1. No category

HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.
G M Kostner, D Gavish, B Leopold, K Bolzano, M S Weintraub and J L Breslow
Circulation. 1989;80:1313-1319
doi: 10.1161/01.CIR.80.5.1313
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1989 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/80/5/1313
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
1313
HMG CoA Reductase Inhibitors Lower LDL
Cholesterol Without Reducing Lp(a) Levels
Gerhard M. Kostner, PhD, Dov Gavish, MD, Beate Leopold, PhD, Klaus Bolzano, PhD,
Moshe S. Weintraub, MD, and Jan L. Breslow, MD
Lp(a) is a plasma lipoprotein particle consisting of a plasminogenlike protein [apo(a)] disulfide
bonded to the apo B moiety of low-density lipoprotein (LDL). Increased plasma levels of Lp(a),
either independently or interactively with LDL levels, have been shown to be a risk factor for
atherosclerosis. Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors,
have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in
up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of
plasma LDL levels. In this study, we examined the effect of HMG CoA reductase inhibitors on
Lp(a) levels in three groups of subjects, five volunteers and two groups of five and 14 patients.
In all 24 subjects, mean decreases were observed in total cholesterol (43±5%), total triglyceride
(35 ±8%), very low-density lipoprotein (45±9%o), and LDL cholesterol (43±5%). The mean
change in high-density lipoprotein cholesterol was an increase of 7±8%. Despite the very
significant decrease in LDL cholesterol levels (p<0.001), Lp(a) levels increased by 33±12%
(p<0.005). This was not associated with a measurable change in the chemical composition or
size of the Lp(a) particle. This emphatically suggests that Lp(a) particles, despite consisting
principally of LDL, are cleared from plasma differently than LDL. The surprising finding of an
increase in Lp(a) levels suggests this class of drugs may have a direct effect on Lp(a) synthesis
or clearance independent of its effect on LDL receptors. (Circulation 1989;80:1313-1319)
L p(a) is a low-density lipoprotein (LDL)like particle with an additional protein,
apo(a), attached through one or more
disulfide bridges to the apo B moiety."2 Apo(a)
has been shown to be a large glycoprotein of
variable size (330-870 kd).34 The cDNA for apo(a)
has recently been cloned, and the deduced amino
acid sequence indicates the protein consists largely
of repeats of a region bearing striking homology to
the kringle 4 domain of plasminogen.5 In vivo
turnover studies have shown that Lp(a) is catabolized more slowly than LDL.6 In vitro studies
have shown that Lp(a) interacts poorly with LDL
receptors on fibroblasts.7-9 The function, if any, of
Lp(a) is unknown.
From the Graz University (G.M.K., B.L., K.B.), Graz, Austria; Rockefeller University (D.G., M.S.W.), New York, New
York.
Supported in part by grants from the National Institutes of
Health (HL-33714, HL-32435, HL-36461, CA-29502), a Fogarty
International Research Fellowship (TW03960), and a General
Clinical Research Center grant (RROO102), as well as general
support from the Pew Trusts. J.L.B. is an Established Investigator of the American Heart Association.
Based on their contributions to the study, both G.M.K. and
D.G. should be considered as first authors.
Address for correspondence: Dr. Jan L. Breslow, Rockefeller
University, 1230 York Avenue, New York, NY 10021.
Received January 18, 1989; revision accepted July 13, 1989.
Plasma Lp(a) levels vary, in humans, from less
than 2 mg/dl to greater than 200 mg/dl. Levels
above 20 or 30 mg/dl, present in 25% of the population, are thought to be a risk factor for atherosclerosis either independently or interactively with elevated LDL levels.10-15 Bile acid binding resins, used
to lower LDL levels, have had no significant effect
on Lp(a) levels.13 Niacin and neomycin, either
separately or in combination, have shown some
ability to reduce Lp(a) levels.'316 Recently, a new
class of lipid lowering drugs, HMG CoA reductase
inhibitors, was discovered that operate by reducing
liver cholesterol synthesis and causing upregulation of liver LDL receptors. This, in turn,
increases the uptake of LDL and decreases plasma
LDL levels.17"8 Because Lp(a) particles resemble
LDL particles, we examined whether this class of
drugs affects Lp(a) levels.
