The effects of clonidine hydrochloride versus atenolol monotherapy on serum lipids, lipid subfractions, and apolipoproteins in mild hypertension

The effects of clonidine hydrochloride versus atenolol monotherapy on serum lipids, lipid subfractions, and apolipoproteins in mild hypertension The study objective was to determine the effects of monotherapy with clonidine and atenolol versus placebo on serum lipids, apolipoproteins, and blood pressure in patients with mild primary hypertension. The protocol comprised a double blind, randomized, placebo-controlled g-month prospective study carried out in an outpatient general internal medicine clinic in a unlversity medical center. There were 92 patients ages 18 to 70, with mild primary hypertension (sitting diastolic blood pressure of > 90 mm Hg and < 105 mm Hg) without significant cardiac, renal, cerebrovascular, hepatic, neoplastic, or hematologic disorders. Patients with severe hyperlipidemia or peripheral vascular disease were also excluded. All factors known to effect serum llpids were held constant throughout the study (i.e., diet, weight, exercise, caffeine, tobacco). Atenolol and clonidine significantly reduced blood pressure when compared with placebo. Atenolol caused significant increases in serum triglycerides and apolipoprotein 6 (p < 0.05) and significant reductions in high-density lipoprotein-cholesterol, apolipoproteins A-l and A-II @ < 0.05). Atenolol also induced a significant adverse effect on all lipid ratios, increasing total cholesterol/high density lipoprotein-cholesterol, low density lipoprotein-cholesterol/high density lipoprotein-cholesterol, apolipoprotein BIapolipoprotein A-l and apolipoprotein B/apolipoprotein A-II ratios and decreasing low density lipoprotein-cholesterol/apolipoprotein-B ratio (p < 0.05). Clonidine caused significant reductions in high-density lipoprotein-cholesterol, apolipoproteins A-l and A-II (p < 0.05 but was neutral on all other lipids, lipid subfractions, and apolipoproteins. Clonidine did not significantly alter any of the lipid ratios. It was concluded that monotherapy with either clonidine or atenolol was equally effective in reducing blood pressure when compared with placebo. Overall, atenolol had an unfavorable effect on serum lipids, whereas clonidine had a neutral effect on serum lipids. These lipid changes must be considered in the overall evaluation of coronary heart disease risk when hypertensive patients are treated. (AM HEART J 1990;120:172.)

Mark C. Houston, MD, Candice Burger, PhD, James Taylor Hays, MD, John Nadeau, MD, Larry Swift, PhD, Charles A. Bradley, PhD, and Laurie Olafsson, RN. Nushuille, Tenn. In the clinical hypertension trials published to date, the pharmacologic treatment of mild to moderate hypertension (diastolic blood pressure 5114 mm Hg) has not convincingly reduced coronary heart disease morbidity, mortality, or myocardial infarction. However, incidents of stroke, congestive heart failure, and renal insufficiency were reduced.l-I1 The reasons for these reductions are unclear, but it has been proposed that certain antihypertensive drugs that were From the Departments of Medicine and Clinical Pharmacology-Hypertension and Pathology, Vanderbilt University Reprint requests: General Internal Ave. and Pierce 4/1/20456

172

(Division

of General Internal Medicine Specialized Center of Research), Medical Center, Nashville, Term.

Mark Houston, MD, Department Medicine, Vanderbilt University, St., Nashville, TN 37232.

of Medicine, Room 2553

Division of TVC, 23rd

used in these trials produced adverse effects on coronary heart disease risk factors that negated the beneficial effects of blood pressure reduction.12-l4 Of particular interest are the adverse effects of diuretics15-23 and /?-adrenergic blocking drugs24-31 on serum lipids, lipid subfractions, and apolipoproteins. Atenolol, a commonly used cardioselective pblocker, causes an increase in serum triglycerides301 32-34 and very low-density lipoprotein30v 31 and causes decreases in high-density lipoproteincholesterol,30, 32,34 HDLz,~~, 34 HDLs,~~ and apolipoproteins A-I and A-II.32l 35-37 Other changes noted include either a slight increase or no change in apolipoprotein B,32* 35-37 total cholesterol,30, 32~34*36,37 and low-density lipoprotein-cholesterol.30, 32s36,37 Such adverse effects on serum lipids (which are sim-

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Atenolol

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(N=30)

Clonidine

(N=31)

Placebo (N=31)

I

Randomized Fig.

