Treatment of primary hypercholesterolemia: Fluvastatin versus bezafibrate

Treatment of Primary Hypercholesterolemia: Fluvastatin Versus Bezafibrate HEINERGRETEN,M.D., FRANKULRICHBEIL, M.D., Hamburg,J~~RGEN SCHNEIDER, M.D., Marburg, PETERWEISWEILER, M.D., MAchen, VICTORW. ARMSTRONG, Ph.D., Gbttingen,CHRISTIANE KELLER,M.D., Miinchen,HANS-ULRICH KL~R, M.D., Giessen, EBERHARD VON HODENBERG, M.D., Heidelberg, GOTTFRIED WEIDINGER, Ph.D., HERBERTESKOTTER, M.D., LOTHARFARBER, M.D., NUmberg, GERD ASSMANN, M.D., Mlnster, Germany

The effects of fluvastatin and bezaiibrate on lipids, lipoproteins, and apoproteins (apo) were investigated in a multicenter randomized, double-blind, parallel-group study. After 8 weeks of strictly controlled (computerbased assessment) dietary stabilization, patients with primary hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] 8160 mg/dL; triglycerides 5300 mg/dL) were enrolled into a 6-week placebo phase. Altogether, 131 patients were randomized to receive either fluvastatin at 40 mg once daily (n = 64; mean age 53 years) or bezafibrate at 400 mg once daily (n = 67; mean age 52 years) for 12 weeks. Compliance with the diet was monitored (3-day food records) after 6 and 12 weeks. Fluvastatin led to significant reductions in LDL-C (-23%), total cholesterol (-17%), LDL-C/high-density lipoprotein cholesterol (HDL-C) ( -24%) and apo B (-19%). Fluvastatin significantly increased LpA-I ( +8%) and apo E ( +20% ). Bezafibrate produced significant reductions in LDL-C (- 17%), total cholesterol (- 13% ), LDL-C/ HDL-C (-24%), triglycerides (-28%), apo B (-16%), and LpA-I (-10%) and significantly increased HDL-C (+12%), apo A-I (+9%), apo A-II (+30%), apo E (+14%), and Lp(a) (+3%). No clinically notable increases in levels of liver enzymes or creatine phosphokinase were observed with either treatment. Both treatments were well tolerated. There

From the Medizinische Kernklinik Universitatskrankenhaus Eppendorf, Hamburg (H.G., F.U.B.); Medizinische Poliklinik der PhilipsUniversitat Marburg (J.S.); Metabolic Research Munich, Munchen (P.W.1; Zentrum lnnere Medizin der Universitatskliniken Gdttingen N.W.A.); Medizinische Poliklink der Universitatskliniken I. d. Isar, Miinchen (C.K.); Medizinische Klinik Ill und Polikknik der Universitat Giessen (H.-UK.); Medizinische Klinik III der Universitat Heidelberg (E.v.H.); Sandoz AG, Niirnberg (G.W., H.E., L.F.); and lnstitut fur Arterioskleroseforschung, Monster lG.A.1, Germany. Requests for reprints should be addressed to PD Dr. med. Frank Ulrich Beil, M.D., Medizinische Kernklinik Universitatskrankenhaus Eppendorf, Martinistrasse 52, 20521 Hamburg, Germany.

was a low incidence of adverse events that tended to be mild and included headache, muscular pain, angina, and dyspepsia. The frequency of adverse events was similar in both treatment groups, and no significant differences in dietary behavior were observed. In conclusion, fluvastatin is a well tolerated 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of primary hypercholesterolemia. Effects of fluvastatin on LpA-I occur irrespective of changes in HDL-C.

