Cardiovascular Drugs and Therapy 4: 1287-1290, 1990 © Kluwer Academic Publishers, Boston. Printed in U.S.A.

The Effect of Celiprolol on the Blood Lipid Profile in Hypertensive Patients with High Cholesterol Levels Roberto Fogari, 1 A n n a l i s a ZoppL ~ Franco TettamantL 1 Giandomenico M a l a m a n L 1 Carlo Pasotti z 1Department of Internal Medicine and Therapeutics, LR.C.C.S. Policlinico S. Matteo, University of Pavia, Italy; 2Hypertension Center, VogheraHospital, Pavia, Italy

Summary. The aim of this study was to compare the effects of chronic antihypertensive therapy with either celiprolol or atenolol on plasma lipids in patients with hypercholesterolemia. Forty-six patients with essential hypertension and a total cholesterol (TC) concentration > 220 mg/dl were studied. After 1 month on placebo, patients were stratified into five classes on the basis of their plasma TC levels and then randomized to receive atenolol 100 mg/day or celiprolol 400 mg/day for I year. Blood pressure (BP), heart rate (HR), and blood samples for evaluation of TC, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides (TG) were taken before and after the placebo period, and every 6 months from the beginning of the active treatment. Celiprolol and atenolol caused similar reduction in BP. Both atenolol and celiprolol decreased TC. Atenolol significantly reduced HDL-C, while eeliprolol increased it (p < 0.01 at 12 months), and the difference between the two drugs was statistically significant in this regard. LDL-C levels were not significantly affected by atenolol, but were progressively reduced by celiprolol (p < 0.05 at 6 months, p < 0.01 at 12 months). TG rose under atenolol but was reduced by celiprolol (p < 0.05). The results of this study show that the celiprolol-induced changes in plasma lipids may be favorable and suggest that, in hypertensive patients with high cholesterol levels, beta-blocker therapy with celiprolol may be effective in lowering BP without worsening the lipid profile. Cardiovasc Drugs Ther 4:1287-1290, 1990 Key Words. celiproiol, hypertension, lipids, hypercholesterolemia, beta blockers

Beta-adrenoceptors blockers have been reported to exert potentially unfavorable effects on lipid metabolism in hypertensive patients, in that they reduce plasma HDL cholesterol (HDL-C) [1-5], which is well accepted as a risk factor for coronary heart disease (CDH) [6,7], and increase plasma triglycerides (TG) [1-5], which are widely suspected to be harmful [8,9]. However, the various studies have shown significant differences between the subclasses of beta blockers in their effects on plasma lipids: beta1 selective beta-

blocking agents produce less pronounced changes in lipid concentrations than nonselective ones [10-13] and beta blockers with ISA (intrinsic sympathomimetic activity) have even more discrete effects [14-16]. Recently there have been some indications that celiprolol, a new betalselective beta-blocking agent with beta2-agonist and mild alpha~-adrenergic blocking activity, may reduce serum TG and increase HDL-C, thus improving lipid status [17-20]. However, most of the evidence that beta blockers alter plasma lipids is based on relatively short-term studies in small numbers of patients, often without a distinction between normolipidemic and dislipidemic subjects. So the effects of long-term treatment and the influence of preexisting lipid abnormalities are not clear. The aim of this study was to compare the effects of chronic monotherapy with either celiprolol or atenolol on plasma lipid concentrations in hypertensive patients with high total cholesterol levels.

Methods

Forty-six patients with mild to moderate essential hypertension, all males, aged 39-63 (mean age 51.3), were investigated. Inclusion criteria included total cholesterol levels > 220 mg/dl, responsiveness to betablocker monotherapy at standard doses, and no contraindications to beta-blocker therapy. All patients gave informed consent. After a 1-month washout phase and a subsequent placebo period of 1 month, patients were stratified

Address for correspondence and reprint requests: Prof. Roberto Fogari, Clinica Medica I, Policlinico S. Matteo, Piazza Golgi, 6 27100 Pavia, Italy.

1287

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Fogari, Zoppi, Tettamanti, Malamani and Pasotti

BP (mmH 9 )

ii

180 170 160 150 140 130 120 110 100 90

p < 0,05

6 months

•

12 m o n t h s

6 MONTHS TC

HDL-C

LDL-C

12 M O N T H S TG

TC

HOL-C

LDL-C

TG

~20 ~-10 0 -10 -2(3 - 30

1 [:3 ATENOLOL

"k~r

ATENOLOL Yr

Placebo

+30

yr'k"

80

[] []

CELIPROLOL ~r

P < 0.01

Fig. 1. Blood pressure (BP) changes during i year treatment with celiprolol or atenolol.

into five classes on the basis of their plasma cholesterol levels and then randomized to receive atenolol 100 rag/day (24 patients) or celiprolol 400 rag/day (22 patients). They were tested for i year. Clinical evaluations were performed before and after the placebo period and every 6 months from the beginning of active treatment. At each visit systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured. Fasting venous blood samples were drawn from evaluation of serum TC, HDL-C, LDL-C, and TG. TC and TG were determined by the enzymatic method of the Chemetron Company. HDL-C was determined by the enzymatic method of Rosclau [21]), after LDL and VLDL precipitation with polyethylene glycol 6000 by the method of Viikari [22]. LDL-C was calculated according to the method of Friedewald [23]. Statistical significance was evaluated by analysis of variance and by the Tuckey test for multiple observations.

