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Effects of Fenofibrate on Bile Lipid Composition

Robert H. Palmer

In humans, clofibrate increases the degree of bile cholesterol saturation and predis- poses patients to cholesterol gallstone formation. To determine if this activity exends to the related hypolipidemic agent fenofibrate, duodenal bile lipid composition was studied in 15 subjects before they participated in a double-blind study of that drug.

Eight subjects were studied again on fenofibrate and six on placebo; five placebo patients were also studied later on open-label fenofibrate. The results were similar in the double-blind and open-label studies, and changes in bile lipid composition were comparable to those seen in studies of clofibrate. Fenofibrate caused a significant decrease in the molar percentage of bile acids and increases in the molar percentage of phospholipids and cholesterol. The changes in bile acids and phospholipids had opposing effects on the cholesterol-holding capacity of bile. A statistically significant increase in the cholesterol saturation index was only apparent when all fenofibrate bile analyses were compared with all untreated bile analyses. The results demonstrat- ed that fenofibrate has clear effects on bile lipid composition that may be associated with an increased propensity for gallstone formation, and when fenofibrate is used, patients should be monitored for this possibility.

(Arteriosclerosis 5:631-638, November/December 1985)

I

t has been established that clofibrate use is associ- ated with changes in biliary lipid composition1"9 and an increased incidence of gallstones.5'10"12 The pres- ent investigations were undertaken to determine if fenofibrate, an effective new hypolipidemic drug, causes similar changes in bile lipid composition and hence should be studied further with respect to pos- sible effects on cholesterol gallstone formation.

Methods Subjects

The subjects were hypercholesterolemic patients participating in a 6-month double-blind study of feno- fibrate compared to placebo. This was followed in some patients by an open-label 6-month treatment period. To be eligible for the double-blind study, pa- tients had to have levels of total cholesterol greater than 250 mg/dl and, on at least one occasion, levels of LDL cholesterol greater than 175 mg/dl as deter-

From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.

This work was supported in part by NHLBI Grant HL 21006 (SCOR in Arteriosclerosis) and Grant RR 00645 (General Clinical Research Center).

Address for reprints: Robert H. Palmer, M.D., Clinical R & D, Smith Kline and French Laboratories, 1500 Spring Garden Street, L217, Philadelphia, Pennsylvania 19106.

Received October 15,1984; revision accepted June 17,1985.

mined by the LRC methodology.13 All patients were men and women between 18 and 65 years of age;

the women were incapable of becoming pregnant and not on estrogen or contraceptive steroid therapy.

Excluded were patients with a history of important medical illness, including liver or gallbladder dis- ease, myocardial infarction or unstable angina within the previous 3 months, a history of alcohol or drug abuse, secondary hyperlipidemia, or a body mass index (weight/height2) greater than 0.0457 Ib/in2.

Subjects were told of the bile study at four centers, and if willing to participate they underwent oral cho- lecystography. If a functioning gallblader without stones was found, those patients were referred to Columbia-Presbyterian Medical Center for the bile lipid studies. Appropriate informed consent was ob- tained in accordance with provisions of the Human investigation Committee of the Columbia Presbyteri- an Medical Center.

Bile Studies

Subjects were hospitalized overnight in the Gener- al Clinical Research Center where, after informed consent had been obtained, a small, mercury- weighted, nasoduodenal tube (Hydromer-Dobbhoff Enteric Feeding Tube No. 14-7158, Biosearch Medi- cal Products, Incorporated, Somerville, New Jersey) was passed and allowed to progress into the duode- num. At bedtime, the patients drank 5 /xCi of 14C- cholic acid (NEC-241, New England Nuclear, Bos- 631

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Table 1. Serum and Bile Llplds In Patients Receiving Placebo or Fenoflbrate Patient

no. Age

Placebo group 231 64 131

205

251

241

258

212 Fenofibrate

203 238 240 210 247 138 214 256

54 60

50

30

60

33 group 49 63 63 62 63 48 55 47

Sex

F M F

M

F

M

M

F M M F

LL

M F M

Weight (lbs)

124 169 119

174

104

200

144

115 157 182 132 216 247 146 197

Sample date 06/22/82 10/06/82 08/13/82 03/11/83 07/16/82 11/23/82 08/16/83 07/29/82 02/28/83 08/26/83 08/13/82 02/28/83 08/23/83 01/07/83 06/30/83 11/22/83 10/06/82 01/10/84 05/04/82 11/09/82 06/29/82 01/07/83 06/30/82 11/24/82 08/13/82 03/11/83 08/13/82 03/02/83 08/25/82 04/11/83 12/07/82 03/02/83 12/10/82 06/30/82

Treat- ment*

P1 P2

i- CM

P1 P2 F3

••- CM CO0.0- LL *- OJ CO0.0. li. ••- CM CO0. Q. li.

