The effect of atorvastatin on serum lipoproteins in acromegaly
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Clinical Endocrinology (2005)
62
, 650–655 doi: 10.1111/j.1365-2265.2005.02273.x
650
© 2005 Blackwell Publishing Ltd
O R I G I N A L A R T I C L E
Blackwell Publishing, Ltd.
The effect of atorvastatin on serum lipoproteins in acromegaly
Manoj Mishra*, Paul Durrington*, Mike Mackness*, Kirk W. Siddals†, Kalpana Kaushal†, Rob Davies*, Martin Gibson† and David W. Ray*
*
Cardiovascular, Medicine and Surgery Central Clinical Academic Group, University of Manchester, M13 9PT, UK and
†
Department of Diabetes, Salford Royal Hospitals, Salford, M8 6HD
Abstract
Objective
Acromegaly is associated with long-term adverse effects
on cardiovascular mortality and morbidity. Reducing growth hormone
secretion improves well-being and symptoms, but may not signific-
antly improve the lipoprotein profile. An additional approach to
cardiovascular risk reduction in acromegaly may therefore be to
target lipoprotein metabolism directly. In this study we investigated
the effect of statin treatment.
Design
Double blind, placebo-controlled, crossover study of the
effects on circulating lipoproteins of atorvastatin 10 mg daily
vs.
placebo.
Each treatment was given for 3 months in random order.
Subjects
Eleven patients with acromegaly.
Measurements
Lipids, lipoproteins, apolipoproteins, enzyme
activity and calculated cardiovascular risk.
Results
Atorvastatin treatment compared to placebo resulted in
a significant decrease in serum cholesterol (5·85
±
1·04 mmol/ l
vs.
4·22
±
0·69 mmol/ l; mean
±
SD;
P
< 0·001), low-density lipoprotein
(LDL) cholesterol (2·95
±
1·07 mmol/ l
vs.
1·82
±
0·92 mmol/ l;
P
< 0·001), very low-density lipoprotein (VLDL) cholesterol
(0·31 (0·21–0·47) mmol
vs.
0·23 (0·13–0·30) mmol/ l median (inter-
quartile range);
P
< 0·05), apolipoprotein B (111
±
28 mg/dl
vs.
80
±
18 mg/dl;
P
< 0·001), and calculated coronary heart disease risk
(6·8 (3·3–17·9)
vs.
2·8 (1·5–5·7)% over next 10 years;
P
< 0·01).
Serum triglyceride was 1·34 (1·06–1·71) mmol/l on placebo and
1·14 (0·88–1·48) mmol/ l on atorvastatin (ns). HDL cholesterol,
apolipoprotein A1 and Lp(a) concentrations and cholesteryl ester
transfer protein and lecithin: cholesterol acyl transferase activities
were also not significantly altered.
Conclusion
Atorvastatin treatment was safe, well tolerated and effec-
tive in improving the atherogenic lipoprotein profile in acromegaly.
(Received 16 January 2004; returned for revision 10 February 2004;
finally revised 4 March 2005; accepted 4 March 2005)
Introduction
Acromegaly reduces life expectancy significantly, largely due to an
excess of cardiovascular deaths.
1–6
There is evidence from observa-
tional, but not randomised studies that reducing mean serum
growth hormone to less than 5 mU/l restores life expectancy towards
normal.
4,6,7
Currently, most patients with acromegaly undergo hypo-
physectomy followed by radiotherapy and/or medical treatment,
depending upon the residual growth hormone levels postoper-
atively.
8,9
Up to 90% of patients with microadenomas and approx-
imately 50% of patients with macroadenomas can achieve growth
hormone concentrations below 5 mU/l following surgery alone.
8,10
Radiotherapy, as initial therapy or combined with surgery, can be
effective, but it may be several years before growth hormone pro-
duction is adequately suppressed. Somatostatin analogues are
widely used, but alone probably only result in satisfactory growth
hormone concentrations and normal age-related IGF-1 concentra-
tions in about half of patients.