8 Weeks

Low Dose

1 Week Taper

1. Study design.Serum lipids measuredat 2-weekintervals starting with the placebo run-in period.

ilar to other &blockers without intrinsic sympathomimetic activity) could counterbalance atenolol’s antihypertensive effect related to coronary heart disease morbidity and mortality. A limited evaluation of clonidine, a central cu-agonist, shows a decrease in total cholesterol,31, 35,38-41 low-density lipoprotein-cholesterol, triglycerides, and very low-density lipoprotein.3g High-density lipoprotein-cholesterol does not change or increases only slightly.3g No published data about clonidine’s effect on HDL2, and HDLs, or apolipoproteins exist at present. Other antihypertensive drugs that improve the serum lipid profile include prazosin,42! 43 terazosin,44 guanabenz,40> 45 guanfacine,31 and the calcium channel blockers-nifedipine, diltiazem, and verapamil.31146-52 To directly assess the actions of clonidine, atenolol monotherapy, or placebo on blood pressure and serum lipids, we compared their effects in a randomized trial group of 92 unmedicated patients with hypertension who were first seen with mild primary hypertension at a general internal medicine clinic. METHODS Participants.

8 Weeks High Dose

Ninety-two patients (between 18 and 70 years of age)with mild primary hypertension (sitting DBP L 90 mm Hg and 5 105 mm Hg) were studied over a period of 5 months. Patients with significant hematologic,renal, hepatic, neoplastic, or peripheral vascular disease(severe hyperlipidemia) (TC 2 400 mg/dl or TG over 1500 mg/dl), hypersensitivity or intolerance to clonidine and atenolol, bradycardia, sinus-nodedysfunction, and heart block were excluded from the study. In addition, there were no patients with congestive heart failure (NYHA ClassIIIV), history of myocardial infarction, angina, coronary heart diseaseor patients with cerebrovascular accident, transient ischemicattacks, diabetesmellitus (fasting blood sugar2 140mg/dl), chronic obstructive pulmonary disease, or asthma. Patients who were taking other antihypertensive drugs, barbiturates, antidepressants, neuroleptic drugs, nasal decongestants,oral contraceptives, corticosteroids, nonsteroidal anti-inflammatory drugs, or other medications known to have an effect on blood pressure and/or serumlipid levels were excluded. This protocol was approved by the Institutional Review Board at this institution, and all patients gave written informed consentfor the study.

Procedure. We recruited 92 patients who had beenfree of all antihypertensive treatment for at least 4 weeks.Patients were randomly assignedto atenolol, clonidine, or placebo (lactose) treatment groups after the 4-week drugfree period (Fig. 1). Both study personneland participants were blinded to the group assignments.Mild hypertension was confirmed at 2-week intervals during a 4-week period during which all patients received placebotwice a day. At the investigator’s discretion, the placebo period was extended for an additional 2 weeksfor three patients to assure a hypertensive baseline. The average of all placebo visits was within the entrance blood pressureof a sitting DBP 2 90 mm Hg and 5 105 mm Hg. Patients were requestedto maintain the samediet, alcohol and caffeine intake, smokinghabits, and exercise program throughout the trial. In addition, they were askedto avoid vigorous exercisewithin the 12-hour fasting period that precededbimonthly clinic visits. During the next 8 weeks,patients received either clonidine 0.1 mg twice a day, atenolol50 mg every morning and matching placeboevery evening, or matching placebotwice a day. For a secondg-week treatment period, the dosage was increased for all patients to either clonidine 0.2 mg twice a day, atenolol 100mg every morning and matching placebo every evening, or two matching placebo capsules twice a day. At the completion of the second&week period, all patients had the study medication tapered over a l-week period and were transferred to the care of their private physicians. Clinic visits occurred every 2 weeksbetween 7 and 11AM. Blood sampleswere drawn with the use of a tourniquet at weeks4,8,10,14, and 16. Blood pressureswere taken with a mercury sphygmomanometerfrom the left arm using phaseV Korotkoff s soundsasthe diastolic blood pressure. After the patient had rested for at least 10 minutes, blood pressureand heart rate were measuredwith the patient in the supine position and repeated in the sitting and standing positions after a 2-minute rest. Reported blood pressuresarethe averagesof three measurementstaken in each position. During the treatment phase, assessmentsof adverseexperiences,medication compliance,and information given in the patient’s daily diary were recorded. Each diary contained detailed information on that patient’s daily diet, amount of exerciseand alcohol, caffeine and tobacco use. In addition, patients were askedfor their perceptions of the medication’s affect on their overall health and on their daily stresslevels during the testing period. Serum Lipid and Apolipoprotein Assays. Triglyceride, total cholesterol, and high-density lipoprotein-cholesterol