ardiovascular disease is the main cause of death in the developed countries. Increased blood cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C), are directly related to an increased risk of coronary artery disease (CAD). The level of high-density lipoprotein cholesterol (HDL-C) has also been shown to be an independent risk factor for CAD, with higher levels considered to be protective [1,2]. The role of triglycerides (TG) as an independent atherogenic factor is under discussion [3-61. Lowering of both total and LDL cholesterol has been shown to reduce the incidence of CAD [7,8] and primary prevention studies have shown a reduction in fatal and nonfatal myocardial infarction [9]. In secondary prevention studies, a reduction in cardiac and total mortality has been achieved [lo]. Furthermore, patients with established CAD benefit from lipid-lowering through a reduction of cardiac events, such as frequency of angina, unstable angina, myocardial infarction, and the need for percutaneous transluminal coronaw angioplasty or coronary artery bypass-grafting [ 1 l- 133. Therefore, for high-risk patients-those with LDL-C levels >190 mg/dL, or ~160 mg/dL in the presence of definite CAD or r2 risk factors for CADlipid-lowering treatment has been recommended [141. The primary treatment of hypercholesterolemia is dietary, but drug therapy is required if diet alone fails to produce an adequate response.

C

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Fibrates such as bezafibrate have been widely used in the treatment of mixed hyperlipidemia. These agents primarily lower TG and increase HDL-C [15]. These agents may lower LDL-C levels in patients with normal levels of TG but, in patients with hypertriglyceridemia, increases in LDL-C have been reported [16]. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, are effective in reducing LDL-C levels [17,18]. Fluvastatin (Lescol; Sandoz) is a new, totally synthetic, hydrophilic HMG-CoA reductase inhibitor [19] that has been shown to be efficient in reducing LDL-C [201. The purpose of this study was to compare the efficacy of fluvastatin at 40 mg daily with that of bezafibrate at 400 mg daily in reducing LDL-C in patients with primary hypercholesterolemia. Effects on other plasma lipid parameters and the relative tolerability of the two drugs were also studied.

PATIENTSAND METHODS Subjects Male and female patients with primary hypercholesterolemia (familial heterozygous hypercholesterolemia, familial combined hyperlipidemia, or polygenie type IIa hypercholesterolemia, as determined by the investigator according to the European Atherosclerosis Society [EAS] 1988 guidelines [21]) aged 18-75 years were recruited from nine centers in Germany. Patients had to have levels of LDL-C 2160 mg/dL (4.1 mmol/L) and TG 5300 mg/dL (3.4 mmol/L) after following a cholesterol-lowering diet to be eligible to participate in the active-treatment period of the trial (see below). Body weight was within 40% of ideal, as defined by Metropolitan Life Insurance tables, and liver and renal function were normal. Patients with other dyslipidemic phenotypes or secondary causes for their hypercholesterolemia were excluded, as were those with conditions that might affect drug handling, safety, or evaluation of results. Other exclusion criteria were myocardial infarction or angioplasty within the 3 months preceding the study, congestive heart failure, severe angina pectoris or untreated hypertension, use of either medications known to interact with the study drugs or probucol within 6 months prior to the study, pregnant or lactating women or those of childbearing age not using adequate contraception, or a history of drug abuse or intake of >65 mL of pure alcohol daily. The study was performed in accordance with the principles of good clinical practice, and the protocol was approved by a national ethics committee.

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Study Design After giving informed consent, all patients completed an initial 8-week dietary stabilization period (weeks O-S) during which American Heart Association phase I or EAS guidelines were followed, dietary counseling was given, and any preexisting lipid-lowering therapy was gradually discontinued (by the end of week 4). The diet was maintained throughout the study. Toward the end of this period, a 3-day food record was completed as a measure of compliance. This check was repeated at 6-week intervals throughout the remainder of the study. Patients successfully adhering to the diet (fat intake ~35% of the patient’s total calorie intake, a potassium: sodium ratio ~0.75, and a cholesterol intake ~350 mg/day) then received placebo for 6 weeks (weeks 9-14), during which baseline efficacy and safety measurements-including an ophthalmological examination (slit-lamp examination of the lens) and apolipoprotein (ape) E phenotypingwere taken. Patients were randomized in a doubleblind manner to receive either fluvastatin at 40 mg daily with bezafibrate as placebo (fluvastatin group) or bezafibrate at 400 mg daily with fluvastatin as placebo (bezafibrate group) for 12 weeks (weeks 15-26). Medication was taken in the evening at least 2 hours after the evening meal. Compliance with the study medication was checked at each visit by counting the remaining dosage units. Visits to the clinic were made every 3 weeks, when blood samples for lipid analysis and determination of liver transaminases and creatine kinase (CK) were taken, measurement of vital signs was carried out, and any adverse events volunteered by the patient or noted by the observer were recorded. In addition, a physical examination, full serum chemistry and hematological determinations, urinalysis, and electrocardiography (ECG) were performed every 6 weeks, and a second ophthalmological examination was performed within 4 weeks of the end of the study.

