In 1997, the Joint National Committee on Detection, Evaluation and Treatment of Hypertension recommended that diuretics or beta blockers be considered as the preferred initial drug therapy for the management of patients with uncomplicated hypertension. Currently, however, the number of prescriptions written for calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors exceeds the number of prescriptions written for diuretics and beta blockers. One of the reasons for using ACE inhibitors and calcium channel blockers is concern about the potentially detrimental effects of diuretics and beta blockers on plasma lipids and lipoprotein profiles (PLPP). Changes in PLPPs in response to long-term therapy with commonly used antihypertensive agents have not been well studied. Lakshman and associates compared the long-term effects of six different antihypertensive drugs and placebo on PLPPs.

The multicenter, randomized, double-blind, parallel-group trial was conducted in 15 Veterans Affairs medical centers. A total of 1,292 ambulatory men with diastolic blood pressures ranging from 95 to 109 mm Hg were randomized to receive placebo or one of six antihypertensive agents: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem or prazosin. After drug treatment, patients with a diastolic blood pressure level of less than 90 mm Hg were followed for up to one year. The primary outcome measure was the percentage of patients achieving a diastolic blood pressure of less than 90 mm Hg at end titration and maintaining the diastolic measurement at less than 95 mm Hg throughout one year. Plasma PLPPs were determined at baseline, after initial titration and at one year.

The first comparison was among various drug treatment groups from baseline to end of titration. A decrease of 9.3 mg per dL (0.25 mmol per L) in total cholesterol after eight weeks of prazosin therapy was significantly different from an increase of 3.3 mg per dL (0.10 mmol per L) after hydrochlorothiazide treatment. A decrease of 5.4 mg per dL (0.15 mmol per L) in apolipoprotein B (ApoB) during prazosin therapy differed significantly from an increase of 2.7 mg per dL (0.05 mmol per L) after diuretic therapy. A decrease of 0.38 mEq per L (0.38 mmol per L) in serum potassium levels after hydrochlorothiazide treatment was significantly different from changes in all other treatments. An increase of 6.7 mg per dL (0.4 mmol per L) in fasting glucose levels in the hydrochlorothiazide group was significantly different from no change in the atenolol group and decreases of 3.2 and 1.4 mg per dL (0.2 and 0.1 mmol per L) in the captopril and placebo groups.

The next comparison was calculated between baseline and after titration. The following decreases in values after titration with prazosin were significantly different from baseline values: triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, apolipoprotein A (ApoA) and ApoB. Clonidine only decreased ApoA. The various drugs also caused the following changes: hydrochlorothiazide decreased serum potassium, atenolol increased serum potassium, captopril increased serum potassium and hydrochlorothiazide increased serum glucose.

A comparison of the study medications from baseline after one year of treatment was performed. Comparison of treatment groups indicated the following changes: atenolol and clonidine decreased HDL cholesterol and clonidine also decreased ApoA. Prazosin decreased levels of HDL-3 cholesterol, and placebo increased levels of HDL-2 cholesterol. Hydrochlorothiazide decreased serum potassium and increased serum glucose. These changes were significantly different from changes in all other groups.

A comparison of plasma lipid parameters in responders and nonresponders to hydrochlorothiazide showed dramatic differences. The effects of hydrochlorothiazide in increasing levels of plasma triglyceride, total cholesterol and LDL cholesterol were found only in nonresponders. The increased titration to higher doses of hydrochlorothiazide probably accounted for the adverse effects on PLPPs in nonresponders and reflected neuroendocrine stimulation. In contrast, hydrochlorothiazide had no significant adverse effects on PLPPs in responders and yet significantly lowered both diastolic and systolic blood pressure compared with nonresponders. Therefore, it appears that low-dose hydrochlorothiazide can be safely prescribed for long-term monotherapy of hypertension in responders.

The authors conclude that none of the drugs had any significant adverse effects on any of the lipid parameters, although hydrothiazide and atenolol tended to cause short-term increases in triglyceride, cholesterol and ApoB levels at the end of titration. The fact that all lipid parameters were unaffected by any of the drugs at one year strongly supports the conclusion that none of the drugs has any long-term adverse effects with respect to coronary heart disease in men. Concern about long-term PLPP effects with any of these antihypertensive agents should be minimal.