease. However, new studies strongly suggest a correlation between progression in renal disease, as measured by fall rate of GFR and level of

HbA 1c . If HbA 1c is satisfactory, with values around 7–8% (reference value 5.5%), progression is slow. This observation was recently confirmed. In patients with type 2 diabetes, progression can be reduced by early intervention. With

overt nephropathy there is no correlation between progression and HbA 1c . The UKPDS clearly documented the role of good glycemic control in preventing microvascular complications.

Intervention Trials in Normoalbuminuria Even in type 1 diabetic patients with normal BP and normal albumin

excretion, renal hemodynamics may be beneficially influenced by ACE inhibi- tion. This study was of experimental nature and treatment of such individuals cannot be recommended, although a trial should be conducted in high-risk normoalbuminuric patients (high normal UAE (?12 lg/min), high HbA 1c

(?9–10%)). However, the Euclid Study did not document any clear effect in normoalbuminuria in a 2-year trial, but longer intervention is likely to be

positive, according to unpublished studies from Denmark.