Effects of Isradipine, a New Calcium Antagonist, Versus Hydrochlorothiazide on Serum Lipids

and Apolipoproteins in Patients with Systemic Hypertension

Paul Samuel, MD, Walter Kirkendall, MD, Ernst J. Schaefer, MD, Bruce Chin, MD, Barton H. Schoenfeld, MD, Leonard M. Gonasun, PhD, and Sidney Lieberman, PhD

The effect of isradipine versus hydrochlorothiazide on the lipid profile of 44 hypertensive patients was investigated in a double-blind, randomized, P-cen- ter trial. Lipid profiles included total cholesterol, serum triglycerides, high density lipoprotein (HDL) cholesterol, HDL. subclasses, (HDl.2 and HD&), low density lipoprotein cholesterol, very low densify li- poprotein cholesterol, apolipoprotein A-l and ap& lipoprotein 6. lsradipine had no effect on the lipid profile in short- (4 and 10 week) or long-term (52 week) studies. Hydrochlorothiazide incrkased se- rum triglycerides in 11 of 13 patiints by a mean of 8% for the group (p <O&S) in long-term (52 week) studies, and total cholesterol by a mean of 9 and 16%, resbectively (p <O.Ol) in 2 of 13 patients, with no difference in other lipid or lipoprotein pa- rameters in short- or long-term studies.

(Am J Cardiol 1988;62:1&8-1071)

From the Long Island Jewish Medical Center, Manhasset, and the Albert Einstein College of Medicine, Bronx, New York, and the Uni- versity of Texas Medical School, Houston, Texas. This study was sup- ported in part by the Coronary Heart Disease Research Foundation, New York, New York. Manuscript received May 17, 1988; revised mariuscript received July 21, 1988, and accepted July 23.

Address for reprints: Paul Samuel, MD, Long Island Jewish Medi- cal Center, 1554 Northern Boulevard, Manhasset, New York 11030.

I n 1955 Perry and Schroeder’ reported that reduction of systemic arterial blood pressure by hydralazine coincided with decreased serum cholesterol levels in

patients with hypertension. A year later, Orvis et al* showed the same decrease in serum cholesterol with the use of ganglionic blocking agents. In 1958, Deming et al3 confirmed these observations in humans and rats, and suggested that there might be a direct correlation between blood pressure and serum chdlesterol. During the past 2 decades, however, many published studies re- ported opposite findings: namely, that reduction of high blood pressure, specifically by diuretics or /3 blockers, increased serum lipids or decreased the concentration of high density lipoprotein (HDL) cholesterol. The shift toward a more atherogenic lipid profile in exchange for the reduction of high blood pressure initiated grave con- cerns in the evaluation of risk factors for coronary ar- tery disease. Recently, increased attention has been paid to calcium antagonists for treatment of systemic hyper- tension. In the present study we report the effects of a new compound, isradipine, on serum lipids and apolipo- proteins and compare it with hydrochlorothiazide.

METHODS New York center: At the New York center 22 pa-

tients (12 men and 10 women) were studied. Their ages ranged from 45 to 73 years (mean f standard deviation 58 f 7). The mean diastolic blood pressure was 100 mg Hg in the supine position after a 3- or 4-week placebo baseline or washout phase. Patients with diabetes melli- tus (drug treated), alcoholic hyperlipidemia, evidence of congestive heart failure, renal or hepatic disease or fail- ure to complete 12 months of treatment with the study medication were excluded. Four of the 22 patients had low density lipoprotein (LDL) cholesterol levels >160 mg/dl, and none of the subjects had fasting baseline triglycerides >250 mg/dl.

At the efid of a 3- to 4-week placebo period, patients were assigned by a rsindom computer program to dou- ble-blind treatment with isradipine or hydrochlorothia- zide. The daily dosage of isradipine was 5 mg (in 7 pa- tients) or 10 mg (in 2 patients) twice daily. Hydrochlo- rothiazide dosage was 25 mg (in 9 patients) and 50 mg (in 4 patients) twice daily, depending on blood pressure response. Subjects with serum potassium of 13.5 mEq/

1068 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

TABLE I Effect of lsradipine and Hydrochlorothiazide on the Lipid Profile in 22 Patients for 52 Weeks (New York Clinic)

TC Triglyceride HDL C HDL2 HDL3 LDL C VLDL C Apo Al Apo 0 No.