Results Celiprolol and atenolol caused similar reductions in both SBP and DBP, which were maintained throughout the study (Figure 1). Table 1 and Figure 2 show the changes in the mean values of TC, HDL-C, LDLC, and TG after 6 and 12 months of treatment. Both atenolol and celiprolol significantly reduced TC; under atenolol such a reduction was evident at 12 months (-2.6%, p < 0.05), while under celiprolol it was more remarkable (-6.2% at 6 months and -2.9% at 12 months) and already significant after 6 months (p < 0.01). HDL-C levels were significantly decreased by atenolol (-14.6% after 6 months, p < 0.01 and -19.5% after 12 months, p < 0.01). However, celi-

[2] CELIPROLOL

~- p ~ o o s

p¢ 0.01

Fig. 2. Changes in total cholesterol (TC), HDL-cholesterol (HDL-C), and triglycerides (TG) during treatment with cellprolol or atenolol.

prolol significantly increased the HDL-C concentration( + 1.4% at 6 months and + 6.1% at 12 months, p < 0.01). As far as the HDL-C changes are concerned, the statistical analysis showed a significant difference between atenolol and celiprolol effects. LDL-C was unaffected by atenolol treatment but was significantly reduced by celiprolol (-8.3% at 6 months, p < 0.05 and - 17.3% at 12 months, p < 0.01). TG significantly rose during atenolol therapy (+4.9% at 6 months, p < 0.05 and + 7.5% at 12 months, p < 0.01). In contrast, celiprolol reduced TG (-6.4% at 6 months and -7.6% at 12 months, p < O.O5).

Discussion The results of this study show that, in hypertensive patients with basal high TC levels, chronic celiprolol and atenolol monotherapy have qualitatively and quantitatively different effects on plasma lipids, which is probably due to their different ancillary properties. Both beta blockers significantly reduced TC, but such a reduction was more remarkable and precocious under celiprolol, reaching statistical significance at 6 months. As TC is considered to be a powerful predictor of CHD [24], the cholesterol lowering effect of celiprolol in patients with high cholesterol levels may be relevant in the long-term treatment of such patients. In our study, atenolol significantly reduced HDL-C levels, which is in agreement with other studies [13,20,25,26]. In contrast, under celiprolol HDL-C tended to increase and was significantly increased after 12 months (+6.1%, p < 0.01). As HDL-C is inversely related to the development of CHD [6,7], celiprolol may offer some potential advantage by not lowering HDL-C and indeed increasing it. LDL-C was not significantly affected by atenolol but was significantly reduced by celiprolol with a significant improvement in the HDL/LDL ratio. Serum TG, which were significantly increased by atenolol treat-

Celiprolol Effects on Plasma Lipids

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Table 1. Changes in total cholesterol (TC), HDL cholesterol (HDL-C), versus LDL cholesterol (LDL-C), and triglycerides (TG) (mean values _+ SD) under treatment with atenolol and celiprolol Placebo

TC (mg/dl) _+ SD HDL-C (mg/dl) _+ SD LDL-C (mg/dl) _+ SD TG (mg/dl) _+ SD

6Months

12Months

Atenolol

Celiprolol

Atenolol

Celiprolol

Atenolol

Celiprolol

283.69_+ 42.17

284.7 _+ 39.23

281.47 _+ 40.47

267.09 _+b 23.70

276.43 _+a 37.27

256.45 --+b'd30.48

41.73 _+ 11.00

41.95 -+ 10.80

35.65 _+b 7.03

48.54 -+e 9.61

33.56 _+b 6.15

44.50 _+b,f11.61

127.02 +_ 44.00

127.29 -+ 48.89

125.18 _+ 42.12

116.70 _+a 40.19

118.85 _+ 42.47

105.85 _+b'°43.01

232.26 _+ 78.94

231.04 _+ 73.70

243.69 _+a 80.46

216.09 _+b 70.92

249.91 +b 79.67

213.40 _+b 68.00

ap < 0.05 versus placebo. bp < 0.01 versus placebo. Cp < 0.05 versus celiprolol 6 months. dp < 0.01 versus celiprolol 6 months. ep < 0.05 versus atenolol 6 months. fp < 0.01 versus atenolol 6 months.

ment, significantly decreased under celiprolol, which confirms previous reports in the literature [17-20]. In conclusion, the results of this study show that the changes in plasma lipids induced by celiprolol may be potentially favorable and suggest that, in hypertensive patients with an already demonstrated atherogenic lipid profile, beta-blocker therapy with celiprolol may be effective in reducing blood pressure, without worsening the lipid risk, and indeed improving it.

11.

12.

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