A long-term comparative trial of cerivastatin sodium, a new HMG-CoA reductase inhibitor, in patients with primary hypercholesterolemia

CLINICAL THERAPEUTICWVOL.

20, NO. 3, 1998

A Long-Term Comparative Trial of Cerivastatin Sodium, a New HMG-CoA Reductase Inhibitor, in Patients with Primary Hypercholesterolemia Jun Sasaki, MD,’ Kikuo Arakawa, MD,’ Kyosuke Yamamoto, MD,2 Shozo Kobori, MD,3 Masato Ageta, MD,4 and Suminori Kono, Mti ‘Department of Internal Medicine, Fukuoka University School of Medicine, Fukuoka, 2Department of Internal Medicine, Saga Medical School, Saga, 3Department of Metabolic Medicine, Kumamoto University School of Medicine, Kumamoto, 4Miyazaki Prefectural Nichinan Hospital, Miyazaki, and ‘Faculty of Medicine, Kyushu University, Fukuoka, Japan

ABSTRACT Cerivastatin sodium, a synthetic and pure enantiomeric 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hypercholesterolemia (total cholesterol I 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterol 2260 mg/dL). After a minimum of 4 weeks’ lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of

0149-2918/98/$19.00

cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary 539

CLINICAL THERAPEUTICS’

hypercholesterolemia. Key words: cerivastatin sodium, cholesterol, HMG-CoA reductase inhibitors, hypercholesterolemia.

INTRODUCTION Hypercholesterolemia is a major risk factor for coronary artery disease. Recent studies have shown that treatment with hypocholesterolemic drugs facilitates the prevention and treatment of coronary artery disease. l-5 Results from large-scale intervention studies using 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors showed that these drugs reduced cardiovascular events as well as total mortality.4-7 Cerivastatin sodium, a pure enantiomeric pyridine derivative, was developed as a novel synthetic HMG-CoA reductase inhibitor. It is 100 to 150 times as potent pharmacologically as conventional HMG-CoA reductase inhibitors8 A Japanese dose-finding study using cerivastatin sodium at a dosage range of 0.05 to 0.2 mg/d9 found that serum total cholesterol (TC) was reduced 11.4% by 0.05 mg/d, 14.9% by 0.1 mg/d, 18.5% by 0.15 mg/d, and 18.6% by 0.20 mg/d. The authors suggested that the initial dose of cerivastatin sodium should be 0.15 mg/d. To investigate the use of a higher dose in the treatment of patients with severe hyperlipidemia (eg, familial hypercholesterolemia), the present study first compared the efficacy and tolerability of cerivastatin sodium 0.3 mg/d with those of cerivastatin sodium 0.15 mg/d over 12 weeks. Treatment was then continued for at least the next 36 weeks (ie, for a total treatment period of at least 48 weeks) to assess the long-term efficacy and tolerability of this new HMG-CoA reductase inhibitor.

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PATIENTS

AND METHODS

Patients Outpatients of either sex, aged 20 to 64 years, who had TC levels of 2260 mg/dL and triglyceride (TG) levels of 1400 mg/dL at the last two visits of a pretreatment observation period were eligible for study participation. Patients with secondary hyperlipidemia, poorly controlled diabetes mellitus or severe hypertension, or a history of alcoholism or heavy drinking were excluded, as were obese patients on diet therapy for weight reduction, women who were pregnant or hoped to become pregnant, and those with any clinically critical condition. Twenty-two patients provided written informed consent and 5 1 provided oral informed consent, in accordance with the good clinical practice guidelines of the Japanese Ministry of Health and Welfare.

Study Design After a minimum of 4 weeks’ lead-in with placebo, eligible patients were randomly allocated to one of two dosage groups. For the first 12 weeks (treatment period l), cerivastatin sodium was administered orally once daily after the evening meal at a dose of 0.15 mg (n = 33) or 0.3 mg (n = 40). Flexible dosing was adopted for at least the next 36 weeks (treatment period 2), for a minimum total treatment period of 48 weeks (Figure 1). All subjective and objective symptoms and abnormal laboratory findings were assessed by study physicians in terms of their possible relation to the study drug, time course, and other factors. Concurrent use of the following drugs that affect serum lipid levels was prohib-

J. SASAKl ET AL.

Cerivastatin 0.15 mg OD Cerivastatin 0.15 mg or 0.3 mg OD

Placebo OD Cerivastatin 0.3 mg OD Pretreatment observation period

.A

Treatment period 1 r7

1

Treatment period 2

Figure 1. Study design. OD = once daily after the evening

ited throughout the pretreatment observation period and the treatment periods: HMG-CoA reductase inhibitors other than the test drug, niacin preparations, clofibrate and related drugs, anion-exchange resins, probucol, any hormonal preparation, major tranquilizers, antidepressants, choleretic drugs, antiobesity drugs, thyroid preparations, and reserpine derivatives.