Placebo 227 f 37 126 f 49 60f20 19 z!z 10 41 f 11 129 f 26 4Of13 175i44 85fll lsradipine 234 f 32 130 f 48 61 f 19 18f9 42f12 126 f 25 46% 13 175 i 42 83f14 ’

Placebo 212 f 40 122&45 52h 12 17 f 10 36-f7 123 i 36 36f 14 14Of23 74+21 Hydrochlorothiazide 218 f 39 132 f 44” 53fll 16f9 38k6 124 f 33 42kl5 147 f 21 72f22 l3

All values are in mg/dl. * p ao5. APO = apolipoprotein; HDL C = high density lipoprotein cholesterol: LDL C = low density llpoproteln cholesterol; TC = total cholesterol; VLDL C = very low density lipoprotein cho-

lesterol.

liter were given potassium supplementation (potassium method of Gidez et al7 and apolipoprotein A-l and B by chloride slow-release tablets, 600 mg twice daily). The the ELISA method.8 This laboratory is monitored for patients were seen by a dietitian. After a diet history accuracy by the Lipid Standardization Program of the was taken, patients were instructed to adhere to a con- Centers for Disease Control, National Heart, Lung, and stant-calorie and composition low salt diet. Drugs Blood Institute. known to influence serum lipid levels were not given. Houston center: At the Houston center 22 patients The weight of the patients remained within f2 kg (12 men and 10 women) were studied. The ages ranged throughout the study. from 24 to 74 years (58 f 10). Nine of the 22 patients

Blood samples were obtained weekly after a 12-hour had LDL cholesterol levels >160 mg/dl. Patients were fast for the 3 to 4 weeks of the placebo periods. At the randomly assigned to double-blind treatment with isra- conclusion of this, study medication was started and ad- dipine or hydrochlorothiazide. The dose of isradipine ministered for 52 weeks. The number of fasting blood was 5 mg (in 8 patients) or 10 mg (in 3 patients) twice samples varied from 14 to 18 during the active treat- daily; hydrochlorothiazide was given as 25 mg (in 7 pa- ment periods (14 in 3; 15 in 17; 16 in 1 and 18 in 1 tients) or 50 mg (in 4 patients) twice daily. Blood sam- patient), and consisted of biweekly blood drawings for ples were obtained at -1 week (control), and after 4 the initial 12 weeks, with monthly samples thereafter. and 10 weeks of the treatment periods. Total cholesterol HDL cholesterol subclasses and apolipoproteins were was determined by the method of Trinder,9 HDL and determined from 3 samples in each patient during pla- LDL cholesterols were measured by the precipitation cebo, and from 7 samples during active treatment peri- method of Warnick and Albers’O combined with the ods beginning at the sixth week. Total serum cholester- Trinder procedure.9 At the end of 10 weeks the Hous- 01~ and triglyceride9 were determined by enzymatic ton center trial was terminated. All other experimental methods, and cholesterol in plasma lipoprotein fractions parameters were identical to those of the New York was measured by the method of Bronzert and Brewer.6 center. Both projects were approved by the Institutional HDL cholesterol subclasses were determined by the Review Boards and informed consents were obtained.

FIGURE 1. Changes in average lipid profile parameters in indi- vidual patients during control periods (C) and during 52 weeks of isradipine administration (Rx). Apo Al = apolipoprotein A-l; Apo B = apolipoproteip 4 CHd = total cholesterol; HDL-C = high density lipoprotein cholesterol; LDL-C = low densi- ty lipoprotein cholesterol; TG = triglycerides; and VLDL-C = very low density lipoprotein cho- lesterol.

ma/d1

-

w ! * I ,

t t I

C t t t t

RX RX Rx C RX

THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 15, 1988 1069 __

ISRADIPINE, HYDROCHLOROTHlAZtDE AND THE LlPtD PROFtLE

TABLE It Effect of lsradipine and Hydrochlorothiazide on the Lipid Profile in 22 Patients for 4 and 10 Weeks (Houston Clinic)

Weeks TC HDL C LDL C No.

Placebo 203f25 54fll 149f22 lsradipine 4 204f28 57fll 148f30 11 lsradipine 10 202f30 59f17 143f32

Placebo 230f68 61&19 169f64 Hydrochlorothiazide 4 234f55 56f9 179zk55 11 Hydrochlorothiazide 10 225f66 57f12 168f66

Abbreviations as in Table I. No difference was statistically significant.

I I

RESULTS The results of the long-term (52 week) administra-

tion of isradipine and hydrochlorothiazide are listed in Table I (New York center). There were no significant differences when the average value for each lipid or li- poprotein parameter during drug administration was compared with the average value during placebo periods (paired t tests). The only exception was for serum tri- glycerides during hydrochlorothiazide administration. The moderate increase (122 mg/dl during placebo, and 132 mg/dl during hydrochlorothiazide administration) was significant at the 5% level. In addition, the average value of total cholesterol for the initial 10 weeks of hy- drochlorothiazide administration was compared in each patient with the average individual value of control peri- ods (Student’s t test). There was a statistically signifi- cant increase (p <O.Ol) in 2 of the 13 patients by 9 and 16%, respectively, during the initial 10 weeks of hydro- chlorothiazide administration. However, in these 2 pa- tients the increase remained significant throughout the 52 weeks of the study (p <O.Ol) when all available cho-

lesterol values were compared with control values. In the other 11 patients neither the initial lo-week nor the total 52-week data showed significant differences com- pared with control values. Isradipine administration had no effect on serum lipids, lipoproteins or apolipoproteins in individual (Student’s t tests) or group (paired t tests) analyses. The changes of each parameter of the lipid profile in individual patients during long-term isradipine and hydrochlorothiazide administration are shown in Figures 1 and 2, respectively.