Analytical Methods Blood samples for the evaluation of total cholesterol, HDL-C, TG, apolipoproteins, and lipoprotein particles (Lp) were taken from patients who had fasted for at least 12 hours, after they had been sitting for 3 minutes. Samples were collected in tubes (Vacutainer) containing sodium/potassium ethylenediaminetetraacetate (EDTA) at 1 mg/mL. Plasma was obtained within 1 hour by centrifugation at 4” C, transferred to a central laboratory (G. Assmann, M.D., Central Laboratory of WWU, Munster, Germany) within 24 hours, and analyzed

June 6, 1994 The American Journal of Medicine Volume 96 (suppl 6A)

SYMPOSIUM ONHYPERLIPIDEMIA / GRETEN ETAL within 48 hours of collection. Samples were stored and transported at 4” C. Levels of total cholesterol, HDL-C, VLDL-C, and TG were determined on a Boehringer Mannheim/Hitachi 737 instrument by enzymatic methods, using standardized procedures (total cholesterol, HDL-C and TG) according to the methods of the National Heart, Lung and Blood Institute (NHLBI, Bethesda, MD)/Centers for Disease Control (CDC, Atlanta, GA) Lipid Standardization Program. External quality-control monitoring of total cholesterol, HDL-C, and TG was performed on an ongoing basis by Medical Research Laboratories (Cincinnati, OH) using the NHLBI/ CDC part III monitoring program. Isolation of HDL-C was by the phosphotungstate/magnesium chloride procedure to precipitate VLDL-C and LDL-C. Ultracentrifugation for 3 hours at a density of 1.006 kg/L and at 100,000 rpm was used to separate VLDL-C, and LDL-C was calculated using the Friedewald formula [22]. Apolipoproteins A-I, A-II, and B were measured by immunoturbidimetry assays, and apo E by immunoenzymometric assays. Apo E isoform analysis was performed on the VLDL-C fraction by singledimension isoelectric focusing (IEF), using the Menzel and Utermann technique [23]. LpA-I was quantified by a commercially available electroimmunodiffusion assay (Sebiachem, Fulda, Germany) [241. Statistical Analysis An intention-to-treat analysis was performed for all patients randomized, using the last available data after week 14 as endpoint data. Data for patients completing the study were analyzed at weeks 17, 20, 23, and 26. For lipids and lipoproteins, the paired t test was used to ~PQT\SSmean percent changes from baseline wit? . treatment groups, and analysis of variance (ANOVA) with the factors treatment, center, and their interaction was used to determine significant differences between treatments. For apolipoprotein and lipoprotein particles, the Wilcoxon signed-rank test was used for withingroup comparisons of median percent changes from zero, and the Kruskal-Wallis test for betweengroup comparisons. The same tests were used to compare median changes in laboratory parameters after range adjustment to give unit-free statistics. The Cochran-Mantel-Haenszel test, adjusting for center, was used to compare categorical data. The number and percent of patients achieving defined mean percentage reductions in LDL-C, and those with normalized LDL-C levels by EAS criteria (< 135 mg/dL for high-risk and < 155 mg/dL for low-

June 6,

TABLEI F;f;$rphic

and Baseline Data for Randomized Fluvastatin [n = 64)

Bezafibrate [n = 67)

Age(yrl: mean(range)

53.0 (18-75)

51.8 122-701

Weight(kg): mean(range)

69.6

71.3

l50-100)

i46-101) 24.7 WO-31.631 37(55.21

Bodymass index(kg/m21:mean(range)

24.6 118.69-31.21)

Number1%)women Number(%)tiite Number1%)smokers Familialheterozygoushypercholesterolemia: n (%) Familialcombinedhyperlipidemia: n I%) Polygenichypercholesterolemia: n 1%)

31157.81 58190.61 16(25.0)

24(37.5) 3 (4.71 37157.81

61191.0)

26(38.81 21i31.3) lO(14.9) 36(53.7)

risk patients [21]) at the end of the study were also calculated. Overall, a response to treatment was defined as a 215% decrease in LDL-C.