Methods
Subjects
This study was performed in two clinical centers,
and three groups of individuals were included.
Groups 1 and 2 were studied in Graz, Austria, and
group 3 was studied at the Rockefeller University in
New York. The patients of the Austrian groups
were selected primarily for high Lp(a) plasma con-
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
1314
Circulation Vol 80, No 5, November 1989
centrations. Group 1 consisted of five male volunteers without evidence of atherosclerotic disease
but with a wide range of initial Lp(a) levels. Two of
them were hypercholesterolemic. Each volunteer
was treated with 40 mg/day of Simvastatin, and
lipoprotein and Lp(a) levels were measured for up
to 6 weeks. Group 1 subjects retained their lifestyle
and dietary habits during the study. Group 2 included
five patients (male and female) referred to the Lipid
Clinic in Graz for treatment of hypercholesterolemia. These patients were treated with Simvastatin
at a dosage of 10-40 mg/day and observed for up to
9 months. Patients of group 2 were advised to
consume a low cholesterol diet (<300 mg/day) with
a caloric distribution of protein, carbohydrate, and
fat of 15%, 55%, and 30%, respectively. The polyunsaturated to saturated fat (P: S) ratio was 1.5.
Group 3 consisted of 14 patients (seven male and
seven female) referred to the clinic of the Laboratory of Biochemical Genetics and Metabolism at
Rockefeller University in New York for treatment
of hypercholesterolemia. All of them had a positive
family history for premature atherosclerosis, and 10
of them had coronary heart disease. The Rockefeller University patients followed an American
Heart Association phase 2 diet. The cholesterol
intake was less than 145 mg/1,800 calories with a
caloric distribution of protein, carbohydrate, and
fat of 15%, 60%, and 25%, respectively. The P:S
ratio was 1.5. Adherence to diet was monitored by
completion of a diet questionnaire and by interview
with a registered dietitian. Baseline lipid, lipoprotein, and Lp(a) levels were measured after 3 weeks
on the diet. These patients were treated with Lovastatin and received each dosage (20, 40, and 80
mg/day) for 4 full weeks; afterward, plasma lipid,
lipoprotein, and Lp(a) levels were measured. The
high dosage (80 mg/day) was continued for 6
months, whereupon levels were remeasured. Liver
function tests, muscle enzymes, renal function
tests, hemoglobin levels, white blood cell counts,
platelet counts, clotting functions, and electrolyte
levels were monitored for the whole period without significant changes in any of the patients.
Secondary hypercholesterolemia was ruled out
before inclusion in the study.
Lipid and Lipoprotein Determinations
Cholesterol and triglyceride in total plasma and
lipoprotein fractions were measured enzymatically
using Boehringer-Mannheim reagents (BoehringerMannheim Biochemicals, Indianapolis, Indiana, or
Biomerieux, France). Some analyses were performed manually, and others were performed with a
Greiner autoanalyzer. In the Graz studies, highdensity lipoprotein (HDL) cholesterol was measured in the supernatant after very low-density
lipoprotein (VLDL) and LDL precipitation by PEG
(polyethylene glycol),20 and LDL cholesterol was
calculated by the Friedewald equation. In the Rockefeller University studies, HDL and LDL cholesterol were measured in the infranatant after a 2hour spin in an airfuge (Beckman, Brea, California)
to float the VLDL. HDL cholesterol was determined after precipitation of the whole plasma with
dextran sulfate magnesium. Appropriate corrections were made for dilution factors, and VLDL,
LDL, and HDL cholesterol levels were calculated.
In all studies, Lp(a) was quantified by Laurell
immunoelectrophoresis21 using a polyspecific antibody from rabbit or horse. The antiserum had been
adsorbed by the addition of plasminogen and was
free of cross reactivity. Special care was taken to
measure Lp(a) in the linear range of standard concentrations that were applied on the same plate.