Table II includes the short-term (4 and 10 weeks) results (Houston center). There were no statistically sig- nificant differences in total cholesterol or HDL and LDL cholesterol in these patients. When data from the 2 centers were combined for the initial 10 weeks of drug administration, there was no difference from the results of each separate center.

There were no major adverse effects during the study. The safety and efficacy of isradipine in reducing blood pressure, and its comparison to hydrochlorothia- zide, have been reported elsewhere.”

DISCUSSION In their original publication Henry and Bentley12

showed that atherogenesis was suppressed in cholester- ol-fed rabbits by nifedipine treatment without alter- ations in serum lipid levels. This finding was confirmed by other investigatorsls-l6 using a variety of calcium an- tagonists. The mechanism of, this protective effect was studied in several laboratories. It was first shown that the uptake and degradation of LDL was markedly in- creased by human skin tibroblasts treated with verapa- mi1,17 primarily due to an increase in LDL receptor number. This mechanism was further emphasized by the lack of effect of verapamil in LDL receptor-negative

mQ/dl

C RX

FtGURE 2. Changes in average lipid profile parameters in indi- vidual patients during control periods (C) and during 52 weeks of hydrochlorothiazide adminis- tration (Rx). Abbreviations as in Figure 1.

1070 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

cells.17 In cultured macrophages nifedipine and verapa- mil (but not diltiazem) were shown to reduce choles- teryl oleate deposition. l6 Another contributing mecha- nism may be the reduction of acyl-CoA:cholesterol acyl- transferase-mediated cholesterol esterification occurring when intact cells are treated with verapamil.ls

The effect of calcium antagonists on the lipid profile of patients with hypertension has been a topic of recent interest.19-21 There is practically unanimous agreement that calcium antagonists have no effect on serum lipid levels in man. In the present study we have demon- strated that the short- or long-term administration of a new calcium antagonist isradipine had no adverse ef- fects on serum lipid, lipoprotein or apolipoprotein levels. Thus, this study adds another compound to the list of the small number of antihypertensive agents reported to have no effect or beneficial effect on serum lipids in long-term trials.22

Another finding of our study concerns the effect of hydrochlorothiazide on the lipid profile. Since the origi- nal publication of Schoenfeld and Goldberger,23 show- ing that thiazide diuretics increased serum cholesterol levels in a small group of cardiac patients, attention has been centered on the effect of these antihypertensive compounds on lipids. It has been suggested that thiazide diuretics may cause short-term alterations of the lipid profile, more specifically increases of total cholesterol of 4 to 13%, LDL cholesterol of 7 to 29%, very low density lipoprotein cholesterol of 7 to 56% and total triglycer- ides of 14 to 37%.24,25 It is claimed, however, that in long-term treatment (11 year) total cholesterol and tri- glycerides usually return to baseline values or below.25 In the present study we found no change in total, LDL or HDL cholesterol levels during short-term administra- tion of hydrochlorothiazide (4 to 10 weeks). In our long- term studies (52 weeks) only serum triglycerides were significantly elevated (by 8%) with no change in any of the other lipid, lipoprotein or apolipoprotein parameters when we compared average values of the entire group (paired t tests). However, in 2 of our 13 patients serum cholesterol levels increased significantly during hydro- chlorothiazide treatment. This increase occurred within the first 10 weeks and remained elevated throughout the entire l-year study. There were no readily recognizable or distinctive features of these 2 patients compared with others in our study population. The moderate but signif- icant increase of triglycerides during hydrochlorothia- zide administration is in general agreement with reports from others.24,25 Yet plasma HDL levels did not relate to the elevation of the triglycerides, but remained un- changed in our group of patients. We have no obvious explanation for the variance with previous reports24,25 concerning total cholesterol levels in patients treated with hydrochlorothiazide. Perhaps there are 2 distinct groups of populations: those who respond with an in- creased cholesterol level and those who do not.

Acknowledgment: The authors wish to express their appreciation to Lois Markowski, Verne Nagle, Lisa Restrepo and Cecilia Gonzalez for excellent technical assistance.

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