RESULTS Demographic and Baseline Characteristics A total of 165 patients were enrolled into the study. During the placebo phase, 34 were discontinued, mainly because of inappropriate baseline lipid levels. Of the remaining 131 patients, 64 were randomized to fluvastatin and 67 to bezafibrate (main demographic characteristics, Table I). Apart from a significant treatment-center effect for age (p cO.05) and a history of genitourinary disease in more patients randomized to fluvastatin than bezafibrate (13 [20.3%] versus 5 [7.5%], respectively; p <0.05), there were no significant differences between the groups. The different types of hyperlipidemia and apo E phenotypes were evenly distributed between the two groups. A total of 12 patients in each group had hypertension. In the bezafibrate group, one patient had diabetes. A total of 16 patients with a personal history of CAD were randomized to the bezafibrate group and 21 CAD patients to the fluvastatin group. There were 90 patients who were considered to be at high risk (definite CAD and/or r2 other risk factors); their mean baseline LDL-C level was 259.2 mg/dL. Of these patients, 43 were randomized to fluvastatin and 47 to bezafibrate. The most common risk factors were a family history of CAD, male gender, and cigarette smoking. The mean LDL-C level in the remaining 41 low-risk patients was 269.2 mg/dL.

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Discontinuations After Randomization

Eight patients discontinued the study prematurely: one patient in each group was uncooperative; onetaking bezafibrateconsideredthe medication ineffective; onein eachgroup had a myocardial infarction; onetaking fluvastatin experienceda severe episodeof angina pectoris; one patient taking fluvastatin developedfatigue and arm pain; and, finally, one patient taking bezafibrate developed calf pain. In no casewere the symptoms considered to be dueto their study-drug treatment. Efficacy

The difference betweentreatment groups in patients who respondedto treatment (defined as a 215% reduction in LDL-C by week 26) was significant (p ~0.05): 70.7%in the fluvastatin group versus 57.2%in the bezafibrate group. The percentagesof patients achievinggiven percent reductions in LDL-C are presentedin Figure 1. A greater number of patients in the fluvastatin group comparedwith the bezafibrategroupnormalized their LDL-C levels (1988EAS criteria [21]) throughout the study. At week 26,15.5%of patients taking fluvastatin and 9.5%taking bezafibratehad normal LDL-C levels (435 mg/dL for high-risk and 455 mg/dL for low-risk patients). Mean percent changesfrom baselinein lipoprotein levels are presentedin Table II. The results at

5-d 5

15-<20

20-~25

Percentage

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June

25.~30

reductbn

6, 1994 The American Journal of Medicine

30-~35

weeks 1’7-26are from patients who completedthe study (Figure 2) whereasthosein the endpointcolumn are the results of the intention-to-treat analysis. Both drugs produced significant reductions in LDL-C by week 17 (third week of treatment), which were maintained until the end of the study. Fluvastatin had a significantly greater effect than bezafibrate.The reduction in total cholesterolwas significant within 3 weeks of starting treatment, and fluvastatin had the greater effect (p co.01 at week 17) although, by week 26, the differencebetween treatments was no longer statistically significant. Fluvastatin producednonsignificantincreasesin HDL-C levels whereasbezafibrateachievedsignificant increases.The differencebetween treatments was significant (p
35-~415

45.~55

in LDL-C

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255

Figure 1. Patients (%) achieving specified percent reductions in LDLC levels with fluvastatin and bezafibrate.