Laboratory Measures Serum lipid and lipoprotein levels were determined at an external laboratory (SRL Inc., Tokyo, Japan). TC, TG, and highdensity lipoprotein cholesterol (HDL-C) levels were assayed by enzymatic methodst”-‘* (coefficients of variation: TC, 1.14%; TG, 1.44%; HDL-C, 2.11%), and apolipoprotein (apo) levels were determined by turbidimetric immunoassay.t3 Levels of low-density lipoprotein cholesterol (LDL-C) were calculated using the Friedewald equation14: LDL-C = TC - HDL-C - 0.2 TG The atherogenic index was calculated ing the following equation:

us-

meal.

Atherogenic

index = TC - HDL-C HDL-C

Statktical Analysis Differences in the distribution of background factors between the dosage groups were examined using the Fisher exact test or the Student f test, according to the nature of the variable, at an a level of 0.15 (two-tailed). Changes in serum lipid values were examined by a paired t test in each dosage group, and intergroup differences in serum lipid levels and percentage changes in serum lipid levels were tested by two-way analysis of variance. Data were expressed as mean f SD.

RESULTS Treatment Period 1 Seventy-three eligible patients at 12 medical institutions in Japan participated in the study between August 1994 and June 1996. Table I shows the pretreatment characteristics of these patients. There were no significant differences in pretreatment characteristics between the dosage groups.

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Table I. Pretreatment

Variable Male/female (no.) Age (Y)+ TC (mg/dL)t LDL-C (mg/dL)t HDL-C (mg/dL)t TG (mg/dL)t Apo B (mg/dL)t

characteristics

of the patients entering treatment period 1.

0.15 mg (n = 33)

0.3 mg (n = 40)

P

8125 56.3 f 8.7 301.2 -c 34.1 218.8 f 36.3 54.9 f 22.4 171.2 + 95.3 178.4 + 31.2

11/29 55.3 + 11.7 308.6 f 29.6 222.8 f 31.6 56.3 + 15.6 147.4 f 71.3 176.0 f 22.5

0.80’ 0.68$ 0.33* 0.631: 0.75$ 0.24* 0.72$

TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density TG = triglycerides; ape = apolipoprotein. *The Fisher exact test. +Values are mean + SD. $The Student t test.

Percentage changes in serum lipid and lipoprotein levels are shown in Table II. In both dosage groups, serum levels of TC and LDL-C decreased significantly at week 4 and remained significantly lower than baseline thereafter. Percentage reductions in TC and LDL-C were significantly greater (P = 0.002 and P = 0.03, respectively) in the 0.3-mg group than in the 0.15-mg group (range for TC, 24.4% to 25.6% versus 19.4% to 21.6%, respectively, and for LDL-C, 33.4% to 35.0% versus 28.8% to 31.3%, respectively). HDL-C levels increased significantly at week 4 and thereafter remained significantly higher than baseline in the 0.3-mg group, whereas no significant change was observed in HDL-C levels in the 0.15mg group. The percentage increase was significantly greater in the 0.3-mg group than in the 0.15-mg group (P= 0.01). TG levels decreased significantly from baseline at weeks 4, 8, and 12 in the 0.3-mg group but did not decrease significantly in the 0.15mg group until week 12. The percentage

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lipoprotein cholesterol;

reduction in TG was significantly greater in the 0.3-mg group than in the 0.15-mg group (P= 0.04). In both treatment groups, the atherogenic index decreased significantly throughout the treatment period. Percentage changes in apolipoprotein levels are shown in Table III. In both dosage groups, apo B, apo C-II, apo C-III, and apo E decreased significantly during the treatment period; percentage reductions in these apolipoproteins were significantly greater in the 0.3-mg group than in the 0.15-mg group (P = 0.0001, 0.0003, 0.02, and 0.004, respectively). No significant differences in apo A-I or apo A-II levels were noted between the two groups. Adverse reactions were observed in one patient in each group. One patient in the 0.15-mg group complained of mild, transient flushing and a hot sensation, and one patient in the 0.3-mg group complained of mild general malaise and requested that treatment be discontinued. The malaise disappeared soon after discontinuation of the drug. Abnormal laboratory values for