P1 F3 P1 F2 P1 F2 P1 F2O. LL *- CM

P1 F2

*- OJ0. Li.

P1 F2

Tl 13 to

Choi 289 276 266 299 240 255 200 284 260 221 419 407 265 214 222 185 367 395 284 232 275 222 290 250 313 270 264 218 274 236 388 174 227 204

Serum lipids TG 128 139 238 388 142 95 43 250 136 107 134 112 95 149 212 142 77 78 216 85 146 76 203 145 305 234 155 110 137 128 517 75 234 111

(mg/dl)t LDL-C

152 158 162 154 173 146 165 267 278 125 117 302 319 211 160 160 101 170 124 210 182 157 115 199 158 144 87 167 140

HDL-C 59 54 26 65 61

CO COCO CO

31 32

CO CO en co

44 54 44 56 46 52 52 53 53 58 50 53 45 44 46 68 34 41

•Treatment: P1 = baseline placebo; P2 = double-blind placebo; F2 = double-blind fenofibrate; F3 = open label fenofibrate.

fBaseline value (P1) is the mean of two determinations. Treatment values (P2, F2, F3) are values obtained at the time of the bile study, or the average of two determinations when the bile study occurred between visits.

^Cholesterol saturation is the mol% of cholesterol required to saturate gallbladder bile at a total lipid concentration of 15 g/dl (see references 18, 19).

§Cholesterol saturation index is expressed as cholesterol content (mol%) divided by the cholesterol saturation.

Choi = cholesterol; TG = triglycerides; BA = bile acids; PL = phospholipids.

ton, Massachusetts) in 2 ml of ethanol and approximately 50 ml of orange juice to enable mea- surement of bile acid pool size by the method of Duane et al.14 In the morning, the position of the tube was checked by x-ray, and if the tip was not in the duodenum, the tube was repositioned and gastric emptying was facilitated by the intravenous injection of 5 mg of metoclopromide (A. H. Robbins Company, Richmond, Virginia). As close as possible to 14 hours after the evening meal, gallbladder contraction was stimulated by intravenous injection of 0.02

/xg/kg sincalide (E. R. Squibb & Sons, Incorporated, Princeton, New Jersey). Bile was aspirated, and 1 to 2 ml of the darkest bile was immediately pipetted into 20 ml of chloroform/methanol (2:1).

Bile Analyses

The chloroform/methanol solution was brought to boiling in a hot-water bath and cooled to room tem- perature. The precipitated proteins were removed by filtration through Whatman No. 1 filter paper. The

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Table 1.

BA

(Continued) Bile lipids (mM)

PL Choi BA

Bile lipids (mol%)

PL Choi

Choi*

sat.

(%)

Chol§

sat.

index 6.41

9.67 9.11 110.0 107.0 187.0 84.0 89.4 91.3 22.5 110.0 24.9 56.2 48.2 31.3 37.5 13.3 4.30

3.65 2.70 3.5 37.4 19.9 43.0 69.8 19.2 39.0 21.2 19.5 9.8 21.6 16.7 16.3 23.8 4.50 3.40

1.46 0.82 1.05 18.9 12.0 14.0 26.4 11.6 12.2 12.2 10.9 4.9 18.6 9.08 10.1 10.3 1.40 1.67

55.6 73.3 66.7 66.2 77.1 76.6 46.7 74.3 64.1 40.3 78.4 62.9 58.3 65.1 54.3 52.4 69.2 45.8

31.7 20.5 25.6 22.4 14.3 17.6 38.7 16.0 27.3 37.9 13.8 24.8 22.4 22.6 28.2 33.2 23.5 36.4