10–14
Current guidelines for the primary prevention of cardiovascular
disease in the general population are based on identification of high-
risk and intervention to improve systolic blood pressure (SBP),
diastolic blood pressure (DBP), serum cholesterol, high density
lipoprotein (HDL) cholesterol, smoking and diabetes.
15,16
Because
one of the objects of management of acromegaly is a reduction in
the risk of cardiovascular disease, a more holistic approach, potentially
including cholesterol-lowering therapy, should therefore be considered.
Active acromegaly is associated with an elevation in serum
triglyceride, Lp(a), and apolipoprotein A1 concentrations.
17–20
Raised triglyceride levels may be linked to insulin resistance, and
thereby increased hepatic very low-density lipoprotein (VLDL) output
and reduced lipoprotein lipase activity. The effects of growth hor-
mone on serum total cholesterol are more controversial.
17,20–22
Serum total cholesterol decreased following a reduction in growth
hormone concentrations in one study in acromegaly,
23
but increased
as a consequence of pegvisomant therapy in a more recent study.
20
This was despite pegvisomant, a growth hormone analogue that
acts as a growth hormone receptor antagonist,
10
being more effective
than long-acting somatostatin analogues at decreasing serum IGF-1
in patients with active acromegaly.
10,12,24,25
Regardless of whether total
serum cholesterol is increased by acromegaly, the condition may be
associated with an increase in low-density lipoprotein (LDL), par-
ticularly the atherogenic small, dense LDL subclass,
26,27
which
Correspondence: David Ray, Endocrine Sciences Research Group, Stopford Building, University of Manchester, Manchester, M13 9PT, UK. Tel.: + 44-161-275-5655; Fax: + 44-161-275-5958; [email protected]
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Atorvastatin in acromegaly
651
© 2005 Blackwell Publishing Ltd,
Clinical Endocrinology
,
62
, 650–655
contributes little to total serum choleterol. Lipoprotein (a) (Lp(a))
has also been reported to be increased in acromegaly.
19,21,28–31
Serum
HDL cholesterol concentrations may be suppressed in acromegaly.
28
Metabolic studies have shown that active acromegaly causes
increased lipoprotein lipid peroxidation, which could further pro-
mote atherosclerosis.
32
In addition to the changes in lipoprotein
metabolism, other growth hormone-dependent risk factors for the
development of cardiovascular disease are often increased in acrome-
galy. These include hypertension, hyperglycaemia, hyperinsulinaemia,
insulin resistance and diabetes.
32–34
Furthermore, there is evidence of
impaired endothelial function and there may be additional, direct
effects on the heart muscle, reviewed by Clayton.
35
Here we report the effects of low-dose atorvastatin on lipoprotein
metabolism and on calculated potential coronary heart disease risk
in patients with acromegaly.
Subjects and methods
Patients and design of study
Eleven patients (5 men, 6 women, mean age 52·5 years, range
35–67) with a diagnosis of acromegaly were recruited from the
Manchester Royal Infirmary Endocrine Clinic (Table 1). All patients
provided written, informed consent and the study was approved
by the Central Manchester Research Ethics Committee. The serum
IGF-1 distribution was determined in a control group recruited by
random sampling from population registers of seven health centres
in Manchester.
36
The serum IGF-1 concentrations in the acromegaly
group at the time of study were significantly higher than those of the
control group (256
±
102 ng/ml
vs.
145
±
50 ng/ml; mean
±
SD;
P
< 0·005 by independent sample
t
-test), and all had evidence of
continuing GH secretion (Table 1).
