Table 3 Serum lipid cholesterol and triglyceride concentrations in lipoprotein fractions isolated by ultracentrifugation after atorvastatin 40mgday, at the
end of Step 4 treatment in receptor-negative and -defective homozygous familial hypercholesterolemia patients compared to the levels in baseline phase and regular treatment phase
a
Regular treatment Number of
Activity of LDL Lipoprotein fractions
Baseline phase End of Step 4
b
receptor phase
subjects 5
391.0 9 84.0 Negative
LDL-cholesterol mgdl 376.3 9 40.8
430.8 9 101.4 11.1 9 23.6
3.7 9 19.1 4
249.8 9 78.7 Defective
270.0 9 74.0 216.0 9 106.2
−22.2 9 22.4 −7.8 9 10.8
9 328.2 9 106.7
Total 329.1 9 77.6
323.4 9 149.7 −5.5 9 27.8
−1.4 9 16.2 5
VLDL-cholesterol mgdl 31.8 9 30.5
13.8 9 14.6 22.5 9 19.5
Negative 68.8 9 137.7
−44.5 9 34.2 4
7.9 9 5.2 Defective
4.7 9 4.7 4.5 9 4.2
213.5 9 402.5 19.6 9 23.8
9 21.2 9 25.2
Total 14.6 9 16.9
9.2 9 11.1 −12.4 9 90.8
133.1 9 275.8 Negative
HDL
2
-cholesterol mgdl 5
15.9 9 2.7 15.8 9 4.5
21.6 9 2.6 D mgdl
4.5 9 4.3 0.0 9 3.8
Defective 4
15.0 9 2.4 14.0 9 4.9
17.1 9 2.9 3.1 9 3.2
1.0 9 5.1 9
15.5 9 2.4 Total
15.0 9 4.5 19.3 9 3.5
3.8 9 3.6 0.5 9 4.1
HDL
3
-cholesterol mgdl Negative
5 16.2 9 2.3
17.0 9 3.0 14.2 9 5.3
2.9 9 3.2 2.0 9 5.9
D mgdl 4
14.9 9 3.8 Defective
16.3 9 3.1 15.2 9 1.2
−1.1 9 1.9 −1.5 9 2.5
9 15.6 9 2.9
15.1 9 4.3 15.6 9 3.0
Total 0.5 9 4.8
0.9 9 3.2 5
LDL-triglyceride mgdl 75.5 9 43.0
Negative 65.2 9 24.7
81.9 9 65.6 13.5 9 56.9
12.4 9 45.5 4
27.0 9 10.3 Defective
32.9 9 22.3 21.8 9 10.4
−6.2 9 24.6 −25.6 9 28.0
Total 9
53.9 9 40.2 50.8 9 28.0
51.8 9 54.1 −6.0 9 46.4
4.1 9 36.9 5
VLDL-triglyceride mgdl 55.0 9 44.7
Negative 86.6 9 88.3
74.9 9 95.2 −34.0 9 20.6
−27.3 9 24.9 Defective
4 16.5 9 7.2
27.1 9 14.8 13.9 9 10.5
−45.3 9 44.5 −25.4 9 47.2
9 37.9 9 37.8
Total 60.1 9 70.5
44.4 9 70.7 −39.7 9 32.6
−28.4 9 33.9 5
HDL-triglyceride mgdl 18.7 9 14.0
Negative 81.5 9 113.8
61.5 9 68.5 −28.5 9 15.9
−42.9 9 34.2 4
9.0 9 2.3 Defective
8.6 9 3.3 7.4 9 3.3
−14.4 9 20.1 15.3 9 46.5
9 14.4 9 11.3
34.4 9 53.4 49.1 9 89.2
Total −17.1 9 48.3
−21.5 9 18.4
a
Mean 9 S.D. change from baseline phase. PB0.05 PB0.02.
b
In one receptor-negative patient, Step 3 data was used in place of the Step 4 data, because the sample at Step 4 was missed.
3
.
8
. Ad6erse e6ents There were no serious adverse effects resulting in any
patients stopping treatments. One patient complained numbness in her right hand, but drug administration
continued without further problem. Some sporadic changes of clinical laboratory tests elevation of ALT,
AST, andor CPK, possibly attributable to atorvas- tatin, were observed in four patients. However, these
changes were mild within double the upper limit of normal range and disappeared during the course of the
trial period. Atorvastatin was well tolerated in all patients.
4. Discussion
Homeostasis of cholesterol in both blood plasma and tissue cells is mediated primarily by LDL-receptors [34].