SYMPOSIUM ON HYPERLFIDEMIA/ GRETENET AL

TABLEII Mean Percent Changes in Lipoprotein Levels (versus Baseline) at Weeks 17,20, 23, and 26 with Fluvastatin (F) and Bezafibrate (B) Percent Changes Parameter/Mment (-0fpstiw

Totalcholesterol Fluvastabn Bezafibrate LDLC Fluvastatin Bezafibrate HDLC Flwastatin Bezaiibrate

Baseline (mg/dL)

week17

(F=64,8=65)

(F=64,8=65)

(F

q

Week 20 62,B = 65)

Week23 (F= 63,B = 62)

IF =!?Yf63)

End@@ (F=64,8=66)

340.3t 76.77

-17.0?r10.81t -11.1t 9.583 +

-17.9? 8.92t -13.0f 10.9ot t

-18.6t 9.21t t -13.9i 11.93t

-16.9t l&27$ -13.0? 11.73$

-17.8f 10.76$ t -13.2f 11.54$

268.9? 88.55 257.4? 75.68

-22.1f 12.65$ -13.4? 12.77$ ’

-23.0f 11.18$ -16.2t 15.40$ +

-24.6t 10.614 -17.8t 15.511 t

-22.8f 11.761 , -16.5i 15.20$

-23.9t 12.161 t -16.82 14.98$

55.2t 12.26 55.2f 12.62

-0.1 ? 11.13 9.9+ 12.12$ t

2.4f 10.88 11.1i 17.301 t

0.9t 11.54 13.3i 16.87t t

2.3t 13.64 12.0+ 14,73t t

2.02 13.5! 12.0t 14.57$ t

352.1 i 89.48

LDLC:HDLC Flwastatin 5.1f 2.09 Bezafibrate 5.0t 2.03 Triglycerides Fluvastatm 143.2+ 48.07 Bezafibrate 138.0f 59.47 V2lluesaremeans* standard deviation.

-22.0i ll.SO+ -20.2f 16.141

-24.5t 12.301 -22.6t 20.06t

-25.0+ 11.774 -25.7t 18.90t

-23.5+ 14.871 -24.0i 18.47t

-24.5i 14.85$ -24.3t 18.271

-4.1 ? 33.43 -28.9A 19.54t ’

-9.4 i 22.57t -27.1+ 26.48$ ’

-4.6 + 31.84 -28.2f 28.431 t

-2.2t 34.67 -28.0? 26.53$ ’

-4.6 f 34.35 -26.92 27.37$ ’

Biasalinevalues , are . means of w@s 11 and 14 (placebo period). %esuns or Imenuon-uxrear analysis. ‘p ~0.05; tp ~0.01; $p
n q

TC

F F

LDL-C

Bezafibrate

TG

0 $ :, j; : i,

z Iii+ -5+! 2!3 -lo-

Fluvaslatin

m

I,“

l .

:: _’ (,_ A

-15l

.*

.

-2oFigure 2. Mean percent changes from baseline in lipoprotein levels after 12 weeks of treatment with fluvastatin at 40 mg/day (n = 60) or bezafibrate of 400 mg/day (n = 63). ‘p co.05; “p
l *

-25-

ns.

Lipoprotein

parameters

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TABLEIII Median Percent Chan es in Apolipoproteins (APO)and Lipoprotein Particles (Lp) versus Baseline at End of Study Percent Changes Parameter/lreatment

Baseline (mg/dL)

Week 26

Endpoint

h-JOB Fluvastatin

138.0i 47.00

Bezafbrate

134.0 + 42.00

-18.82 16.03$ -15.3t 20.5Ot

-20.5i 16.70t -15.3t 18.46$

Ape A-l Flwastabn

129.0+ 28.00

Bezafibrate

131.0 + 30.00

0.82 15.54 8.7t 14.5Ot +

0.0t 16.86 8.9f 13.711 ’

Apo All Fluvastatin

39.0+ 7.00

Bezafibrate

39.0 + 9.00

-2.4 t 16.34 30.4? 24.16$ ’

-2.6? 15.31 30.4i 23.36$ ’

20.0t 69.6Ot 14.32 8485+

20.0t 66.67+ 14.3+ 68.18+

Apo E

6.0+ 4.50 6.0+ 4.00

Fluvastatin Bezafibrate Lplal Fluvastatin

12.0? 16.50

9.1i 40.53

8.3i 40.53

Bezabbrate

14.0 + 30.00

3.1 t 29.56+

3.1 i 27.69+

LPN

55.0+ 19.00 54.0f 19.00

Fluvastatin Bezafibrate

.,

8.1i 28.79+ -9.5? 24.11t t

8.3i 28.56+ -9.5 222.07+ t

,.