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Table I. Pretreatment characteristics of the three treatment groups. Treatment

Characteristic

group

Clonidine In = 31)

Atenolol (n = 30)

Placebo (n = 31)

190 (39) 68 (5) 105 48 (II) 65 26

184 (39) 69 (4) 80 45 (9) 73 13

179 (32) 67 (4) 74

141 (17) 96 (7)

136 (15) 96 (6)

144 (17) 97 (7)

Mean weight (lb) Mean height (in) Mean activity (min/wk) Mean age* Male ( % ) NonCaucasian ( !‘O) Blood pressure, sitting Systolic Diastolic

52 (9) 45 23

*Mean age significantly different between the groups (F =3.37, p < 0.05).

II. Blood pressuremeasuresfor placebo and highdosedrug periods (mm Hg).

Table

Clonidine

Supine systolic Placebo High dose Supine diastolic Placebo High dose Sitting systolic Placebo High dose Sitting diastolic Placebo High dose Standing systolic Placebo High dose Standing diastolic Placebo High dose

Atenolol

Placebo

(SD)

(SD)

(so)

143 (12) 130 (14)

141 (13) 125 (16)

146 (13) 141 (12)

93 (6) 84 (7)

94 (6) 62 (7)

94 (4) 89 (6)

141 (13) 125 (13)

136 (13) 122 (14)

144 (15) 140 (13)

96 (5) 85 (8)

96 (5) 83 (7)

97 (5) 91 (6)

142 (15) 125 (14)

136 (13) 122 (12)

144 (15) 140 (14)

98 (7) 88 (9)

97 (6) 85 (7)

98 (5) 94 (7)

IQQO

Journal

terol calibration procedure. HDLz cholesterol was calculated by subtracting the HDLs cholesterol from the total high-density lipoprotein-cholesterol obtained previously. RESULTS Pretreatment.

Univariate

analyses were used to

compare the three treatment groups’ pretrial characteristics. The groups differed only in average age (Table I), which did not significantly correlate with the reported measures and did not change the results from any reported analysis and, therefore results without age correction are reported here. There were no significant differences between groups related to diet, weight change, exercise, use of alcohol, tobacco, or caffeine initially, during or at the end of the study. Treatment effects. Three blood pressure measurements were taken at each visit in each position (i.e., supine, sitting, standing), and the average was recorded. The average blood pressure from three visits during the period before treatment with drugs and from the two visits during the period of treatment with placebo and high-dose drugs were used in the following analyses. The average of two serum measurements for the placebo and the high-dose periods were used to calculate group differences in the lipid values. Differences within groups were assessed with paired t tests. Change scores from placebo run-in to high-dose drug period were calculated for each measure and used in analyses of variance to assess group differences. Post hoc tests were used to determine pairwise differences in the change scores. Because of lost or spoiled samples, some lab values are missing; however, only participants with at least one measure at both placebo run-in and high-dose drug periods were included in these analyses. Treatment

were quantitated on a Hitachi 705 lipid analyzer (Hitachi: Instruments, Inc., Danbury, Conn.) with enzymatic reagents.53These procedureswere standardized according to the Lipid ResearchClinic Program54with the useof calibrators and controls supplied by the Centers for Disease Control. High-density lipoprotein-cholesterol was isolated by the heparin-2M MnzCi procedure.55Low-density lipoprotein-cholesterol was calculated with the formula of Friedewald et a1.56Apolipoproteins A-I and B were quantitated by electroimmunoassay5”and apolipoprotein A-II by enzyme-linked immunosorbent assay5sHDLs and HDLs cholesterollevels were successivelydetermined. After HDLs was isolated by preparative ultracentrifugation (for 20 hours at 4’ C at a density of 1.125g/ml), the HDLs cholesterol content was quantitated on the Hitachi 705 lipid analyzer with the high-density lipoprotein-choles-

Heart

effects

on blood

pressure.