12.7 6.2 7.7 11.3 8.6 5.7 14.6 9.7 8.6 21.8 7.7 12.3 19.3 12.2 17.5 14.4 7.3 17.9

8.9 7.3 8.3 7.9 5.9 6.6 8.6 6.4 8.6 8.5 5.7 8.4 8.3 8.0 8.8 8.9 8.0 8.6

1.43 0.85 0.93 1.43 1.46 0.86 1.70 1.52 1.00 2.56 1.35 1.46 2.32 1.53 1.99 1.62 0.91 2.08 4.66

29.0 6.33 109.0

76.8 40.2 74.4 30.1 118.0 37.3 135.0 20.5 11.0 12.7 31.7 26.9

2.44 16.5

2.31 43.4 14.2 12.4 17.1 13.9 28.0 20.8 29.3 7.39 2.89 7.76 7.80 16.2

1.17 6.19 1.27 8.15 10.3

6.17 11.5

7.3 8.0 6.3 11.5 5.25 1.81 5.67 4.41 7.55

56.3 56.1 63.9 67.9 75.8 68.4 72.3 58.7 76.7 57.9 76.8 61.8 70.2 48.6 72.2 53.1

29.5 31.9 23.3 27.0 14.0 21.1 16.6 27.1 18.2 32.3 16.7 22.3 18.3 29.7 17.8 31.9

14.2 12.0 12.8 5.1 10.2 10.5 11.1 14.3 5.2 9.8 6.6 15.9 11.6 21.6 10.1 14.9

8.9 8.9 8.2 8.4 5.8 7.6 6.6 8.7 6.7 8.9 6.4 8.1 7.0 8.9 6.8 8.9

1.60 1.35 1.56 0.61 1.80 1.38 1.68 1.64 0.78 1.10 1.03 1.96 1.66 2.43 1.49 1.67

paper was washed with the solvent, and the com- bined solvent was made up to 20.0 ml. Exactly 5 ml was taken for cholesterol determination by the meth- od of Hanel and Dam.15 Aliquots of 0.1 and 0.2 ml were taken to dryness for total phosphorus determi- nations by the method of Bartlett,18 and additional aliquots were taken for enzymatic analysis of total bile acids as described previously.17 Separate ali- quots were counted for radioactivity using external standards for quench correction.

Experimental Design

All subjects (seven women and eight men) had an initial bile analysis either before beginning the medi- cation or during an initial single-blind placebo period.

Patients then entered the double-blind study and re- ceived either placebo or 300 mg/day of fenofibrate according to an allocation scheme that reserved cer-

tain study numbers at each center for bile-study pa- tients. Patients then had a second bile analysis be- tween 3 and 6 months of the double-blind study, except for Patient 212 who was studied again only after entering the open study. An additional four pa- tients in the placebo group were also studied a third time after 3 to 6 months of fenofibrate administration during the open study.

Calculations

Cholesterol saturation indices (CSI) were calculat- ed from the tables of Carey18 or from the equations of Carey and Small,19 based on a gallbladder bile total lipid of 15 g/dl (a concentration typical of healthy controls but slightly higher than usually seen in pa- tients with gallstones). Comparisons between groups were made by paired or unpaired Student's f tests as applicable.

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Results

Data on the subjects and the results of the bile and plasma lipid analyses are shown in Table 1. Seven patients were assigned to the placebo group (six of whom were studied for the second time during place- bo administration), and eight were assigned to the fenofibrate group. Five of the placebo patients were also studied again during open-label fenofibrate ad- ministration. Statistical analyses of paired bile data from the double-blind study are presented in Table 2, and analyses of paired data from the open-label study are presented in Table 3. Unpaired compari- sons of all data are given in Table 4.

The placebo group and the fenofibrate group were comparable at baseline. There were three women and four men in the placebo group, with a mean age of 50.1 ± 13.5 years (SD) and a mean weight of 148

± 34.6 pounds. There were four women and four men in the fenofibrate group, with a mean age of 56.3

± 7.3 years and a mean weight of 174 ± 44.7 pounds. The baseline cholesterol and triglycerides during the single-blind placebo period were 297 ± 72 mg/dl and 160 ± 62 mg/dl in the placebo group, and 289 ± 47 mg/dl and 239 ± 125 mg/dl in the fenofibrate group. Thus, the fenofibrate group was slightly older, heavier, and had higher triglyceride levels than the placebo group, but the differences were not statistically significant.