The trial was a double-blind, random order, crossover study of
atorvastatin 10 mg daily and placebo each for 12 weeks. The two
treatment phases were separated by a 4-week washout period. At
baseline all patients completed a questionnaire for cardiovascular
disease symptoms, history of cardiovascular events and coexisting
cardiovascular risk factors including smoking, exercise and positive
family history. Patients aged over 70 years, already receiving cholesterol-
lowering therapy, having uncontrolled diabetes or hypertension, or
who already fulfilled the criteria for statin therapy according to the
Management Guidelines of the Standing Medical Advisory Committee
to the Chief Medical Officer of Health in the UK; namely, pre-existing
ischaemic heart disease or a coronary risk of greater than 30% over
10 years,
37
were excluded. Ten of the 11 patients recruited had
previously undergone hypophysectomy, 7 had received external
beam pituitary radiotherapy, and 7 were on long-acting somatostatin
analogue therapy. Three patients were receiving thyroxine replacement,
two were on gonadal steroid replacement and four were receiving
cortisol replacement. Three patients had a diagnosis of diabetes
mellitus, one of whom was treated with insulin. Four patients were
currently cigarette smokers.
The 11 patients studied were recruited from a series of 31 patients
of whom 9 were excluded from the trial because they were
already receiving statin therapy, 7 because they had ischaemic
heart disease, and 4 because of comorbidity (malignancy, epilepsy
or dementia).
After the baseline screening, all participants received a 1-month
run-in on daily placebo medication. At the end of the month,
run-in compliance was checked by tablet count and patients were
randomised to a 12-week period of treatment with either placebo
or atorvastatin 10 mg once daily. Halfway through this 12-week
period, they attended for a safety check of serum creatine kinase and
aspartate amino transferase activity. At the end of the first 12-week
treatment period, all patients were seen again for a full biochemical
evaluation. Immediately following this, subjects continued into a
1-month washout period again taking placebo before entering the
second 12-week treatment period, again with a safety check midway
through before a final visit for full biochemical evaluation. Com-
pliance was checked by a tablet count at every visit. Venous blood
was collected at each visit after an overnight fast.
Laboratory Methods
Serum IGF-1 was measured by a previously reported assay with
detection limit 28 ng/ml, and both between and within assay
coefficients of variation of less than 10%.
36,38
Insulin was measured
by the Mercodia ELISA kit for intact insulin (Uppsala, Sweden).
Glucose was measured by an automated glucose oxidase method.
HbA1c was measured by ion-exchange high performance liquid
chromatography (HPLC) using a variant II supplied by Bio-Rad
Laboratories (Hemel Hempstead, UK). The method is diabetes
control and complications trial (DCCT) aligned. Aspartate
aminotransferase (AST) and creative kinase (CK) were assayed on
the Roche Modular D and P unit. Reagents are supplied by Roche
Diagnostics Limited (Lewes, UK).
Very low-density lipoprotein was isolated by ultracentrifugation
of plasma at D = 1·006 g/ml at 144 000
×
g
for 22 h 17 min in a
Table 1. Demographics of patients
Subject Age
Previous
Rx Current Rx IGF-1
GTT
GH
Mean
GH BP
1 67 – Oct 366 – 3·2 +
2 62 S, D Oct, insulin 325 – 6·8 +
3 49 S, D Oct, T4 329 – 5·3 –
4 52 S, D Oct, Cort 149 – 1·0 –
5 55 S, D T4, Cort 181 1·0 – +
6 64 S – 240 1·3 – –
7 35 S Oct, Cort 206 – 13·8 +
8 50 S – 184 1·4 – +
9 42 S, D Oct 185 – 3·5 –
10 47 S, D Oct 178 – 1·4 +
11 66 S, D Cab, T4, Cort 472 – 2·7 +
Eleven patients were studied. Previous treatment modalities were surgery (S), or conventional external beam deep X-ray therapy (D). Current treatments were octreotide (Oct), cabergoline (Cab), thyroxine (T4), and cortisol (Cort). IGF-1 concentration is in ng/ml. Growth hormone concentrations (mU/l) were either determined on the basis of a five-point day curve (mean GH), or the nadir following a glucose load (GTT GH). Hypertension (BP) was diagnosed on the basis of concurrent therapy with antihypertensives, or blood pressure greater than 140/90.