One batch of standards was used throughout this
study. All Lp(a) measurements were performed in
triplicate. The coefficient of variation of the measurement was less than 3%. The same antibody and
the same techniques were used in both laboratories.
Lipoproteins were separated by density gradient
ultracentrifugation for compositional analysis, gradient polyacrylamide gel electrophoresis, and negative staining electron microscopy by previously
described methods. The hydrated density of lipoprotein fractions was estimated by equilibrium banding density gradient ultracentrifugation. In this analysis, plasma was spun in an SW 41 rotor (Beckman)
at 40,000 rpm for 24 hours.
Sample Handling
Venous blood was drawn from the forearm and
transferred to tubes containing sodium EDTA (ethylenediaminetetraacetic acid). Samples were immediately centrifuged at 1,500 rpm for 15 minutes, and
0.5 ml aliquots of plasma were either kept at 40 C
for immediate assay or stored at -70° C for further
analysis. Storage under these conditions did not
affect Lp(a) measurements. LDL (density, 1.0251.050), Lp(a) (density, 1.063-1.12), and other lipoproteins were separated by density gradient ultracentrifugation as previously described.19
Results
The lipoprotein profiles before treatment for each
person are presented in Table 1, and the effects of
treatment on LDL cholesterol and Lp(a) levels are
shown in Figure 1. In the volunteers of group 1,
Simvastatin treatment for 6 weeks resulted in a
significant decrease of total cholesterol and triglycerides of 31±4% and 27+9%, respectively. VLDL
cholesterol was reduced by 26+9%, LDL cholesterol decreased by 47+5%, and HDL cholesterol
increased by 17.7+11%. In group 1, treatment
increased Lp(a) by 18+16%. A variety of responses
Statistical Analysis
Statistical analysis was performed using a paired t
test with Bonferroni's correction for multiple comparisons to compare pretreatment and treatment values.
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
{~20
Kostner et al Reductase Inhibitors Do Not Decrease Lp(a) Levels
TABLE 1. Patient History and Pretreatment Lipoprotein Levels
Patient
Group 1
Sex
Age
WtfHt2
Total
cholesterol
(mg/dl)
1
2
3
4
5
M
M
M
M
M
23
23
35
48
56
21.1
21.8
24.6
21.7
26.1
190
224
424
198
254
122
109
259
72
162
F
F
M
M
M
58
62
46
35
51
26.1
26.8
23.5
24.7
25.3
274
304
318
285
345
187
133
246
58
128
M
M
M
F
M
F
F
M
F
F
M
F
F
M
63
57
65
52
42
68
69
32
65
65
61
70
72
69
24.8
27.0
25.0
27.0
27.2
26.5
26.0
31.0
25.3
26.3
21.6
29.7
22.4
24.0
355
331
391
431
434
373
400
427
356
323
379
670
333
313
129
231
136
95
170
190
258
245
Cholesterol (mg/dl)
6
7
8
9
10
Group 3
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Lp(a)
protein
Triglycerides
(mg/dl)
VLDL
LDL
HDL
(mg/dl)
25
21
51
14
32
112
149
307
129
183
53
54
66
55
39
95
82
88
9
77
37
21
49
12
25
186
226
227
217
283
51
57
42
56
37
64
37
43
11
71
72
94
60
42
83
55
111
83
61
127
59
16
42
23
211
195
292
329
310
267
251
312
257
152
289
590
72
42
39
60
41
51
38
32
38
44
31
70
67
44
5
5
5
96
12
4
5
29
4
5
10
6
Group 2
285
320
194
78
97
166
218
246
VLDL, veiy low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
LDL mg/dI
LP(a) mg/dl
4001
10
LDL mgldl
15
8
GROUP Ill
GROUP 11
GROUP I
1315
LP(a) mg/dI
LDL mgldl
1
LP(a) rngldl
Group I
150
140
130
120110
\
~~~~3
-4-4
\
-0-5
Group II
-0--
6
7
100
10
90
Group IIl
40
50
30 -
0
rr
3
6
o0 l
0
--r
3
6
Weeks of therapy
o0 +
0
-r
3
6
o0 .i
0
4
Months of therapy
-r
9
1
' '
' '
'
0 20 40 60 80 80-
/
-
12
-*0--- 15
-a--- 16
17
---18
19
20
10
4
-.