In FH patients, who lack this receptor function, plasma
LDL and cholesterol levels markedly increase. This situation is most severe in homozygous individuals
[2,17]. Although the cholesterol level can be reduced by statins in heterozygous individuals [1,2], antilipidemic
drugs, except probucol, show almost no effect against homozygous FH, because of the almost complete ab-
sence of receptor-mediated LDL removal from the plasma [2,17,35 – 37]. In the earliest report on the effect
of compactin, the first HMG-CoA reductase inhibitor, an extremely large dose of the drug was slightly effec-
tive in reducing the serum cholesterol even in a ho- mozygous
FH patient
of the
receptor-negative phenotype [17]. However, the appearance of a serious
adverse event involving muscular symptoms put strong limitations on the use of statins at a very high dosage.
Recently, Raal et al. reported that a very high dose of simvastatin 80 or 160 mgday was successful in LDL
reduction in homozygous FH including one receptor- negative type patient [18]. No serious adverse effects
occurred during their study.
Atorvastatin is a second generation statin produced by chemical synthesis [38]. Reportedly, it has an addi-
tional cholesterol-lowering ability mediated by the sup- pression of VLDL secretion from the liver. This
mechanism is independent of the LDL-receptor mecha- nism [21,22]. Most of the cholesterol-lowering effect of
statins is mediated by the enhancement of LDL-recep- tor expression induced by even a small decrease in
intracellular cholesterol concentration, especially in the liver [39]. Therefore, the additional lipid-lowering effect
of atorvastatin seems to be a unique characteristic of this drug [40,41]. In addition, atorvastatin has a wider
range of tolerability without the appearance of adverse effects than older statins [42]. Therefore, the drug can
be used at a very high dose. Treatment of homozygous FH patients is now mainly
done by using LDL-apheresis extracting LDL and other apo-B containing lipoproteins through an extra-
corporeal circulation system [6,7]. However, a marked rebound of cholesterol takes place after the apheresis
treatment. Because of the almost complete lack of LDL-receptors and also the increase in synthesis of
cholesterol, the rebound is very severe in homozygous FH patients [16], making it difficult to keep the LDL-
cholesterol level in an optimal range where the develop- ment of atherosclerosis can be minimized [16,30]. Even
by repeating the apheresis treatment once a week, the progression of atherosclerotic vascular lesions cannot
be prevented completely.
A recent report from South Africa demonstrated that high doses of atorvastatin amorphous type, 80 mg
day was effective in suppressing cholesterol synthesis and keeping LDL-C levels lower in patients with ho-
mozygous FH
compared with
the conventional
apheresis treatment without drugs [23]. However, most of the subjects of that study had a receptor-defective
phenotype peculiar to South Africa [43]. Therefore our experiments tested the generality of this result regard-
less of the type of LDL-receptor mutation and also in ethnic populations with different dietary conditions.
Atorvastatin was effective in suppressing cholesterol rebound after apheresis mainly in receptor-defective
individuals. In subjects with residual LDL-receptor ac- tivity, statin may act by increasing the expression of the
receptor protein. Interestingly, there was a decrease in VLDL-C and -TG in patients with receptor-negative
type FH. In addition, the increase in HDL-C was greater in receptor-negative than in receptor-defective
patients. Atorvastatin also effectively reduced LDL-C in one receptor-negative patient. The excretion of
mevalonic acid in urine was markedly decreased in this patient, while the decrease was seen in general irrespec-
tive of the molecular types of the receptor mutation. These results indicate that both cholesterol synthesis
and secretion of VLDL were suppressed by atorvastatin even in patients who completely lacked LDL-receptors.
Because of the large content of cholesterol in both tissue and plasma, it may be difficult to reduce total
plasma cholesterol significantly in a short period of time by suppressing cholesterol synthesis without the
up-regulation of LDL-receptors. The presence of lecithin-cholesterol
acyl transferase
LCAT and
cholesteryl ester transfer protein CETP increases es- terified cholesterol content of LDLs [44,45]. Conse-
quently, there should be high amounts of esterified cholesterol in LDL fraction in patients with a complete
lack of LDL-receptors. Even if cholesterol is extracted from the tissue by HDL, cholesterol will stay as a
Fig. 4. Changes in a 24 h urinary excretion of mevalonic acid by the administration of atorvastatin at a dose of 40 mgday. Values for
individual patients are plotted.
constituent of LDL due to the presence of LCAT and CETP and the absence of LDL-receptors. However, the
suppression of cholesterol synthesis will certainly give advantages to homozygous FH patients such as im-
provement of clinical symptoms or, at least, slowing the progression of vascular lesions, as previously shown
using large doses of compactin [17]. Since homozygous FH is very severe, the suppression of cholesterol synthe-
sis even to a small extent is beneficial. Further clinical approach using expanded-dose can be tried in the
future.
5. Conclusion