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652
M. Mishra
et al.
© 2005 Blackwell Publishing Ltd,
Clinical Endocrinology
,
62
, 650–655
Beckman L8–55
ultracentrifuge (Beckman Coulter, High Wycombe,
UK).
39,40
High-density lipoprotein (HDL) was isolated from the
infranatant by precipitating LDL with heparin/Mn
2+
after tube
slicing to remove VLDL in the supernatant. LDL cholesterol was
calculated by subtracting VLDL and HDL cholesterol from the total
serum cholesterol.
Serum total cholesterol and lipoprotein cholesterol were deter-
mined by the CHOD-PAP method (ABX Diagnostic, Shefford UK).
Serum triglycerides were measured by the enzymatic GPO-PAP
(ABX Diagnostic, Shefford, UK) method. Apolipoprotein AI and B
were determined by immunoturbimetry on a Cobas Mira-S analyser
(Hoffman-LaRoche, Basel, Switzerland) using reagents, standards
and controls provided by the manufacturer. Lecithin cholesterol acyl-
transferase (LCAT) and cholesteryl ester transfer protein (CETP)
activities were determined using our in-house assay which employs
autologous lipoproteins.
41
Lipoprotein (a) concentrations were
determined by a commercial ELISA (Mercodia, Uppsala, Sweden).
Coronary heart disease risk is multifactorial and thus in order to
gain some appreciation of the likely impact of any changes in LDL
and HDL on the risk of coronary disease in the patients studied, we
estimated risk before and after treatment using the Framingham risk
equation
42
programmed into a computer. This equation is widely
recommended to assist in clinical decisions, such as whether to intro-
duce antihypertensive or statin therapy.
15
It takes into account age,
gender, presence of diabetes, serum cholesterol, HDL cholesterol,
smoking and blood pressure.
Statistical Analyses
The mean results obtained at the beginning and end of placebo and
at baseline before atorvastatin for each patient were compared pair-
wise with those at the end of atorvastatin treatment using Wilcoxon
signed rank test for non-Gaussian variables or paired
t
-test for those
with a Gaussian distribution. Data are shown as mean
±
SD or, if
non-Gaussian, as median (interquartile range). Spearman rank
order correlations were performed to investigate relationships
between the variables.
Results
Compared to a previously published
43
healthy British reference
population matched for age and gender, LDL cholesterol, fasting
triglycerides, apo B, Lp(a), LCAT, and CETP were similar, whereas
the serum HDL cholesterol of the patients with acromegaly was
lower. Throughout the trial compliance was on average 88%. Ator-
vastatin treatment resulted in a significant 28% decrease (
P <
0·001)
in serum total cholesterol compared to placebo (Table 2), and a 38%
fall in LDL cholesterol (
P <
0·001) (Table 2). Serum triglycerides
were some 15% lower on atorvastatin than placebo, a difference
which did not quite achieve statistical significance (
P =
0·06). Very
low-density lipoprotein cholesterol, however, showed a significant
26% decrease on active treatment (
P <
0·05). Consistent with the
atorvastatin effect of VLDL and LDL cholesterol, serum apo B
declined by 35% on active treatment (
P <
0·001). Lp(a), HDL
cholesterol and apo AI concentrations showed no statistically signi-
ficant change. Neither were plasma LCAT nor CETP activity
changed significantly by atorvastatin treatment. No significant
changes in lipid lipoprotein or apolipoprotein levels occurred on
placebo treatment.
Atorvastatin treatment significantly reduced the calculated coronary
heart disease risk over 10 years by 59% (
P <
0·01) (Table 3).
There was no change in the IGF-1, IGFBP-1, fasting insulin, fasting
glucose, or glycosylated haemoglobin concentration in response to
atorvastatin treatment (Table 3).