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Table II. Mean (+ SD) lipid levels during treatment period 1 in the 0.15mg (n = 33) and 0.3-mg (n = 40) groups. The figures in parentheses represent percentage of change.* Baseline

Week 4

TC (mg/dL) 0.15mg group

301.2 f 34.1

0.3-mg group

308.6 zt 29.6

242.1 _+43.4+ (-19.4 f 10.8)+ 232.5 * 30.1+ (-24.4 f 9.5)+

237.2 f (-21.2 f 228.4 f (-25.6 f

40. I+ 10.2)+ 33. I+ 10.9)+

236.2 + 39.0’ (-21.6 + 9.5)+ 232.7 f 34.0+ P = 0.002 (-24.4 zt 10.9)+

LDL-C (mgNL) 0.15mg group’

218.8 2 36.3

0.3-mg group

222.8 f 31.6

157.3 f 49.4+ (-28.8 f 12.7)+ 147.2 + 32.7+ (-33.4 + 13.1)+

152.1 f (-31.3 f 144.0 f (-35.0 f

42.3+ 9.5)+ 34.1+ 14.2)+

151.6 f 40.4+ (-31.2 zt 10.2)+ 147.2 + 29.6+ (-33.6 * 14.4)+

HDL-C (mgNL) 0.15-mg group

54.9 + 22.4

0.3-mg group

56.3 f 15.6

55.9 f (4.0 f 59.5 2 (7.6 f

18.6 13.9) 14.6” 15.5)s

55.5 f (3.3 f 61.3 f (11.4 +

19.8 16.3) 14.2% 20.1)+

153.9 + 106.8 (-3.3 + 48.6) 124.5 f 59.2% (-11.6 f 29.1)s

166.2 f (3.9 f 121.0 f (-7.3 f

105.1 58.7) 55.2” 37.0)

Variable

TG @W-U

0.15-mg group

171.2 f 95.3

0.3-mg group

147.4 f 71.3

Atberogerticindex 0.15-mg group 0.3-mg group

5.2 f 2.2 4.8 + 1.6

56.6 f (4.3 f 60.8 f (8.3 f

21.8 14.6) 14.76 15.8)s

157.9 f 84.9 (3.1 f 49.5) 122.4 zt 53.15 (-9.6 f 35.6)” 3.8 k (-26.3 f 3.0 f (-35.5 f

1.7+ 15.0)+ 1.1+ 14.2)+

Week 8

3.8 f 2.3+ (-27.9 + 19.7)+ 3.1 f 1.3+ (-35.9 zt 18.5)+

Week 12

ANOVA

P = 0.03

P = 0.01

P=O.o4

3.7 + 1.9+ (-26.7 f 21.8)+ 2.9 zz0.9+ P = 0.0003 (-36.4 f 17.3)+

ANOVA = analysis of variance; TC = totalcholesterol;LDL-C = low-densitylipoproteincholesterol;HDL-C = high-density lipoprotein cholesterol; TG = triglycerides. ‘Intragroup comparisons were performed using the paired f test. +P < 0.001. *Four patients with TG levels >400 mg/dL were excluded. BP < 0.01. “P < 0.05.

which a relation to the test drug could not be ruled out (ie, laboratory adverse reactions) were observed in 7 patients in the 0.15mg group and 9 patients in the 0.3-mg group. Laboratory adverse reactions included decreased red blood cell count, decreased hemoglobin levels, and increased eosino-

phi1 count in 1 patient in the 0.15mg group; increased aspartate aminotransferase (AST) in 2 patients in both groups; increased alanine aminotransferase (ALT) in 2 patients in the 0.15mg group and 1 patient in the 0.3-mg group; increased lactate dehydrogenase in 2 patients in the 0.3-mg group; increased alkaline phos-

543

CLINICAL THERAPEUTICS’

Table III. Mean (+ SD) apolipoprotein (apo) levels during treatment Period 1 in the 0.15-mg (n = 33) and 0.3-mg (n = 37*) groups.+ Percentage Change Baseline

Week 4

Week 8

Week 12

ANOVA

A-I 0.15mg group 0.3-mg group

153.1 f 43.3 149.5 f 35.2

-1.2 f 10.6 0.5 zt 12.3

-1.3 + 9.6 0.2 + 14.7

-0.4 f 9.3 4.2 + 13.8’