o
-
°
C1204060808
--
-
-
21
22
24
23
Dose of Lovastatin mg/day
FIGURE 1. Plots of individual change in LDL cholesterol and total Lp(a) in all groups. The dose of Simvastatin in group
1 was 10 mg/day (patient 1), 20 mg/day (patients 2 and 4), and 40 mg/day (patients 4 and 5). All group 2 patients received
40 mg/day. *80 mg Lovastatin for 6 months.
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
1316
Circulation Vol 80, No 5, November 1989
TABLE 2. Effect of Lovastatin Therapy on Lipid and Lipoprotein Levels in 14 Patients With Hypercholesterolemia
Total
Cholesterol (mg/dl)
Lp(a)
protein
% Change
Lovastatin
cholesterol
Triglycerides
(mg/day)
VLDL
LDL
HDL
(mg/dl)
(mg/dl)
in LDL
(mg/dl)
79+7.3
391+25
0
0
179+21
272+21
48+4
15+6.5
316+19
48+6.5
19±8
20
148+16
211+18
49+4
-22.8+1.9t
40
284±14
132+13
43±5.4
185±17
18.5±9
-32.1±2.3t
49.5±2.5
158±14
80
245±19
37+4.3
48+2.9
21.3±10.3
-43.4 2±2t
115+10
80
121±11
144±9
236±11
42.5±5
21.7±10
-46.8±2.74
48+2.9
% Change
in Lp(a)
0
+27.0±6.3t
+23.0±7.0*
+28.8±4.5*
+33.7±6.342
Data are mean ±SEM.
Therapy lasted for 6 months.
*p<0.05 tp<0.01, *p<0.005 by paired t test.
were seen. In volunteers 1 and 2, Lp(a) levels
remained constant, whereas in volunteers 3 and 4,
levels rose slightly. In volunteer 5, Lp(a) levels
increased by more than 30%. Lp(a) levels were
noted to return slowly to baseline after cessation of
treatment, whereas lipoprotein levels returned to
baseline within 3 weeks after stopping therapy.
In the hypercholesterolemic patients of group 2,
Simvastatin treatment resulted in a significant
decrease of total cholesterol and triglycerides of
24±9% and 21+± 10%, respectively. VLDL cholesterol was reduced by 15 +±13%, LDL cholesterol
decreased by 31±+ 11%, and HDL cholesterol
increased by 5 ±5 %. In group 2, treatment increased
Lp(a) by 18+20%. In patients 6, 9, and 10, Lp(a)
levels did not change, but in patients 7 and 8, increases
of 54% and 26%, respectively, were observed. The
changes in lipid, lipoprotein, and Lp(a) levels were
present up to 9 months of treatment.
Group 3 consisted of 14 patients referred for
treatment of hypercholesterolemia. Mean lipid, lipoprotein, and Lp(a) levels at baseline and on each
dose of Lovastatin are given in Table 2. Lovastatin
treatment at 80 mg/day resulted in a significant
decrease of total cholesterol and triglycerides by
37±10% and 35±15%, respectively. VLDL cholesterol was reduced by 50±20% (p<0.005), LDL
cholesterol decreased by 44±5% (p<0.001), and
HDL cholesterol did not change. Although Lovastatin did not change the mean HDL cholesterol
levels of group 3, individual changes in HDL cholesterol were seen and ranged from an increase of
25% and 31% in patients 18 and 21, respectively, to
a decrease of 18% and 22% in patients 11 and 16,
respectively. In group 3, as in the other two groups,
treatment with an HMG CoA reductase inhibitor
affected Lp(a) levels differently than LDL cholesterol levels (Figure 1). Compared with baseline,
treatment increased Lp(a) by 34±20% (p<0.005).