Bile Acid Pool Size

The bile acid pool averaged 9.4 ± 8.4 mmol in placebo determinations (n = 21) and 8.4 ± 3.4 mmol in fenofibrate determinations (n = 13). Howev- er, measurements of bile acid pool size were quite varied, and it is doubtful that the method gave reli- able information when used in this manner. Certain- ly, no firm conclusions can be drawn, but there was no suggestion that fenofibrate influenced pool size.

Bile Lipids

When the individual bile lipids were examined, it was clear that fenofibrate produced substantial changes in the relative amounts of the three constitu- ents. In the double-blind study, fenofibrate de- creased the relative proportion of bile acids from 70.5% to 59.1 % (p = 0.01), increased the proportion of phospholipids from 19.3% to 27.9% (p = 0.001), and increased cholesterol from 10.2% to 13.0% (not significant). In the placebo group, neither the change in bile acids from 69.5% to 66.2%, in phospholipids from 20.7% to 23.5%, nor the change in cholesterol from 9.8% to 10.3% was significant. When the treat- ment values for the placebo group and the fenofi- brate group were compared by unpaired f tests, the differences in bile acids and phospholipids were not significant (p = 0.09 and 0.08 respectively).

Similar results were obtained in five placebo pa- tients when the baseline bile compositions were compared with the compositions on open-label feno- fibrate, except that the differences were slightly larg- er and statistically more significant; during open-la- bel fenofibrate, the increase in cholesterol was significant (p = 0.01), although not as striking as the increase in phospholipids (p = 0.008) or the de- crease in bile acids (p = 0.003).

Finally, similar differences were observed when all 21 untreated samples (obtained prior to the study or while on placebo) were compared with all 13 fenofi- brate samples. In this comparison, the changes were highly significant (Table 4).

Bile Cholesterol Saturation and Cholesterol Saturation Index

The increased proportion of phospholipids that re- sulted from fenofibrate administration increased the cholesterol-holding capacity of bile in spite of the decreased proportion of bile acids. This was a con-

Table 2. Bile Lipids: Double-Blind Study

Bile adds (mol%) Placebo (n = 6) Fenofibrate (n = 8) Phospholipids (mol%)

Placebo Fenofibrate Cholesterol (mol%)

Placebo Fenofibrate

Cholesterol saturation (mol%) Placebo

Fenofibrate

Cholesterol saturation index Placebo

Fenofibrate

Baseline

X

69.5 70.5 20.7 19.3 9.77 10.20 7.20 7.05 1.37 1.45

SD

8.72 7.15 7.20 4.88 2.21 3.01 1.37 1.00 0.23 0.35

Treatment

X

66.2 59.1 23.5 27.9 10.3 13.0 7.93 8.55 1.27 1.52

SD

7.94*

6.85*

4.08t 4.37f 4.42 4.89 0.85 0.48 0.45 0.55

Difference

X

- 3 . 3 0 - 1 1 . 5

2.80 8.61 0.50 2.79 0.73 1.50 - 0 . 1 1 0.07

SD

11.90 9.37 8.71 4.56 4.75 5.89 1.60 0.88 0.52 0.62

Paired t - 0 . 6 8 - 3 . 4 6 0.78 5.34 0.26 1.33 1.12 4.81 0.49 0.22

P NS 0.01 NS 0.001

NS NS NS 0.002

NS NS 'Unpaired t = 1.81; p = 0.09.

fUnpaired t = - 1 . 9 4 ; p = 0.08.