Change duringplaceboperiod All patients entered the study with elevated blood pressures as determined over three prestudy visits (Table II). There was a significant treatment effect in the multivariate analysis of variance (F(10,172) = 3.11, p < 0.001) for blood pressure changes from the prestudy period to the placebo run-in period. With the exception of the clonidine group, which did not differ from the placebo group in the systolic supine measure, both the clonidine and atenolol groups differed from the placebo control group for all blood pressure measures based on post hoc pairwise comparisons in the analyses of variance of each blood pressure category (p < 0.05). Changes during drug trial When assessment of blood pressures for each position were made during the high-dose drug period in the analyses of covariante (adjusting for age and blood pressure during placebo run-in), F values for the differences between

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Table III. Mean lipid levels and standard deviations from subjects with complete data for placebo and high-dose drug level period Clonidine N=27 Total cholesterol Placebo High dose Triglycerides Placebo High dose HDL total Placebo High dose HDLp Placebo High dose HDLs Placebo High dose LDL Placebo High dose Apo A-I Placebo High dose Apo A-II Placebo High dose Apo B Placebo High dose *Significant tsignificant

(SD)

Atenolol (SD) N = 27

Placebo N=

(SD) 29

212.1 208.8

(19.8) (22.3)

210.3 210.6

(30.7) (29.4)

217.7 216.6

(35.1) (31.8)

152.2 156.8

(65.6) (69.8)

132.2 (60.0) 142.4 (67.8)

151.8 132.9

(78.2) (73.5)*

46.4 (12.4) 45.6 (12.8)

48.2 (10.9) 46.5 (10.5)

49.8 (12.4) 53.8 (12.6)*

15.4 (6.6) 14.1 (5.6)

15.9 (6.4) 15.3 (7.4)

16.6 (7.2) 18.7 (8.4)

30.9 (7.4) 30.7 (7.5)

31.4 (5.6) 31.3 (5.9)

32.9 (6.8) 34.4 (8.2)

139.0 134.8

(22.8) (23.8)

136.8 (28.6) 135.5 (28.6)

141.1 140.3

(29.9) (29.3)

136.1 131.0

(18.4) (20.4)*

139.2 (14.6) 135.4 (17.0)

146.2 151.1

(18.4) (17.4)

56.0 (14.1) 51.5 (11.3)*

53.8 (10.3) 50.6 (11.2)*

54.9 (9.0) 54.2 (10.6)

134.3 (27.0) 144.8 (31.6)*

139.8 (29.8) 137.6 (31.9)

145.8 146.6

(20.2) (18.7)

Group differencesf

p
p < C,AI

P > CAT

p
change by paired t test at p < 0.05 level. group differences based on comparison of change scores.

treatment groups in the supine diastolic, standing systolic, and standing diastolic blood pressures were significant beyond the 0.05 level. In all cases, the two drug groups had lower blood pressures than the placebo group. However, when the p value was adjusted for multiple comparisons, none of these F tests reached the critical p value of 0.008, which confirms the multivariate analysis. Treatment effects on lipid subfractions. Nine lipid subfractions were measured beginning in the placebo run-in period of this study. The average placebo and high-dose drug levels of each measure are shown in Table III. Analyses of both changes within a group and the differences between groups are noted in this table. Changes in the triglyceride levels of the atenolol and placebo groups were significantly different. Triglycerides increased during the study for both clonidine (3%) NS) and atenolol (8%) NS) groups and declined in the placebo (12%) group, which represented the only significant change within groups during the study. Total cholesterol and low-density lipoprotein did

not change significantly within any group over the study, and there were no differences in the amount of change experienced by each group. However, there was a slight decrease in total cholesterol (2%) NS) and low-density lipoprotein-cholesterol (3 % ) in patients who were treated with clonidine. Total high-density lipoprotein-cholesterol change differed significantly between the placebo control and each of the drug groups. High-density lipoprotein declined slightly in the clonidine (2 % , NS) and atenolol(4%, NS) groups (4%) and was statistically significantly increased in the placebo-control (6% ) group. None of the within or between-group changes in HDLz or HDLs were significantly different. There were trends Cp = 0.08) for the change in high-density lipoprotein in the atenolol group and the change in HDL3 among the patients in the placebo-control group, but these were due to the multiple-test strategy adopted here. Differences between both the clonidine and atenolol levels from the placebo patients were approaching significance (p = 0.08) when those with complete lipid data were included. Clonidine- and

July 1990

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Table

Houston et al.

