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; David.W.Ray@man.ac.uk

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.

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.

Atorvastatin in acromegaly

653

© 2005 Blackwell Publishing Ltd,

Clinical Endocrinology

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, 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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