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Table 3. Bile Llplds: Open-Label Study

Bile acids (mol%) Phospholipids (mol%) Cholesterol (mol%)

Cholesterol saturation (mol%) Cholesterol saturation index

Placebo

X

72.8 18.0 9.10 6.80 1.35

SD

5.58 4.66 1.96 1.12 0.26

Fenofibrate

X

48.7 33.7 17.6 8.58 2.06

SD

6.87 6.67 3.16 0.22 0.40

Difference

X

- 2 4 . 1 15.7 8.50 1.78 0.70

SD

8.43 7.04 4.27 0.97 0.50

Paired t - 6 . 4 0

4.98 4.45 4.09 3.15

P 0.003 0.008 0.01 0.015 0.03 Results shown are for five patients studied first at baseline and again during open label fenofibrate (see Table 1).

sistent finding in both studies, and also was seen when the results of all analyses were pooled. Never- theless, the increased cholesterol content in the open-label study was still sufficient to increase the cholesterol saturation index (CSI) significantly, al- though the increase in the double-blind study was less and not statistically significant. When all of the results were pooled, the difference in the CSI was statistically significant at the p = 0.02 level.

Changes In Plasma Llplds and Llpoprotelns At the time of the second bile study (during the double-blind period), the plasma cholesterol in the fenofibrate group had fallen from 289 mg/dl to 226 mg/dl (p = 0.02), whereas the plasma cholesterol in the placebo group was unchanged (285 mg/dl vs 287 mg/dl). Similarly, plasma triglycerides decreased in the fenofibrate group from 239 mg/dl to 121 mg/dl (p

= 0.04), whereas they were unchanged in the place- bo group (174 mg/dl vs 180 mg/dl). When changes in plasma lipoproteins were examined, LDL cholesterol increased in the placebo group (n = 6) from 191 mg/dl to 202 mg/dl (5.6%) and decreased in the feno- fibrate group (n = 8) from 177 mg/dl to 133 mg/dl (-25%); the difference was highly significant (p <

0.001). Conversely, HDL cholesterol in the placebo group was unchanged at 46 mg/dl, while it rose in the treated group from 46 mg/dl to 53 mg/dl (15%). The mean plasma cholesterol value for the total group of the 21 untreated samples was 291 mg/dl, and the mean value for the total group of 13 fenofibrate sam- ples was 236 mg/dl. The corresponding triglyceride values were 186 mg/dl and 110 mg/dl. There was no apparent relationship in the treated patients between the extent of plasma lipid reduction and the change in biliary lipids.

Discussion

The major finding of this study was a highly signifi- cant change in the relative proportions of bile lipids during fenofibrate therapy. The proportion of bile acids decreased, whereas the proportions of phos- pholipids and cholesterol increased. Because the proportions of the two solubilizers of cholesterol (bile acids and lecithin) changed in opposite directions, the effects on bile saturation with cholesterol were inconclusive.

The experimental design of this study resulted in moderate variability in the determination of bile lipid composition. The analyses were based on only one sample of bile, whereas some studies (particularly those in bile fistula patients where sample collection is simple) have utilized multiple bile samples. In addi- tion, it is not possible to be sure that all samples were strictly comparable, as it is impossible to quantitate the extent to which bile was diluted with intestinal and/or gastric contents (particularly when metaclo- promide was used to facilitate tube passage) and to know whether the collected bile was representative gallbladder bile, diluted gallbladder bile, or hepatic bile. Thus, even though three samples had bile acid concentrations of less than 5 mM, all samples were used in the analysis. Attempts were made to stan- dardize the amount of time between the last meal (and hence the last stimulated gallbladder contrac- tion) and the bile sample, as it has been shown that bile saturation changes with the length of time the enterohepatic circulation has been interrupted by fasting;20'21 nevertheless, some variation in this inter- val was inevitable.

The variables just discussed did not prevent the demonstration of highly significant changes in bile iipid composition, and even omitting the dilute bile

Table 4. Bile Llplds: All Studies Combined

Bile acids (mol%) Phospholipids (mol%) Cholesterol (mol%)

Cholesterol saturation (mol%) Cholesterol saturation index

Placebo (n =

X

69.0 21.1 9.97 7.39 1.35

21)

SD

7.48 5.36 3.11 1.08 0.35

Fenofibrate (n =

X

55.1 30.1 14.8 8.56 1.72

13)

SD

8.40 5.88 4.76 0.39 0.55

Unpaired t 5.01 - 4 . 6 1 - 3 . 5 7 - 3 . 7 4 - 2 . 4 4

P

<0.001

<0.001 0.001

<0.001 0.02

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samples from the analysis did not alter the findings appreciably. In general, these changes are qualita- tively similar to those seen in previous studies exam- ining the effect of clofibrate on bile lipids,3-5' "•9 which have shown a decrease in the molar percentage of bile acids and an increase in the molar percentage of phospholipid and/or cholesterol. In air clofibrate stud- ies, the changes in bile lipid composition resulted in an increased CSI, whereas the qualitatively similar changes that we observed with fenofibrate were quantitatively slightly different, and the resulting in- crease in cholesterol-holding capacity prevented the demonstration of a significant increase in the CSI except when the results of all the studies were pooled.