American

Heart

Journal

IV. Placebo and high-dosemean lipid levels for various ratios Clonidine

LDL-C/HDL ratio Placebo High dose Cholesterol/HDL Placebo

Highdose LDL-C/APOB Placebo High dose Apo BlApo A-I Placebo High dose Apo BlApo A-II Placebo High dose *Significant tSignificant

(SD)

Atenolol

(SD)

Placebo

(SD)

3.30 (1.05) 3.25 (0.99)

2.96 (0.79) 3.05 (0.83)*

3.01 (0.97) 2.87 (0.99)*

4.92 (1.25) 4.92 (1.25)

4.56 (1.00) 4.71 (0.99)*

4.67 (1.28) 4.39 (1.31)*

0.95 (0.16) 0.94 (0.14)

1.02 (0.21) 0.95 (0.19)*

1.00 (0.16) I .03 (0.26)

1.10 (0.32) 1.10 (0.34)

0.97 (0.19) 1.08 (0.26)*

0.98 (0.25) 0.94 (0.29)

2.93 (0.94) 3.00 (0.8’7)

2.62 (0.64) 3.01 (0.76)*

2.63 (0.62) 2.70 (0.91)

in paired t test at p < 0.05 level. group difference based on comparison

Group

differences7

P
P < A,C

P
~,f change scores.

atenolol-treated groups had lower levels of apolipoprotein AI (4 % and 3 % , respectively) at the highdose drug phase, and the placebo group had a higher apolipoprotein AI (3 % ) level at the end of the study. The only significant difference in apolipoprotein AI from the predrug period to the high-dose drug period was among the patients in the clonidine-treated group. Although there were no noteworthy differences in change scores among the three groups in apolipoprotein AI1 levels, the atenolol(6 % decrease) and clonidine (8% decrease) groups had significantly lower levels during the high-dose drug period. There was a trend for apolipoprotein B levels in the atenolol group to be larger than those in the placebo group (p = 0.07); however, the atenolol group had a significantly higher level of apolipoprotein B (8 % increase) during the high-dose drug period. An additional way of combining the subfraction measures was considered by calculating ratios of lipid subfractions that have been studied previously. (Mean values of other ratios are found in Table IV). A significant effect appears in the differences in the total cholesterol/high density lipoprotein ratio, lowdensity lipoprotein/high density lipoprotein ratio and apolipoprotein B/apolipoprotein A-I ratio (F = 7.59, p < 0.001) in the treatment groups. Both the clonidine and atenolol groups were different from the placebo group in post hoc comparisons of the total cholesterol/high-density lipoprotein ratio (p < 0.05), but only the atenolol group differed from the placebo group in the low-density lipoprotein/ high-density lipoprotein and apo B/ape A-I ratios (p < 0.05). The level of total cholesteroI/high-density lipoprotein decreased in the placebo-control group during the study. The atenolol group showed a

significant increase in total cholesterol/high-density lipoprotein ratio (3 % ); however, there was no change in the patients treated with clonidine. Based on univariate relationships, the patients treated with atenolol also had significantly higher ratios of low-density lipoprotein/high-density lipoprotein (3 % ), apo B/ape AI (11% ) and apo B/ape A-II (15 % ) and lower low-density lipoprotein/ape B ratio (7%) (paired t test = -3.01, p < 0.01). A significant within-group difference was found among the participants treated with placebo in total cholesterol/high-density lipoprotein and low-density lipoprotein/high-density lipoprotein ratios (p < 0.02). DISCUSSION

Blood pressures were reduced overall during the course of this study. Close supervision of patients with mild hypertension (assumption of a healthier life style, greater patient awareness or other factors) led to a major improvement in blood pressure without an active drug, although atenolol- and clonidinetreated groups experienced further blood pressure improvement. Most notable was the improvement in blood pressure (standing position) during the active drug phase. Significant changes in various lipids, lipid subfractions, apolipoproteins, and lipid ratios were seen within both the clonidine and atenolol groups and when compared with the patients treated with placebo. Atenolol caused an increase in triglycerides and apolipoprotein B and a reduction in high-density lipoprotein-cholesterol and in apolipoproteins A-I and A-II. AU the lipid ratios demonstrated a significant adverse effect with atenolol, increasing the total cholesterol/high-density lipoprotein, low-density

