General Considerations in Selecting A&hypertensive Agents in Patients with Type II Diabetes Mellitus and Hypertension LENNART’ANDR~N, M.D., Ph.D. Goteborg, Sweden

The Working Group on Hypertension in Diabetes recommends starting pharmacologic treatment of hypertension with a small dose of a thiazide, beta-blocker, prazosin hydrochloride, angio- tensin-converting enzyme inhibitor, or calcium chanriel blocker. Thus, these alternatives are re- garded as first-line treatment in hypertensive pa- tients with diabetes mellitus. Both thiazides and beta-blockers can cause deterioration in glycemic control and have an unfavorable influence on the lipoprotein profile. These metabolic side effects may partly counteract beneficial effects. Non- selective beta-blockers should probably be avoided in diabetic patients, since blockade of the beta-2 receptor may be associated with a compromise in peripheral blood flow and with problems associ- ated with hypoglycemia. Cardioselective beta- blockers, which may have primary preventive ef- fects on coronary disease, are beneficial in this patient group. In patients with non-insulin-depen- dent diabetes mellitus without nephropathy or overt fluid retention, diuretic therapy could be replaced by sodium restriction and/or calcium chamiel blocker therapy, since these agents also have a mild diuretic effect. Calcium channel blockers, angiotensin-converting enzyme inhibi- tors, and prazosin hydrochloride have minimal metabolic side effects, making them suitable for treatment of hypertension in this patient group.

From the Department of Medicine, Ostra Hospital, University of Gbteborg, Gdteborg, Sweden. Requests for reprints should be addressed to Dr. Lennart AndrBn, Depari- rne”,t of Mediune, Ostra Hospital, University of Gdteborg, S-416 85 Gdteborg, Swe-

T he prevalence of hypertension among diabetic patients is high. Estimates vary between 10 and

80 percent in different populations [1,2]. Both systolic and diastolic elevations in blood pressure are associ- ated with an increased mortality rate among diabetic patients [3,4]. Because blood pressure reduction de- creases secondary complications of diabetes mellitus, treatment of hypertension in diabetic patients is very important [5-71.

NONPHARMACOLOGIC TREATMENT The risk profile of hypertensive diabetic patients

may be affected by nonpharmacologic intervention. Thus, a program of weight reduction, smoking cessa- tion, sodium and fat restriction? and alcohol modera- tion should be instituted in addition to suitable phar- macologic antihypertensive treatment [2].

PHARMACOLOGIC TREATMENT The Working Group on Hypertension in Diabetes

recommends a small dose of a thiazide diuretic, beta- blocker, prazosin hydrochloride, angiotensin-convert- ing enzyme (ACE) inhibitor! or calcium channel blocker as initial pharmacologic treatment of hyper- tension. All of these drugs are considered potential first-line therapy in hypertensive patients with diabe- tes mellitus. However,the differences in metabolic side effects for these various agents render some more appropriate than others in treating hypertensive pa- tients with concomitant diabetes.

Thiazide diuretics and beta-blockers may cause a deterioration of glycemic control and have an unfavor- able effect on lipoproteins [8-X]. Beta-blockers with intrinsic sympatheticomimetic effects have less influ- ence on lipoproteins [15], and cardioselective beta- blockers have less effect on glucose homeostasis than non-selective beta blockers [17,18]. The antihyperten- sive effect of beta-blockers is mediated through block- ade of beta-l receptors, and nothing is gained by addi- tional blockade of the beta-2 receptors. It therefore is reasonable to avoid giving non-selective beta-blockers to patients with diabetes mellitus because they have a more negative impact on glycemic control, may aggra- vate hypoglycemic problems, and may further com- promise peripheral blood flow [17,18]. Cardioselective beta-blockers may, however, be used, and their po- tential primary preventive effects on coronary disease are highly beneficial to this patient group [19]. Thia- zide diuretics have serious metabolic side effects that may counteract their beneficial effects [8-121. In dia- betic patients with nephropathy, thiazides are less ef- fective, and loop diuretics are a more appropriate choice. In non-insulin-dependent diabetes mellitus without nephropathy or overt fluid retention, sodium restriction alone, or in combination with a calcium

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SYMPOSIUM ON DIABETES AND HYPERTENSION / ANDREN

channel blocker, which also has some diuretic effects, is a better choice [20,211.

Prazosin is a postsynaptic alpha-l adrenoceptor blocker. Its antihypertensive effects are well docu- mented and it has a positive metabolic profile [22,23]. The drug may be used for treatment of diabetic hyper- tensive subjects. Although orthostatic hypotension may be a complication of prazosin therapy, some of these effects can be avoided if the initial dose is low.

ACE inhibitors are effective antihypertensive agents, do not affect the lipoproteins [24-301, and do not impair glucose control. In contrast, lowered blood glucose and hemoglobin A,c levels have been reported [29,30]. ACE inhibitors reduce proteinuria, slow down the progression of renal disease in diabetic patients with nephropathy [‘7,31-331, and also have positive effects on quality of life [34]. Thus, ACE inhibitors ameliorate secondary complications of diabetes with- out serious side effects and are a good choice for treat- ment of hypertension in diabetic patients.

Calcium channel blockers have a great potential to influence carbohydrate homeostasis because there are many calcium-dependent processes involved in glyce- mic control [35-381. Calcium channel blockers inhibit insulin release in vitro [39,40]. In vuivo, however, few reports are available regarding negative effects of cal- cium channel blockers on glycemic control [41-471. It is clear that an overdose of verapamil can induce hy- perglycemia [41], and there are undoubtedly some persons who are susceptible to nifedipine and diltia- zem [45-471. There have been more studies of the dia- betogenic effects of nifedipine [42-441 than of the other available calcium channel blockers.

Verapamil, the dihydropyridines, and diltiazem are all potent antihypertensive agents [48-551. Verapamil improves glucose control in diabetic patients [56], or is at least neutral [48]. Nifedipine may impair glucose homeostasis in some patients [42-461, but seems to be neutral in most patients [57-621. Fewer studies have been conducted with the newer dihydropyridines. Studies with nitrendipine, nicardipine, nisoldipine, and felodipine have not revealed any negative effects of these drugs on glycemic control in non-insulin- dependent diabetic patients [58,63-661. Diltiazem does not seem to affect glucose homeostasis [53, 67,681. Calcium channel blockers also have a favorable effect on lipoprotein profile [48,53,69] and may be used for treatment of angina pectoris [70,71]. Diltia- zem is also effective in preventing early re-infarction and severe angina pectoris after a non-Q-wave myo- cardial infarction [72]. Calcium channel blockers are efficacious for antihypertensive treatment of non- insulin-diabetic patients. Because coronary artery dis- ease is common in these patients, calcium channel blockers, especially diltiazem, may be a good alterna- tive to cardioselective beta-adrenoceptor blockers.

In summary, calcium channel blockers, ACE inhibi- tors, and prazosin hydrochloride do not have negative metabolic side effects. These agents are therefore a good alternative for treatment of hypertension in non- insulin-dependent diabetic patients. As with all new drugs, more long-term studies are needed to evaluate the incidence of less common effects. The role of the calcium channel blockers and ACE inhibitors in the treatment of diabetic hypertension will probably in- crease in the future, and the use of non-selective beta- blockers and thiazide diuretics will probably decline.

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