In patients 16 and 17, treatment did not change
Lp(a) levels. In patients 15, 18, and 22, Lp(a) levels
increased moderately (<25%), and in patients 12,
13, 14. 19, 20, 21, and 23, Lp(a) levels increased
markedly (33-65%). In patients 11 and 24, Lp(a)
decreased 15% and 19% on therapy, respectively.
The percent change in Lp(a) levels was similar in
patients with high or low initial Lp(a) levels. How-
ever, the absolute increase in Lp(a) levels was
greater in patients with higher initial Lp(a) concentrations. Most of the effect on Lp(a) levels was
observed on the 20 mg/day dosage and higher
dosages resulted in either no further change or even
a decrease in Lp(a) levels. The effect on Lp(a)
levels was sustained as long as the drug was used
for up to 6 months.
Statistical analysis was performed using each
dose as a separate comparison with pretreatment
measurements as the control. Because we used data
derived from three groups of patients, Bonferroni's
correction was used after the paired t test. The
increase in Lp(a) was significant (p<0.005). Comparison between different doses of Lovastatin did
not show a significant change in Lp(a) levels with
higher doses of Lovastatin (>20 mg/day).
In summary, when baseline pretreatment measurements were compared with treatment measurements of 20 mg Simvastatin (groups 1 and 2) or 40
mg Lovastatin (group 3), all subjects showed a
decrease in total cholesterol of 43±5% (p<0.001,
mean±SEM), LDL cholesterol of 43±5%
(p<0.001), total triglycerides of 35±8% (p<0.005),
and VLDL cholesterol of 45±9% (p<0.005). HDL
cholesterol increased by 7±8% (NS), and Lp(a)
increased by 33±12% (p<0.005). The increase in
Lp(a) was greater than the generally accepted 5%
margin of reproducibility for Lp(a) determination in
half of the patients.
The marked change of LDL cholesterol levels
after treatment with HMG CoA reductase inhibitors
without a significant change or an increase in Lp(a)
levels was a surprising finding. This aroused concern that drug treatment might have in some way
altered Lp(a) particle composition resulting in altered
immunoreactivity. Because this could confound our
observations, physical methods were used to verify
that the drugs did not alter Lp(a) composition and
that treatment had differing effects on the amounts
of LDL and Lp(a). Plasma samples from all of
group 1 and from patients 6 and 10 of group 2 were
obtained before and during treatment. Lp(a) was
isolated by density gradient ultracentrifugation and
analyzed chemically. As shown in Table 3, there
were no gross changes induced by treatment in the
chemical composition of either LDL or Lp(a). In
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
Kostner et al Reductase Inhibitors Do Not Decrease Lp(a) Levels
1317
TABLE 3. Chemical and Physicochemical Properties of Lp(a) and Low-Density Lipoprotein Compared Before and
After Simvastatin Therapy
Low-density lipoprotein
Lp(a)
Before
After
Before
After
therapy
therapy
therapy
therapy
Parameter
23.4+2.2
24.5+2-0
32.6+1.9
Protein
32.6+2.1
9.9:1.2
10.4+0.7
10.6--1.6
11.8:1.5
Free cholesterol
22.4+1.9
21.4+2-0
Phospholipid
19.7±1.8
19.1+1.5
40.01.8
39.0+1.6
33.6±2.0
34.2±2.2
Cholesteryl ester
4.3 + 1.0
3.8+0.9
5.1+1.2
2.7+0.9
Triglyceride
1.034+0.003
1.033±0.002
1.074j0.007
l.072±0.005
Hydrated density
22.2+0.7
22.1+0.8
Diameter (nm)*
25-9f0.5
26.1±0.6
0.108±0.004
0.217+0.007
0.218
+0.006
0.108+0.003
Electrophoretic mobilityt
Data are mean+SD.