There have been limited studies on the effect of other clofibrate derivatives on bile composition.

Most,7'22-23 but not all,24 of the studies demonstrated similar changes. Two of the studies included fenofi- brate. Schlierf et al.7 found that the increase in the CSI produced by fenofibrate was slight and statisti- cally not significant (lipid composition not given). In recent studies published while the present results were being analyzed, von Bergmann and Leiss23 found that fenofibrate decreased bile acids from 72.7% to 58.6%, increased bile cholesterol from 8.2% to 14.3%, and increased bile phospholipids from 19.1 % to 27.1 %. The lipid changes were similar to those seen in the present study, but did result in a statistically significant increase in the CSI from 1.31 to 1.77. The change in CSI found by von Bergmann and Leiss was almost identical to the change ob- served in the present study for the pooled analyses (1.35 vs 1.72).

The mechanism by which these compounds alter bile lipid composition has not been completely estab- lished, in part because the mechanisms governing the secretion of bile constituents are not entirely un- derstood. The relative decrease in bile acids and increase in both cholesterol and phospholipids would be consistent with either a decrease in bile acid secretion (presumably secondary to decreased synthesis and pool size, or possibly decreased recy- cling), an increase in the secretion of cholesterol and phospholipids, or both. The present studies provide no direct evidence on this question. Previous work22 has shown that bile acid secretion rates are unaffect- ed by ciprofibrate. Clofibrate does decrease bile acid synthesis,2 either directly by affecting enzymatic (7a- hydroxylase) conversion of cholesterol to bile acids, or indirectly by reducing the microsomal (perhaps regulatory) pool of cholesterol that serves as sub- strate. An indirect effect is suggested because: 1) clofibrate inhibits whole body cholesterol synthesis;2 2) fenofibrate inhibits 3-hydroxy-3-methylglutaryl CoA (GMG-CoA) reductase in monocytes;25 and 3) hepatic LDL receptors are upregulated by bezafi- brate and fenofibrate, and whole body receptor-me- diated uptake of LDL is increased.26'27 These studies argue persuasively that the major effect of these drugs is to decrease the regulatory microsomal pool

of cholesterol, probably through a primary effect on cholesterol synthesis, with secondary effects of in- creased LDL uptake and reduced bile acid synthesis.

However, the secondary increase in LDL uptake would provide more cholesterol and tend to normal- ize bile acid synthesis; the extent to which that hap- pens may indicate the extent to which LDL cholester- ol ester can be hydrolyzed and compete with newly synthesized cholesterol as a substrate for bile acid synthesis.

The second possible explanation for the change in bile lipid composition would be enhanced secretion of cholesterol and phospholipids. Studies with cipro- fibrate in eight patients showed a statistically signifi- cant increase in bile cholesterol secretion for the five patients in whom bile cholesterol saturation in- creased.22 In the studies of Grundy et al.,2 clofibrate appeared to mobilize cholesterol from tissues. This hypothesis is supported by the early studies of Grundy and Mok,4 in which the bile changes induced by clofibrate appeared to be transient, and by the studies of Angelin et al.8 in which the lithogenic effect of clofibrate that was apparent after 6 weeks of treat- ment had largely disappeared in studies done after 6 months of treatment. Since the half-time for transfer of cholesterol between the slowly turning over pool and the plasma is 35 days,28 6 months of treatment might be expected to result in mobilization of most of the excess tissue stores and lead to a new equilibri- um. If these inferences are correct, it might explain why the present results were quantitatively some- what less significant than those of other studies, as most of the analyses in this study were done after 3 to 6 months of therapy (150 ± 41 days for the eight fenofibrate patients during the double blind study:

179 ± 34 days for the five patients on open-label fenofibrate). Thus, it seems reasonable to suggest that the period of greatest vulnerability with respect to developing cholelithiasis resulting from the admin- istration of clofibrate derivatives may be limited to a few months. On the other hand, the decreased pro- portion of bile acids shown in the present study could still be demonstrated after 3 to 6 months. It is possi- ble that agents such as clofibrate and fenofibrate or ciprofibrate may share a common mechanism of ac- tion with respect to reducing serum lipids and mobi- lizing cholesterol from tissues, but may differ in hav- ing different effects on the coupling of bile acid secretion to cholesterol and phospholipid secretion;

these effects may result in differing effects on the bile cholesterol saturation index. Such differences in coupling might lead to changes in the ratio of choles- terol/phospholipids in bile, and increases have been seen in studies where the hypolipidemic agent was associated with increases in bile cholesterol satura- tion indices.8- ^ a Such changes were not marked in the present study, where the ratio changed from 0.47 to 0.49, and the changes did not correlate well with changes in the saturation indices in individuals.

The present study indicates that fenofibrate use should be monitored to detect any possible tendency

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to increase gallstone formation. The changes in bile saturation were barely significant and not consistent, but the changes in lipid composition were definite and similar to those seen with clofibrate. However, it should be noted that changes in lipid composition can not be used to predict with any certainty whether an increased rate of gallstone formation will occur or not, and it is important to emphasize that increases in bile cholesterol content or saturation do not neces- sarily lead to gallstone formation. It is well estab- lished that the bile of most people is supersaturated with cholesterol at some time or other, usually in the morning,21 and it may well be that the relative propor- tions of substances that enhance or inhibit nuclea- tion or crystal formation are more important than the cholesterol content of bile in determining whether gallstones will occur in any individual.29"33 It would be of interest to ascertain whether the administration of clofibrate affects the nucleation time of bile and, if so, whether this property is shared by fenofibrate and other clofibrate derivatives. But despite these reser- vations, the changes we found make it prudent to recognize the possibility that fenofibrate may in- crease gallstone formation.

Even if it should be proven that fenofibrate does predispose to gallstone formation, this fact alone should not constitute a contraindication to the use of this drug in appropriate circumstances. As with any drug, the risks have to be weighed against the bene- fits. In this case, the possible increased risk would have to be quantified and weighed against the bene- fits of effective serum lipid reduction. In this small study, fenofibrate reduced LDL cholesterol by 25%, while it increased HDL cholesterol by 15%, resulting in approximately a 30% decrease in the LDL/HDL ratio. (These results are slightly greater than, though not dissimilar to, those obtained in the larger, multi- center trial to be reported separately.) It is possible that enhanced bile secretion of cholesterol is a con- comitant of any hypolipidemic agent that mobilizes cholesterol from tissues, and that some increased risk of gallstone formation is inherent in all effective agents. It is also possible that any such risk could be minimized or abolished by concomitant bile acid ad- ministration,7 and that any new stones (presumably being pure cholesterol stones), would be highly sus- ceptible to medical dissolution with bile acids. Clear- ly, more work needs to be done on the relation of hypolipidemic agents to bile cholesterol secretion.

For the present, the changes observed in this study should be construed as a warning, not as a contrain- dication. Whether they have established a definitive or unusual risk remains to be determined.

Acknowledgments

The help of Marian Adams and the staff of the General Clinical Research Center in doing the clinical studies and the excellent assistance of Dean Gittleman and Lakshmi Gollapudi in the labo- ratory are gratefully acknowledged.

References

1. Thistle JL, Schoenfleld LJ. Induced alterations in composi- tion of bile of persons having cholelithiasis. Gastroenterology 1971;61:488^»96

2. Grundy SM, Atirens EH Jr, Salon G, SchreJbman PH, Nes- tel PJ. Mechanisms of action of clofibrate on cholesterol me- tabolism in patients with hyperlipidemia. J LJpid Res 1972;

13:531-551

3. Pertsemlldls D, Panvellwalla D, Ahrens EJ Jr. Effects of clofibrate and of an estrogen-progestin combination on fast- Ing biliary lipids and cholic acid kinetics In man. Gastroenter- ology 1974;66:565-573

4. Grundy SM, Mok HYI. Colestipol, clofibrate, and phyto- sterols in combined therapy of hyperlipidemia. J Lab Clin Med 1977:89:354-366

5. Bateson MC, Maclean D, Rosa PE, Bouchler IAD. Clofi- brate therapy and gallstone induction. Digestive Dis 1978;

7:623-628

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Eur J Clin Invest 1981 ;11:185-189

9. Kesanleml YA, Grundy SM. Clofibrate, caloric restriction, supersaturatkxi of bile, and cholesterol crystals. Scand J Gastroenterol 1983;18:897-902

10. The Coronary Drug Project Research Group. Gallbladder disease as a side effect of drugs Influencing lipid metabolism.