P = 0.29

A-II 0.15mg group 0.3-mg group

39.7 + 8.1 37.3 + 6.5

-1.2 f 11.1 -3.7 f 9.4$

-4.1

f 10.4* -3.8 f 10.2*

-2.0 f 11.6 0.3 + 13.4

P = 0.40

B 0.15-mg group 0.3-mg group

178.4 + 31.2 176.0 + 22.5

-22.7 f 14.9” -30.9 f 11.25

-27.0 f 15.79 -31.9 f 13.25

-23.5 f 17.3s -30.4 f 13.10

P = 0.0001

C-II 0.15mg group 0.3-mg group

5.9 + 2.0 5.7 f 2.0

-10.5 + 21.5” -14.7 + 14.39

-15.3 f 21.45 -16.5 -I 16.55

-10.3 f 21.3” -17.9 * 18.29

P = 0.0003

C-III 0.15mg group 0.3-mg group

16.3 + 6.9 14.5 + 5.5

-9.3 + 21.5$ -15.3 + 19.20

-15.0 f 21.15 -13.9 f 17.38

-10.0 2 23.5t -11.4 f 19.59

P = 0.02

E 0.15-mg group 0.3-mg group

7.7 f 2.0 7.4 f 1.8

-17.0 f 20.00 -18.8 f 15.49

-17.2 f 21.85 -19.4 f 14.60

-15.2 zt 22.70 -18.5 f 13.10

P=O.o04

Variable

ANOVA = analysis of variance. *Baseline values were missing for three patients. Qntragroup comparisons were performed using the paired *P < 0.05. PP < 0.001. “P < 0.01.

phatase (ALP) in 1 patient in both groups; increased gamma-glutamyltransferase (GGT) in 2 patients in the 0.15-mg group and 1 patient in the 0.3-mg group; increased blood urea nitrogen in 1 patient in the 0.3-mg group; and increased creatine phosphokinase (CPK) in 3 patients in the 0.15-mg group and 7 patients in the 0.3-mg group. The highest AST, ALT, ALP, and GGT values were 189 U/L, 328 U/L, 682 U/L, and 228 U/L, respectively,

544

t test.

all recorded in one patient, possibly attributable to flu. Another patient whose highest CPK value was 1128 U/L, had often developed high CPK values (eg, 300 U/L) prior to participation in the trial; fatigue was hypothesized as a possible cause. None of these laboratory adverse reactions were clinically significant (no associated subjective or objective symptoms were noted) or required discontinuation of treatment.

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ET AL.

T - T

50

T

40 I

(0.23)

(0.23)

(0.23)

(0.25)

T iii,, +

(0.25)

(0.26)

20

24

(0.26)

LDL-C

(0.26)

-60

I 0

4

6

12

16

36

46

Week Figure 2. Percentage change in serum lipid levels during treatment period 2. Intragroup comparisons were performed using the paired r test. Figures in parentheses represent the mean dose in mg/d. *P c 0.05; tP c 0.001. TC = total cholesterol; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

Treatment Period 2 Fifty-eight (42 in the 0.3-mg group,* 16 in the 0.15-mg group) of the 73 patients who completed treatment period 1 continued to long-term treatment and underwent assessment for drug efficacy. The 15 patients who discontinued study period 2 included 10 with no visit by week 44,4 who failed to comply with the study

*This included 11 patients whose dose was increased from 0.15 mg to 0.3 mg during treatment period 2.

protocol, and 1 with uncontrolled diabetes mellitus. Results were not broken down by treatment group during period 2; mean percentage reductions were calculated on the combined results of the 0.3- and 0.15mg groups. Changes in serum lipid levels during the 48-week treatment period are shown in Figure 2. TC and LDL-C levels decreased significantly at week 4, remained stable until week 48, and were significantly lower than baseline levels throughout the treatment period. Mean percentage reductions in TC and LDL-C 545

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levels at week 48 were 22.5% and 31.3%, respectively. At week 48, the HDL-C level had increased by 6.2%, the TG level had decreased by 5.6%, and the atherogenie index had decreased by 30.9% from baseline. After the end of treatment period 1, mild erosive gastritis occurred in one patient in the 0.3-mg group. The generalized flushing and hot sensation that had occurred during treatment period 1 did not recur during the long-term treatment extension, and symptoms were therefore judged not to be related to the study drug. Laboratory adverse reactions were observed in 16 patients after the end of treatment period 1, but no serious alterations in laboratory values were noted during treatment period 2.