We investigated the relationships between IGF-1 and the lipid
parameters and found no significant correlations. The treatment
responses did not vary according to IGF-1 concentrations. Under
basal conditions (at the end of placebo), after placebo treatment,
there were the expected strong positive correlations seen between
Table 2. Lipid and lipoprotein concentrations on placebo and after atorvastatin 10 mg daily for 3 months
Units Placebo Atorvastatin
Serum cholesterol mmol/ l 5·85 ± 1·04 4·22 ± 0·69***
VLDL cholesterol mmol/ l 0·31 (0·21–0·47) 0·23 (0·13–0·30)*
LDL cholesterol mmol/ l 2·95 ± 1·07 1·82 ± 0·92***
HDL cholesterol mmol/ l 1·56 ± 0·52 1·54 ± 0·43
Serum triglyceride mmol/ l 1·34 (1·06–1·71) 1·14 (0·88–1·48)
Lipoprotein (a) mg/dl 13·8 (3·1–40·6) 8·8 (2·5–34·8)
Apolipoprotein B mg/dl 121 ± 32 79 ± 18***
Apolipoprotein A1 mg/dl 139 ± 30 141 ± 29
LCAT activity nmol/h/ml 45·0 (34·7–57·4) 47·7 (29·4–57·1)
CETP activity nmol/h/ml 17·6 (14·6–18·6) 17·2 (12·3–18·9)
Comparison of results after placebo (12 weeks) and after 10 mg Atorvastatin (12 weeks). Treatments were given in random order separated by a 4-week washout period. Results are presented as mean ± SD for parametric data, and median with interquartile range (IQR) for nonparametric data. Comparisons were made by paired t-test for parametric and Wilcoxon signed rank test for nonparametric data. Parametric data is indicated by + SD, and nonparametric by (interquartile range). Significance is indicated *P < 0·05, **P < 0·01, ***P < 0·001.
Table 3. Coronary risk and metabolic parameter measurements on placebo and after atorvastatin 10 mg daily for three months
Units Placebo Atorvastatin
Fasting insulin pmol/l 5·17 (3·79–10·91) 6·06 (3·25–10·11)
Fasting glucose mmol/l 5·07 (4·60–6·50) 5·30 (4·90–6·70)
Fasting IGF-1 ng/ml 209 (175–366) 247 (181–334)
Fasting IGF-BP1 ng/ml 36.2 (15.0–43.9) 27.9 (17.2–38.4)
Coronary risk
Over 10 years % 6·8 (3·3–17·9) 2·8 (1·5–5·7)**
Comparison of results after placebo (12 weeks) and after 10 mg Atorvastatin (12 weeks). Treatments were given in random order separated by a 4-week washout period. Results are presented as mean ± SD for parametric data, and median with interquartile range (IQR) for nonparametric data. Parametric data is indicated by + SD, and nonparametric by (interquartile range). Comparisons were made by paired t-test for parametric and Wilcoxon signed rank test for nonparametric data. Significance is indicated *P < 0·05, **P < 0·01, ***P < 0·001.
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Atorvastatin in acromegaly
653
© 2005 Blackwell Publishing Ltd,
Clinical Endocrinology
,
62
, 650–655
apoA1 and HDL cholesterol (
r
= 0·92;
P
< 0·0001), apoB and LDL
cholesterol (
r
= 0·836;
P
< 0·001) and VLDL cholesterol and trigly-
cerides (
r
= 0·957;
P
< 0·0001). We also found a positive correlation
between CETP and apo B (
r
= 0·9;
P
< 0·05).
Atorvastatin was well tolerated in all 11 patients with no elevation
in serum muscle or hepatic enzyme concentrations.
Discussion
In a group of acromegalic patients who had not yet developed
clinically evident coronary heart disease (CHD) we have shown
that atorvastatin in a dose of 10 mg daily will significantly decrease
LDL cholesterol VLDL cholesterol and apolipoprotein B (the
principal protein component of LDL and VLDL). The patients as
a group were not markedly dyslipidaemic, apart from having
relatively low HDL cholesterol.