The chemical composition is given as the percent of the weight of the particle.
*The diameters were determined from electron micrographs after negative staining with Na-phosphotungstate.
Only lipoproteins from two patients (group 1: subject 5 [T.K.]) (group 2: subject 1 [Z.K.]) were analyzed; the SD
include the variation observed within one micrograph.
tThe electrophoretic mobility was determined in 3.5% polyacrylamide gels and calculated in relation to albumin.
particular, the cholesterol content and the lipid to
protein ratio remain constant for both particles.
Plasma samples were also subjected to gradient
polyacrylamide gel electrophoresis (2.5-10%), which
showed that the apparent size of the Lp(a) particles
did not change on drug therapy (data not shown).
Finally, plasma from the 10 group 1 and 2 subjects
before, during, and after therapy was subjected to
equilibrium banding density gradient ultracentrifugation. An example is shown in Figure 2. As can be
seen, there were striking changes in the intensity of
the LDL band without a noticeable change in concentration or in hydrated density of the Lp(a) band.
Discussion
Lp(a) are apo B containing lipoproteins.1 By
composition, they are closely related to LDL and
1
2
3
5
4
are thought to be atherogenic. 10-15,22,23 A new class
of cholesterol-lowering drugs, HMG CoA reductase
inhibitors, are now in clinical use. They have proven
to be very effective in lowering plasma levels of apo
B containing lipoproteins, such as VLDL and
LDL.17,18 In the present study, we examined whether
or not the HMG CoA reductase inhibitors also
lower Lp(a) levels, and we were surprised by the
results. In three clinical studies, of a total of 24
individuals, this class of drugs decreased VLDL
and LDL cholesterol levels 45--9% and 43+5%,
respectively, whereas this class did not reduce and
on the average significantly increased Lp(a) concentration bY 33+ 120% (p<OOi5) This was probably not
the result of altered immunoreactivity of Lp(a)
particles, because the composition of the particles
did not change. Furthermore, the physical method
6
FIGURE 2. Density gradient
ultracentnfuigation separation
4a
-l LP(A)
-1 M
HDL-2
-HDL-
~-
BOTTOM
of lipoproteins. Two milliliters
plasma from subject 5 ofgroup
1 was separated in an SW 41
rotor (Beckman) after spinning for 24 hours at 40,000
rpm. The samples are plasma
obtained before (1), after 3
weeks (2), after 6 weeks (3) of
treatment, and 1 week (4), 3
weeks (5), and 6 weeks (6)
after cessation of the drug.
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
1318
Circulation Vol 80, No 5, November 1989
of equilibrium banding density gradient ultracentrifugation confirmed that drug treatment decreased
LDL concentration markedly without similarly
affecting Lp(a). Thus, the HMG CoA reductase
inhibitors do not have the same effect on all classes
of apo B containing lipoproteins. Hypercholesterolemic individuals with very high Lp(a) levels who
are treated with this class of drugs might not receive
the same degree of expected benefit as would
patients with low Lp(a) levels.
These findings also suggest that the metabolism
of Lp(a) is significantly different from LDL. In vivo
studies have shown that Lp(a) particles turn over at
a slower rate than LDL particles.6 In vitro cell
culture studies with human skin fibroblasts and
human hepatoma cells (HepG2) indicate a much
lower affinity of Lp(a) particles compared with LDL
for the LDL receptor.7-9 ,24 The HMG CoA reductase inhibitors are thought to act in vivo primarily
by increasing liver LDL receptors.25 Our results
indicate this does not lower Lp(a) levels. This
strongly suggests that in vivo Lp(a) particles are not
cleared by the LDL receptor but are cleared by
another unspecified mechanism. In a previous study,
cholestyramine was also tested for its effect on
Lp(a) levels.24 This cholesterol-lowering drug, by
interrupting the enterohepatic circulation of bile
acids and cholesterol, also increases liver LDL
receptors and has no effect on Lp(a) levels. Thus,
drugs that lower LDL levels by increasing liver
LDL receptors, which in turn increases LDL catabolism, appear not to simultaneously lower Lp(a)
levels. This suggests that LDL receptors may not
play an important physiologic role in clearing Lp(a)
particles. It is plausible to suggest that the disulfide
bonding of the large apo(a) glycoprotein (330-870
kd) to the apo B of LDL may sterically interfere
with LDL receptor binding.