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lipoprotein-cholesterol/high-density lipoprotein, apo B/ape A-I and apo B/ape A-II ratios and decreasing the low-density lipoprotein-cholesterol/ape B ratios. Clonidine caused reductions in high-density lipoprotein, apolipoproteins A-I and A-II; however, it did not alter any of the lipid ratios. It should be noted that the reduction in high-density lipoprotein by either drug was significant only in comparison with placebo and was not significant in comparisons within each treatment group. Several interesting trends were noticeable, and neither drug approached statistical significance, perhaps because of the small sample size or some other factor (such as lost samples) (n = 30 per study group). Total cholesterol and low-density lipoprotein-cholesterol were reduced by clonidine therapy but essentially unchanged by atenolol and placebo therapy (Table III). The total cholesterol/high-density lipoprotein ratio has been suggested as a sensitive and specific indicator of the risk of coronary heart disease5’y 60; higher ratios are associated with an increased risk of coronary heart disease, lower ratios with a lower coronary heart disease risk. Clonidine caused no change in the total cholesterol/high-density lipoprotein ratio, compared with a 3% increase with atenolol and a 6 % decrease with placebo (Table IV). According to the Lipid Research Clinics Coronary Primary Prevention TrialG1 and the Helsinki Heart Study,62 a 1% reduction in the total cholesterol/high-density lipoprotein ratio with lipid-lowering drugs may be associated with a 2% to 4% reduction in coronary heart disease morbidity and mortality. Although clonidine was neutral in respect to the total cholesterol/high-density lipoprotein ratio compared with the adverse effects of atenolol, the placebo group experienced a modest reduction. Actual apolipoprotein concentrations may be more sensitive and specific indicators of the risk of coronary heart disease than traditional lipid or lipid subfraction ratios.60, 63-75Specifically, apolipoprotein AI, the major protein component of high-density lipoprotein, is inversely correlated with the risk of coronary heart disease, whereas apolipoprotein B, the major protein component of low-density lipoprotein is positively correlated with risk.63-67, 73,74 Several studies have shown small differences of only 5 to 15 mg/dl of apolipoproteins A-I and B between normal control subjects and patients with coronary heart disease.63p 68-73In one study73 that compared children whose fathers did not report a myocardial infarction with children whose fathers did report an infarction, the second group had a lower mean level of apolipoprotein A-I (137 vs 141 mg/dl), a lower ratio of low-densitylipoprotein-cholesterol/apolipoproteinB

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177

(1.08 vs 1.1 l), and a higher ratio of apolipoprotein B to apolipoprotein A-I (0.64 vs 0.61). In addition, elevated levels of low-density lipoprotein apolipoprotein B in the absence of increased levels of low-density lipoprotein-cholesterol or a decreased low-densitylipoprotein-cholesterol/apolipoproteinB ratio (“hyperapobetalipoproteinemia”) may be associated with the development of premature coronary artery disease.66> 73175 In this study, the total cholesterol/high-density lipoprotein, low-density lipoprotein-cholesterol/high-density lipoprotein, apo B/ape A-I and apo B/ape A-II ratios increased significantly with atenolol, but no significant changes occured with clonidine. The decrease in low-density lipoproteincholesterol/apolipoprotein B ratio coupled with increases in the other ratios affected by atenolol may predict a greater risk of myocardial infarction in patients treated with this drug compared with patients treated with clonidine or placebo (assuming the equal reductions in blood pressure by each treatment are of equal significance to those lipid changes that occur naturally) and that such effects are persistent. Several other studies indicate that changes in lipids and lipid subfractions induced by diuretics and o-blockers are persistent, adverse, and quantitatively significant.8> 76-77These adverse lipid effects may account for some lack of reduction in coronary heart disease in clinical trials of mild hypertension that used P-blockers or diuretics or first-line therapy. Antihypertensive drugs with a “favorable” or neutral effect on serum lipids, lipid subfractions, and apolipoproteins may have definite advantages in reducing the risk of coronary heart disease compared with those antihypertensive drugs that have “unfavorable” effects (p-blockers without intrinsic sympathomimetic activity or diuretics). In addition, important changes in apolipoproteins or apolipoprotein ratios may occur without significant changes in total lipid levels (total cholesterol, triglycerides) or lipid subfractions (HDLi, HDLz, HDLs, low-density lipoprotein-cholesterol), which can be misleading when calculating the risk of coronary heart disease. The “lipid-favorable” or “lipid neutral” effects of clonidine compared with the “lipid-unfavorable” effects of atenolol may provide advantages in drug therapy for mild hypertension in the reduction of the risk of coronary heart disease. It would seem prudent to obtain a baseline fasting lipid profile in all patients with hypertension before institution of antihypertensive drug therapy, then to measure serial fasting lipids at specific time intervals (1 month, 2 months, 6 months). If adverse effects occur, particularly in patients at high risk of coronary heart disease, then