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13. LJpid Research Cllnlca Program. Manual of laboratory op- erations: LJpid and lipoprotein analysis (NIH) publication 75- 628. Bethesda, Maryland: National Heart Lung and Blood Institute, 1975

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17. Palmer RH. The enzymic assay of bile acids and related 3a- hydroxysteroids: its application to serum and other biological fluids. In: Colowtek SP, Kaplan N, eds. Methods in enzymol- ogy. XV: Steroids and terpenoids. New York: Academic Press, 1969:280-288

18. Carey MC. Critical tables for calculating the cholesterol satu- ration of native bile. J Lipid Res 1978;19:945-955 19. Carey MC, Small DM. The physical chemistry of cholesterol

solubility in bile. Relationship to gallstone formation and dis- solution In man. J Clin Invest 1978;61:998-1026

20. Bloch HM, Thornton JR, Heaton KW. Effects of fasting on the composition of gallbladder bile. Gut 1980;21:1087-1089 21. Metzger AL, Adler R, Heymsfleld S, Grundy SM. Diurnal variation in biliary lipid composition. N Engl J Med 1973;

288:333-336

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Eur J Clin Invest 1984;14:73-78

23. von Bergmann K, Lelss O. Effect of short-term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in

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patients with hyperlipoproteinaemia. Eur J Clin Invest 1984;

14:150-154

24. Takeuchi N, Kukita H, Kajiyama G et al. Effect of clinofi- brate, a new hypolipidemic agent, on biliary and serum lipids in patients with hyperlipidemia. Atherosclerosis 1982;42:

129-139

25. Schneider AG, Ditschuneit HH, Strange EE, Ditschuneit H. Regulation of 3-hydroxy-3-methylglutaryl Coenzyme A re- ductase in freshly isolated human mononuclear cells by feno- fibrate. In: Carlson LA, Olsson AG, eds. Treatment of hyper- lipoproteinemia. New York: Raven Press, 1984:181-184 26. Stewart JM, Packard CJ, Lorimer AR, Boag DE, Shepherd

J. Effects of bezafibrate on receptor mediated and receptor independent low density lipoprotein catabolism in Type II hyperlipoproteinemic subjects. Atherosclerosis 1982;44:

355-365

27. Shepherd J, Caslake MJ, Lorimer AR, Vallance BD, Pack- ard CJ. Fenofibrate reduces low density lipoprotein catabo- lism in hyper- triglyceridemic subjects. Arteriosclerosis 1985;

5:162-168

28. Smith FR, Dell RB, Noble RP, Goodman DS. Parameters of the three-pool model of the turnover of plasma cholesterol in normal and hyperlipidemic humans. J Clin Invest 1976;

57:137-148

29. Holzbach RT, Kibe A, Thiel E, Howell JH, Marsh M, Her- mann RE. Biliary proteins. Unique inhibitors of cholesterol crystal nucleation in human gallbladder bile. J Clin Invest 1984;73:35-45

30. Holan KR, Holzbach RT, Hermann RE, Cooperman AM, Claffey WJ. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 1979;

77:611-617

31. Small DM. Cholesterol nucleation and growth in gallstone formation. N Engl J Med 1980;302:1305-1307

32. Sedaghat A, Grundy SM. Cholesterol crystals and the for- mation of cholesterol gallstones. N Engl J Med 1980;302:

1274-1277

33. Burnstein MF, llson RG, Petrunka CN, Taylor RD, Stras- berg SM. Evidence for a potent nucleating factor in the gall- bladder bile of patients with cholesterol gallstones. Gastroen- terology 1983;85:801-807

Index Terms: fenofibrate • bile • hypolipidemia • gallstones

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References

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