The 38% reduction in LDL cholesterol with atorvastatin 10 mg
daily compares to a 40% reduction reported with the same dose in
a meta-analysis of the nonacromegaly population
44
and a 40%
decrease in a large group of type 2 diabetic patients in the Collabo-
rative Atorvastatin Diabetes Study (CARDS).
45
The relative decrease
in triglycerides amounting to about half that in LDL cholesterol and
the lack effect of atorvastatin on HDL cholesterols are also consistent
with the findings of CARDS. We considered an order of treatment
effect, but in a large meta-analysis of statin trials no differences were
seen in response between parallel and crossover study designs,
suggesting no significant order of treatment effect (Law’s personal
communication).
The excess risk of coronary heart disease in acromegaly has
multiple causes. We considered it important therefore to attempt to
gain some insight into the potential impact of statin-induced
changes in cholesterol and HDL cholesterol of the magnitude
reported here on coronary risk. The 59% reduction in calculated risk
in our subjects compares to a 36% actual reduction in clinical trials
in the non-acromegaly population
44
and a 37% in CARDS.
45
The
greater reduction in calculated risk is likely to be because of the
2–3-year period before the full effect of statin therapy on cardio-
vascular risk is achieved.
44
While this indicates that the benefit
of statin treatment in acromegaly is not likely to be unduly ameliorated
by other immutable risk factors, we must nonetheless concede that
the exact quantitative relationship between coronary risk factors in
acromegaly may differ from that of the general population from
which the Framingham risk equation is derived.
42
Furthermore,
although this is the first trial of statin treatment in acromegaly, evidence
from statin trials suggests that the source of increased coronary and
cerebrovascular atherosclerosis risk, be it principally hypertension,
diabetes, raised LDL cholesterol, low HDL cholesterol or pre-existing
vascular disease, makes no difference to the relative decrease in
cardiovascular risk with statin treatment.
46
As cardiovascular deaths
occur at significant excess in patients with acromegaly, effective
strategies to reduce cardiovascular risk in acromegaly should be
adopted, because it may not be possible to reduce growth hormone
and/or IGF-1 concentrations to normal in all patients. In addition,
there is a clear excess of cardiovascular mortality in patients who are
GH deficient, so overtreatment of GH excess also carries adverse
effects.
47–49
Therefore a multifactorial risk reduction strategy should
be considered, including management of hypertension, smoking,
and circulating lipid profile.
Elevated concentrations of Lp(a) independently predict cardio-
vascular risk.
50
Although in the present study median Lp(a) values
appear to be lower on atorvastatin, this difference did not approach
statistical significance. Serum Lp(a) in nonacromegalic populations
is, also characteristically resistant to statin therapy. It has been
proposed that Lp(a) is positively regulated by growth hormone or
IGF1.
19,21,28–31
In one study, Lp(a) concentrations were shown to fall
in a group of acromegalic subjects following normalization of serum
IGF-1 concentrations.
20
It is noteworthy that three of our subjects were receiving
thyroxine replacement for secondary hypothyroidism as a conse-
quence of their pituitary tumours and treatments directed at the
pituitary. Untreated hypothyroidism is a powerful risk factor
for development of myositis on statin therapy.
51
It is particularly
important that all trophic hormone deficiencies are fully corrected
before starting atorvastatin treatment and that potential drug
interactions are avoided.
52
To conclude, we have shown that statin therapy is highly effective
at improving the serum lipoproteins profile and reducing the calculated
coronary heart disease risk in acromegaly.
Acknowledgements
We are grateful to Dr Aram Rudenski, Clinical Biochemistry, Salford
Royal Hospitals, UK, Ms Karen Morgan and Dr Simon Anderson,
University of Manchester for helpful discussion and Ms C. Price for
expert preparation of this manuscript.
Parke-Davis and Co Ltd provided the study medication and
financial support for the laboratory analyses DWR received a Glaxo-
SmithKline Fellowship.
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