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alternate antihypertensive drugs should be selected. These results need verification with large numbers of patients by determining whether the effects persist with long-term therapy and by documenting whether these changes correlate with the risk of coronary heart disease in long-term prospective clinical trials. The following individuals are gratefully acknowledged: deanne Williams and Tammy Hamilton for typing and technical assistance; Evan Stein for iaboratory support with lipid assay; and Garrett Fitzgerald, MD, Mike Lichtenstein, MD, Marie Griffin, MD, Ben Byrd, MD, Evan Stein, MD, Anderson Spickard, MD, Craig R. Heim, MD, and David Robertson, MD for critical review of manuscript. Boehringer Ingelheim Laboratories Pharmaceutical Company of Ridgefield, Connecticut provided investigative grant support.

REFERENCES

Veterans Administration Cooperative Study Group or Antihypertensive Agents. Effects of treatment on morbidity in hypertension II results in patients with diastolic blood pressure averaging 90 through 114 Hg. JAMA 1970;213:1143-52. 2. Smith W. U.S. Public Health Service Hospitals Cooperative Study Group. Treatment of mild hypertension: results of a ten-year intervention trial. Circ Res 19??;4O(supp I):(S)I-98I-105. Heart, Lung, and 3. Perry W. Veterans Administration-National Blood Institute Study Group for Cooperative Studies on Antihypertensive Therapy: Mild Hypertension. Treatment of mild hypertension: preliminary results of a two year feasibility trial. Circ Res 19?7;40(1):1-180-I-187. 4. Hypertension Detection and Follow-up Program Cooperative Group. Five year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure including mild hypertension. JAMA 1979;242:2562-71. .5. Helgland A. Treatment of mild hypertension: a five-year controlled drug trial. The Oslo Study. Am J Med 1980;69:725-32. 6. The Report by the Australian Therapeutic Trial in Mild Hypertension Management Committee. The Australian therapeutic trial in mild hypertension, Lancet 1980;1:1261-7. 7. Greenberg G, Brenman PJ, Miall WE. Effects of diuretic and beta blocker therapy in the medical research council trial. Am J Med 1984;?6:45-51. 8. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA 1982;248:1465-77. 9. Amery A, Birkenhaser W, Brixro P, Bulpitt C, Clement D, Deruyttere M. Mortality and morbidity results from the European working party of high blood pressure in elderly trial. Lancet 1985;1:1349-54. 10. MieHinen TA, Huttuen JK, Naukicarlnen V, Stranbers T. Multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA 1985;254:2097-102. 11. Wilhelmsen L, Tibblin G, Werko L. A primary prevention study in Gotenburg, Sweden. Prev Med 1972;1:153-60. 12. Ames RP. Metabolic disturbances increasing the risk of coronary heart disease during diuretic-based antihypertensive therapy: lipid alterations and glucose intolerance. AM HEART J 1983;106:120?-14. 13. Ames, RP. Negative effects of diuretic drugs on metabolic risk factors for coronary heart disease: possible alternative drug therapies. Am J Cardiol 1983;51:632-8. 14. Grimm RH, Hunninghake DB. Lipids and hypertension: implications of new guidelines for cholesterol management in the treatment of hypertension. Am J Med 1986;8O(suppl 2A\):5663. 1.

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