?&es are mearans ana mterquartne ranges. Baselinevalues are from week 14 (placebo period). +p ~0.01; $p ~0.001 versus baselineare from Wilcoxon sIgnedrank test for median % change equal to 0. Between-groupdifferences are from Kruskal-Wallistest.

creased by both drugs. Bezafibrate produced larger increases in both apo A-I [8.‘7% (p ~0.001) vs 0.8% (not significant) with fluvastatin; p co.01 between groups] and apo A-II (30.4% vs -2.4%, respectively; p
Compliance with the study medication was >97.2% with both compounds at all visits. Compliance with the diet was less complete: 24.1% of fluvastatin patients and 25.4% of bezafibrate patients were noncompliant at week 26. The main reasons for dietary noncompliance were a polyunsaturated to saturated fat ratio of <0.‘75 and a fat intake of >35%. Tolerability and Safety

Both drugs were equally well tolerated as assessed by the investigators’ and patients’ subjective ratings. Altogether, 21 (32.8%) patients taking fluvastatin and 16 (23.9%) taking bezafibrate reported at least one adverse clinical event. The most common adverse events were headache (four fluvastatin and three bezafibrate patients); ar6A-6DS

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Journal of Medicine

thropathy, dyspepsia, and angina pectoris (two fluvastatin patients each); gastritis and back pain (two bezafibrate patients each). Two patients in each group experienced serious clinical adverse events: two patients taking bezafibrate and one taking fluvastatin had a myocardial infarction, and one fluvastatin patient experienced severe angina pectoris. In all four patients, the events were thought to be due to underlying CAD. All four discontinued the study. Analysis of primary safety parameters showed no clinically notable changes in aspartate @GOT) or alanine (SGPT) transaminases, or in alkaline phosphatase, defined as a >3 x upper limit of normal (ULN) increase on two consecutive occasions for the transaminases or increases >3 x ULN for alkaline phosphatase. One patient in the fluvastatin group developed an asymptomatic increase in y glutamyltransferase (r-GT) levels to 125 U/L (normal range O-28 U/L) but, after 2 weeks, the r-GT level was 18 U/L. One patient in the bezafibrate group developed a clinically notable (>lO x ULN) CK level of 968 U/L (normal range lo-80 U/L) following a muscular injury. Levels returned to normal with treatment. There were no clinically relevant changes in any other blood chemistry variables and no clinically relevant abnormalities in the results of the hematological or urine tests.

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SYMPOSIUM ON HYPERLIPIDEMIA/ GRETEN ET AL

Ophthalmologicalexaminationdid not reveal any new or worsening lens abnormalities associated with reduced visual acuity. Overall, new or worsened lens abnormalities were observed in three fluvastatin and eight bezafibrate patients. DISCUSSION The results show that both drugs significantly reduced LDL-C and total cholesterol within 3 weeks of starting treatment and maintained these reductionsthroughout the study. Fluvastatin, however, led to a significantly greater reduction in LDL-C and tended to lower total cholesterolto a greater extent than did bezafibrate. Both drugs produced a similar lowering in the LDL-C to HDL-C ratio, which can be consideredbeneficial. Only bezafibrate significantly reduced TG and increased HDL-C. This pattern is similar to that found in comparisons of bezafibrate with other statins (simvastatin [25-291and lovastatin [30]) in patients with type II hyperlipidemias.The changes seen with bezafibrate in the present study were within the ranges found in the above-mentioned studies, and also in comparisonswith placeboand with pretreatment lipid and lipoprotein values [31331.However, in contrast to our study, in none of these other trials was strict adherenceto diet (as investigated by computerizedanalysis of food records) an inclusion criterion. The different effects of the two drugs on lipoprotein particles may be explained in terms of their modes of action. Fluvastatin prevents the production of intracellular cholesterolin the liver by inhibiting HMG-CoA reductase, the rate-limiting enzyme in biosynthesis.This leads to a reducedproduction of LDL [34], and the shortageof intracellular cholesterol stimulates an increasedproduction of high-affinity LDL receptors on hepatocyteswith a consequentincreaseduptake of LDL from the circulation [17,35].The LDL receptor is also partly responsiblefor clearanceof VLDL that carry TG [36].Both are therefore clearedfrom the circulation to some extent, and some constituents are usedto form HDL [3’7-391.Thus, with HMG-CoA reductase inhibitors, the main effect is on LDL-C with small changesin VLDL, TG, and HDL-C as a consequence. Bezafibrate,on the other hand,acts in a complex manner that has not yet beenfully elucidated.The main effect appearsto be an enhancedactivity of lipoprotein and hepatic lipases [38,40]resulting in an increasedcatabolism of VLDL and consequent clearanceof TG from the circulation [38,41&l. Certain surface constituentscombinewith other particles to produce HDL [37,39,43],and other compo-