Two cholesterol-lowering drugs, neomycin and
niacin, have been shown to decrease LDL levels
and Lp(a) levels.13416 In one study, the combination
of these two drugs decreased Lp(a) levels 40%.14 In
vivo LDL turnover studies suggest nicotinic acid
acts to decrease lipoprotein production. Thus, in
contrast to drugs that act to increase LDL catabolism, those that decrease synthesis appear to lower
Lp(a) levels. The mRNA of apo(a), and presumably
the protein, is made primarily in the liver. The
regulation of apo(a) synthesis is not known nor is
the exact location of where it becomes attached to
apo B. However, if apo B attachment is required for
secretion, then the synthesis of apo B may be rate
limiting in the amount of Lp(a) in plasma. Drugs
that act to decrease apo B synthesis in the liver may
therefore lower plasma Lp(a) levels. Our observation that HMG CoA reductase inhibitors actually
increase Lp(a) in some people actually indicates
that the drug may increase Lp(a) synthesis. This
could be accomplished by either increasing the
synthesis of apo(a) or apo B. This might be quite
different from person to person because the drug
effect on increasing Lp(a) levels was highly variable. The variability was not a function of the
degree of LDL cholesterol lowering caused by the
drug, and the mechanism whereby this might occur
is totally unknown.
The heightened awareness of increased Lp(a)
levels as a risk factor for coronary heart disease led
us to evaluate the effect of the HMG CoA reductase
inhibitors on these levels. The surprising result that
this potent LDL-lowering class of drugs may actually increase Lp(a) levels, especially in patients
with high initial Lp(a) levels, suggests that individuals with high Lp(a) levels may require treatment
not only with LDL-lowering drugs but also with
drugs that lower Lp(a). However, because the
increase of Lp(a) due to HMG CoA reductase
inhibitors therapy was observed only in half of the
patients studied, further work is necessary to identify patients likely to increase Lp(a) levels on treatment with this class of lipid-lowering drugs.
References
1. Utermann G, Weber W: Protein composition of Lp(a) lipoprotein from human plasma. FEBS Lett 1983;154:357-361
2. Goubatz JW, Heideman C, Gotto AM Jr, Morrisett JD,
Dahlen GH: Human plasma lipoprotein(a): Structural prop-
erties. J Biol Chem 1983;258:4582-4589
3. Fless GM, Rolih CA, Scanu AM: Heterogeneity of human
plasma lipoprotein(a). J Biol Chem 1984;259:11470
4. Utermann G, Kraft HG, Menzel H, Hopferwieser T, Seitz
C: Genetics of the quantitative Lp(a) lipoprotein trait. Hum
Genet 1988;78:41-46
5. McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen
EY, Fless GM, Scanu AM, Lawn RM: cDNA sequence of
human apolipoprotein(a) is homologous to plasminogen.
Nature 1987;330:132-137
6. Krempler F, Kostner GM, Bolzano K, Sandhofer F: Turn-
over of lipoprotein(a) in man. J Clin Invest 1980;65:1483
7. Bolzano K, Sandhofer F: Studies on the role of specific cell
surface receptors in the removal of lipoprotein(a) in man. J
Clin Invest 1983;71:1431-1441
8. Havekes L, Vermeer BJ, Brugman T, Emeis J: Binding of
Lp(a) to the low density lipoprotein receptor of human
fibroblast. FEBS Lett 1981;132:169-173
9. Armstrong VW, Walli AK, Siedel D: Isolation, characterization, and uptake in human fibroblasts of an apo(a)-free
lipoprotein obtained on reduction of lipoprotein(a). J Lipid
Res 1985;26:1314-1323
10. Armstrong VW, Cremer P, Eberle E, Manke A, Schulze F,
Wieland H, Kreuzer H, Seidel D: The association between
serum Lp(a) concentrations and angiographically assessed
coronary atherosclerosis-Dependence on serum LDL levels. Atherosclerosis 1986;62:249-257
