change = [trough concentration after dose in- crease − trough concentration before dose increase
trough concentration before dose increase] × 100
2
.
6
. Statistical analysis Comparisons were performed using one-way analysis
of variance ANOVA for repeated measures followed by student Newman – Keuls method for post hoc com-
parisons using Sigmastat Statistical Software for Win- dows Jandel, CA. The relationship between the
changes in MVA and LDL cholesterol was explored by univariate regression analysis using JMP Statistical
Software Package Version 3.1 SAS Institute. In all comparisons, P B 0.05 was considered significant. Re-
sults are expressed as mean 9 S.E.M.
3. Results
A total of 35 HoFH patients, 18 males and 17 females, participated in the study Table 1. Twenty-
seven subjects were confirmed to have LDLR muta- tions in both LDL alleles. The majority were genetically
compound heterozygotes, having inherited two differ- ent LDLR mutations rather than true homozygotes.
Twenty-three of these patients were homozygote or compound heterozygote for the FH Afrik-1, -2 or -3
Table 1 Patient characteristics
a
Sex MF Age years
Patient BMI kgm
2
FH genotype Baseline lipid levels mmoll
number Total
Triglyceride LDL
HDL cholesterol
cholesterol cholesterol
Afrik 1 14.8
1.6 13.4
0.6 F
1 12
21.1 0.8
15.0 1.8
16.6 FH 664664
2 15.0
15 M
3 1.2
M 25.4
0.5 6
13.9 Afrik 22
26.5 F
21 20.4
FH664664 4
18.9 1.0
17.3 1.1
5 0.7
17.3 2.8
19.4 ?
21.8 29
M M
26 23.5
Afrik 11 6
11.7 2.3
1.0 9.7
Afrik 11 35.1
20 F
7 0.3
14.6 15.6
1.4 Afrik 12
20.6 1.3
19.1 0.8
F 8
27 26.6
M 34
25.7 Afrik 13
9 14.3
1.8 12.8
0.6 4.1
10.7 0.6
10 M
33 28.1
Afrik 12 13.2
0.9 13.1
0.5 14.1
Afrik 12 M
22.9 20
11 0.6
16.5 18.5
2.9 Afrik 11
12 22.6
M 39
Afrik 1? 30.4
39 F
12.2 13
1.6 10.2
1.2 15.5
M 1.5
14.4 0.4
10 16.6
Afrik 1? 14
18.1 F
2.3 16.5
0.5 11
19.8 Afrik 11
15 1.1
9.7 0.3
10.9 Afrik 33
16 26.7
27 M
0.6 20.6
0.9 17
F 23
26.6 Afrik 22
21.9 15
M 18
Afrik 11 19.5
15.8 0.9
14.8 0.5
1.4 19.8
0.8 19
F 37
25.8 Afrik 22
21.3 1.1
13.6 0.7
14.8 Afrik 11
F 21.5
20 20
0.4 15.2
16.9 2.9
Afrik 12 21
16.9 F
2 Afrik 12
20.8 27
F 20.7
22 1.7
18.9 0.9
17.8 F
1.1 15.9
1.4 35
27.9 Afrik 12
23 15.8
M 1.7
14.3 0.5
23 26.0
Afrik 13 24
0.9 9.95
1.3 11.5
? 25
17.3 11
M ?
12.6 1.2
11.4 0.6
26 M
17 17.7
27 1.1
17.4 1.3
19.1 Afrik 11
14.8 10
M 14.8
1.1 15.8
Afrik 11 0.5
27.8 24
M 28
0.7 10.0
29 1.3
F 25
26.0 Afrik 11
11.6 18.8
1.7 17.1
0.9 30
Afrik 1? M
24 19.8
14.6 0.6
15.6 0.7
31 Afrik 33
F 25
31.2 0.9
15.1 CT2CT2
0.7 16.3
21.2 25
F 32
CT2CT2 16.5
13 F
21.0 33
1.1 19.7
0.8 4.3
M 12.6
0.6 27
25.6 Afrik 1?
15.2 34
0.6 14.5
35 1.0
F 13
18.6 Afrik 11
15.8
a
FH, familial hypercholesterolaemia; ?, LDL receptor gene mutation yet to be fully characterized. Established coronary artery disease.
Table 2 Effect of atorvastatin on lipids, enzymes and mevalonic acid MVA
levels in 35 patients with homozygous familial hypercholesterolaemia
a
Parameter Atorvastatin dose mgday
40 80
Total cholesterol 16.5 9 0.6
13.8 9 0.6 12.3 9 0.6
, c
mmoll 1.6 9 0.2
Triglyceride 1.3 9 0.1
1.2 9 0.1 mmoll
0.8 9 0.1 HDL cholesterol
0.8 9 0.0 0.9 9 0.1
mmoll 15.0 9 0.6
LDL cholesterol 12.4 9 0.6
10.9 9 0.5
, c
mmoll 27.7 9 2.5
18.4 9 1.5 Alanine
25.8 9 2.7 transaminase
IUl Aspartate
26.2 9 1.7 20.7 9 1.1
27.1 9 2.6 transaminase
IUl 92.7 9 11.1
118.4 9 15.2 Creatine kinase
100.1 9 10.4 IUl
55.0 9 7.1 21.8 9 2.4
16.1 9 2.8 Plasma MVA
pmolml 2.3 9 0.3
Urine MVA 0.8 9 0.1
0.6 9 0.1 mmolday
a
Values are mean 9 S.E.M.; for MVA measurements n = 25. Significantly different from baseline, PB0.05.
Significantly different from baseline, PB0.01.
c
Significantly different from Atorvastatin 40 mgday, PB0.01.
Triglyceride levels decreased by 9 on the 40 mgday dose and by 18 on the 80 mgday dose P B 0.01.
There was no significant change in HDL cholesterol levels.
Plasma MVA levels were elevated at baseline and decreased by 56 and 63 on the 40 and 80 mgday
dosage of atorvastatin P B 0.01. Reduction in the 24-h urinary excretion of MVA was similar with a 57 and
63 reduction P B 0.01; Table 2. There was a strong correlation between the baseline 24-h urinary excretion
of MVA and the reduction in urinary MVA excretion in response to treatment with atorvastatin r = 0.92;
P B 0.01; Fig. 1. There was also a significant correla- tion between the magnitude of reduction in LDL
cholesterol and the reduction in urinary MVA excretion r = 0.38; P = 0.02; Fig. 2. There was no correlation
between baseline LDL cholesterol levels and baseline urinary excretion of MVA however.
The dose of atorvastatin was increased to 120 mg day in 20 of the 35 patients but this increase in dose did
not yield any further reduction in LDL cholesterol despite a 107 increase in plasma atorvastatin concen-
tration. A further increase in dose to 160 mg of atorvas- tatinday was made in 13 of the patients but this also
did not result in any further reduction in LDL choles- terol levels despite a further 84 increase in plasma
atorvastatin concentration Table 3. In addition, there was no further reduction in plasma MVA or urinary
excretion of MVA on these higher doses of atorvastatin Fig. 3. Transaminase and creatine kinase levels in-
creased modestly on the higher doses of atorvastatin but the medication was extremely well tolerated with no
adverse clinical or biochemical effects occurring during the study.
4. Discussion