nents act as precursorsof LDL; thus, LDL and associatedapo B levels may rise [44]. Bezafibrate hasbeenshownto inhibit HMG-CoA reductasein rats [45], and this could increasethe number of LDL receptors.[15]. There are no convincing data to suggestthat fibric-acid derivatives are competitive inhibitors of HMG-CoA reductase 130,461. Correction of structural defectsin LDL resulting in improved receptorbinding and increased clearancemay also occur [38,4X]. Bezafibrate may raise LDL-C levels during treatment of hypertriglyceridemic patients who have increased VLDL levels, but not normotriglyceridemic hypercholesterolemic patients [16]. Bezafibrate mainly lowers LDL-C when pretreatment levels are >160 mg/dL [47]. Only bezafibratesignificantly lowered TG. However, TG may not be an independentrisk factor for CAD in men, as suggestedin multivariate analyses [5,6]. On the other hand, hypertriglyceridemia is a coronary risk factor in the presenceof a plasma LDL-C : HDL-C ratio >5.0 [2]. Changesin apolipoproteinsreflect changesin lipoproteins.Apo B is mainly associatedwith VLDL and LDL [44] and therefore fell in correlation with LDL-C with both drugs.Apo A-I and A-II are components of HDL, and both rose during treatment with bezafibrate but not with fluvastatin. Despite the effects on apo A, LpA-I was decreasedby bezafibrate but significantly increased by fluvastatin. A similar pattern of effect on LpA-I was observed in a comparative trial of simvastatin and fenofibrate [43]. LpA-I has been described as the main antiatherogenicparticle in HDL by some investigators 149,501, but this has yet to be confirmed in further studies.Thus, despitethe lack of effect on HDL-C, the observed increase in LpA-I with fluvastatin may be regardedas beneficial.Changes in Lp(a) were too small to allow any interpretation. Both drugs were well tolerated as assessedsubjectively and by measurementof laboratory parameters. Only onepatient developeda clinically significant increasein -y-GT.In a review of the adverse effects of lipid-lowering drugs, Steiner et al [51] reported increasedtransaminaselevels in approximately 2% of patients taking lovastatin. No clinically notable increasesin transaminaseswere observed in our study. The ophthalmologicalabnormalities observedin our study are similar to thosereported by Smith et al 1281.HMG-CoA reductaseinhibitors have been found to producecataractsin dogs,but this has not been confirmed in human studies [51,52].During the developmentof fluvastatin, no differenceswere found in either the prevalenceor incidenceof newly

June 6, 1994 The American Journal of Medicine Volume 96 (suppl 6A)

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occurring or worsening with placebo.

lens opacities

compared

CONCLUSION Both fluvastatin (40 mg/day), a new HMG-CoA reductase inhibitor, and bezafibrate (400 mg/day) effectively produced beneficial changes in lipid, lipoprotein, and associated parameters. Fluvastatin reduced LDL-C and increased LpA-I to a significantly greater extent than did bezafibrate. Significant reductions in TG and increases in HDL and apo A were apparent only with bezafibrate. Both drugs were well tolerated.

ACKNOWLEDGMENT The study was supported by Sandoz AG Niirnberg.

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