11. Berg K, Dahlen G, Frick MH: Lp(a) lipoprotein and preBeta-lipoprotein in patients with coronary heart disease.
Clin Genet 1974;6:230-235
12. Dahlen G, Guyton JR, Attar M, Farmer JA, Koutz JA, Gotto
AM Jr: Association of level of lipoprotein Lp(a) plasma
lipids and other lipoproteins with coronary artery disease
documented by angiography. Circulation 1986;79:758-765
13. Kostner GM: The affection of lipoprotein(a) by lipid lowering drugs: Recent aspects of diagnosis and treatment of
lipoprotein disorders, in Impact on Prevention of Atherosclerotic Disease. New York, Alan R. Liss, 1988 pp 255-263
14. Rhoads GG, Dahlen G, Berg K, Morton NE, Danenberg AL:
Lp(a) lipoprotein as a risk factor for myocardial infarction.
JAMA 1986;256:2540-2544
15. Hoff HF, Beck GJ, Skibinski CI, Jurgens G, O'Neil J,
Kramer J, Lytle B: Serum Lp(a) level as a predictor of vein
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014
Kostner et al Reductase Inhibitors Do Not Decrease Lp(a) Levels
16.
17.
18.
19.
20.
graft stenosis after coronary artery bypass surgery in patients.
Circulation 1988;77:1238-1244
Gurakar A, Hoeg JM, Kostner GM, Papadopoulos NM,
Brewer HB: Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment.Atherosclerosis 1985;57:293-301
The Lovastatin Study Group II: Therapeutic response to
lovastatin (mevinolin) in non-familial hypercholesterolemia:
A multicenter study. JAAL 1986;256:2829-2834
Olsson AG, Molgaard J, Von Scnek H: Synvinolin in hypercholesterolemia. Lancet 1986;2:390-393
Knipping G, Birchbauer A, Steyrer E, Kostner GM: Action
of LCAT on LDL in native pig plasma. Biochemistry 1987;
26:7945-7949
Kostner GM, Molinari E, Pichler P: Evaluation of a new
HDL-2/HDL-3 quantitation method based on precipitation
with polyethylene glycol. Clin Chim Acta 1985;148:139-147
21. Kostner GM, Avogaro P, Cassolato G, Murth E, Bittolobon
G: Lipoprotein Lp(a) and the risk for myocardial infarction.
Atherosclerosis 1981;38:51-61
1319
22. Durrington PN, Lynt L, Ishola M, Arrol S, Bhatnagar D:
Apolipoprotein(a), Al and B and parental history in men
with early onset ischemic heart disease. Lancet 1988;
2:1070-1073
23. Hoefler 0, Harnocourt F, Pascke E, Mirth W, Pfeiffer KH,
Kostner GM: Lipoprotein Lp(a): A risk factor for myocardial infarction. Arteriosclerosis 1988;8:398
24. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL:
Mevinolin and colestipol stimulate receptor mediated clearance of low density lipoprotein from plasma in familial
hypercholesterolemia heterozygotes. Proc Natl Acad Sci
USA 1983;80:4124-4128
25. Kostner GM, Klein G, Krempler F: Can serum Lp(a)
concentrations be lowered by drugs and/or diet? In Carlson
LA, Olsson AG (eds): Treatment of Hyperlipoproteinemia.
New York, Raven Press, 1984, pp 151-156
KEY WORDS * lipoproteins * Lp(a) * atherosclerosis
HMG CoA reductase inhibitors
Downloaded from http://circ.ahajournals.org/ by guest on September 11, 2014