DISCUSSION AND CONCLUSIONS In the present study, the efficacy and tolerability of cerivastatin sodium 0.15 and 0.3 mg/d were compared in patients with severe primary hypercholesterolemia (ie, a TC level of 2260 mg/dL). During treatment period 1, the percentage reduction in TC level was significantly greater in the 0.3-mg group than in the 0.15-mg group. As noted earlier, a previous dose-finding study using dosages of 0.05 to 0.2 mg/d concluded that the initial dose of cerivastatin sodium should be 0.15 rngId.9 However, results of the present study support the use of a higher dose in patients with severe primary hypercholesterolemia. The percentage reduction in TC level at week 12 was 24.4% in the 0.3-mg group; this reduction was greater than that observed for pravastatin treatment (20.5%) at the highest approved dosage level (20 mg/d) in Japan. l5 No comparable data are available regarding reductions in TC levels in Japanese patients receiving 10 mg/d of simvastatin (also the highest approved

546

dosage in Japan). Percentage reductions in LDL-C and apo B levels also were greater in the 0.3-mg group than in the 0.15-mg group. These findings clearly indicate that the use of cerivastatin sodium at a dosage of 0.3 mg/d may be much more effective than 0.15 mg/d in patients with severe primary hypercholesterolemia. Clinical adverse reactions were observed in only one patient in each group. Laboratory adverse reactions were observed in several patients in both groups, with no significant difference in reactions between the two groups. Such laboratory adverse reactions as elevations in AST, ALT, GGT, and CPK levels are commonly noted in the course of treatment with conventional HMG-CoA reductase inhibitors.‘&‘* We therefore conclude that the tolerability profile of cerivastatin sodium 0.3 mg/d is similar to that of cerivastatin sodium 0.15 mg/d and that cerivastatin sodium’s overall tolerability profile is similar to that of other HMG-CoA reductase inhibitors. The present study extended treatment with cerivastatin sodium for at least 36 weeks after the initial la-week treatment period to assess the long-term efficacy and tolerability of the drug. The observed changes in TC and LDL-C levels suggest that the hypocholesterolemic effect produced by cerivastatin sodium at a dosage of either 0.15 or 0.3 mg/d is remarkably stable, continuing for as long as 48 weeks without diminishing. With regard to tolerability, only one case of mild erosive gastritis was observed during long-term treatment. Clinically insignificant laboratory adverse reactions occurred in a small number of patients at the end of treatment period 1. Based on these results, we conclude that cerivastatin sodium is effective and well tolerated in the treatment of patients with

J. SASAKI ET AL.

severe hypercholesterolemia, which usually requires a long period of treatment.

7-45-l Nanakuma 8 14-80, Japan.

ACKNOWLEDGMENTS

REFERENCES

This study was supported by a research grant from Bayer Yakuhin, Ltd., Osaka, Japan. The authors wish to thank the following members of the Kyushu Cerivastatin Study Group in Japan: Akira Matsunaga, MD, Department of Internal Medicine, Fukuoka University School of Medicine, Fukuoka; Susumu Kajiwara, MD, and Takahiro Sakai, MD, Department of Internal Medicine, Saga Medical School, Saga; Masaya Kasho, MD, and Motoaki Shichiri, MD, Department of Metabolic Medicine, Kumamoto University School of Medicine, Kumamoto; Toshifumi Taguchi, MD, Miyazaki Prefectural Nichinan Hospital, Miyazaki; Yasushi Yokokawa, MD, Hamanomachi Kyosai Hospital, Fukuoka; Masatoshi Nohara, MD, and Hisaaki Fukumoto, MD, Social Insurance Kurume Daiichi Hospital, Fukuoka; Hideo Fukushima, MD, Adult Disease Center, Tamana Central Hospital, Kumamoto; Yasufumi Sato, MD, Kazuyuki Hamaguchi, MD, and Toshiie Sakata, MD, Department of Internal Medicine, Oita Medical University, Oita; Kohei Yamaguchi, MD, Oita Prefectural Hospital, Oita; Masahide Hara, MD, and Takeshi Takakura, MD, Health Insurance Nankai Hospital, Oita; Haruhito Kumagai, MD, and Susumu Nakagawa, MD, Miyazaki Prefectural Miyazaki Hospital, Miyazaki; and Wataru Matsumoto, MD, and Keiichi Nakahara, MD, Imakiire General Hospital, Kagoshima.

Address correspondence to: Jun Sasaki, MD, Department of Internal Medicine, Fukuoka University School of Medicine,

Jonan-ku,

Fukuoka

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