The effect of atorvastatin on serum lipoproteins ... - Wiley Online Library

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effects on circulating lipoproteins of atorvastatin 10 mg daily vs.placebo. ..... rative Atorvastatin Diabetes Study (CARDS).45 The relative decrease in triglycerides ...
Clinical Endocrinology (2005) 62, 650– 655

doi: 10.1111/j.1365-2265.2005.02273.x

ORIGINAL ARTICLE

The effect of atorvastatin on serum lipoproteins in acromegaly

Blackwell Publishing, Ltd.

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

Introduction 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 significantly 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 (interquartile 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 effective 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)

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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Acromegaly reduces life expectancy significantly, largely due to an excess of cardiovascular deaths.1–6 There is evidence from observational, 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 hypophysectomy followed by radiotherapy and/or medical treatment, depending upon the residual growth hormone levels postoperatively.8,9 Up to 90% of patients with microadenomas and approximately 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 production is adequately suppressed. Somatostatin analogues are widely used, but alone probably only result in satisfactory growth hormone concentrations and normal age-related IGF-1 concentrations 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 highrisk 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 hormone 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), particularly the atherogenic small, dense LDL subclass,26,27 which © 2005 Blackwell Publishing Ltd

Atorvastatin in acromegaly 651 contributes little to total serum choleterol. Lipoprotein (a) (Lp(a)) has also been reported to be increased in acromegaly.19,21,28–31 Serum 28 HDL cholesterol concentrations may be suppressed in acromegaly. Metabolic studies have shown that active acromegaly causes increased lipoprotein lipid peroxidation, which could further promote 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 acromegaly. 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).

Table 1. Demographics of patients

Subject Age

Previous Rx

Current Rx

IGF-1

GTT GH

Mean GH

BP

1 2 3 4 5 6 7 8 9 10 11

– S, D S, D S, D S, D S S S S, D S, D S, D

Oct Oct, insulin Oct, T4 Oct, Cort T4, Cort – Oct, Cort – Oct Oct Cab, T4, Cort

366 325 329 149 181 240 206 184 185 178 472

– – – – 1·0 1·3 – 1·4 – – –

3·2 6·8 5·3 1·0 – – 13·8 – 3·5 1·4 2·7

+ + – – + – + + – + +

67 62 49 52 55 64 35 50 42 47 66

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. © 2005 Blackwell Publishing Ltd, Clinical Endocrinology, 62, 650– 655

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 cholesterollowering 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. Compliance 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

652 M. Mishra et al. Beckman L8–55  ultracentrifuge (Beckman Coulter, High Wycombe, UK).39,40 High-density lipoprotein (HDL) was isolated from the 2+ infranatant by precipitating LDL with heparin/Mn 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 determined 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 acyltransferase (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 equation42 programmed into a computer. This equation is widely recommended to assist in clinical decisions, such as whether to introduce 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 pairwise 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 43

Compared to a previously published 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%. Atorvastatin 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 significant change. Neither were plasma LCAT nor CETP activity

Table 2. Lipid and lipoprotein concentrations on placebo and after atorvastatin 10 mg daily for 3 months

Serum cholesterol VLDL cholesterol LDL cholesterol HDL cholesterol Serum triglyceride Lipoprotein (a) Apolipoprotein B Apolipoprotein A1 LCAT activity CETP activity

Units

Placebo

Atorvastatin

mmol/ l mmol/ l mmol/ l mmol/ l mmol/ l mg/dl mg /dl mg/dl nmol /h /ml nmol /h /ml

5·85 ± 1·04 0·31 (0·21–0·47) 2·95 ± 1·07 1·56 ± 0·52 1·34 (1·06–1·71) 13·8 (3·1–40·6) 121 ± 32 139 ± 30 45·0 (34·7–57·4) 17·6 (14·6–18·6)

4·22 ± 0·69*** 0·23 (0·13–0·30)* 1·82 ± 0·92*** 1·54 ± 0·43 1·14 (0·88–1·48) 8·8 (2·5–34·8) 79 ± 18*** 141 ± 29 47·7 (29·4–57·1) 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

Fasting insulin Fasting glucose Fasting IGF-1 Fasting IGF-BP1 Coronary risk Over 10 years

Units

Placebo

Atorvastatin

pmol /l mmol /l ng/ml ng/ml

5·17 (3·79–10·91) 5·07 (4·60–6·50) 209 (175–366) 36.2 (15.0–43.9)

6·06 (3·25–10·11) 5·30 (4·90–6·70) 247 (181–334) 27.9 (17.2–38.4)

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.

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 © 2005 Blackwell Publishing Ltd, Clinical Endocrinology, 62, 650–655

Atorvastatin in acromegaly 653 apoA1 and HDL cholesterol (r = 0·92; P < 0·0001), apoB and LDL cholesterol (r = 0·836; P < 0·001) and VLDL cholesterol and triglycerides (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 population44 and a 40% decrease in a large group of type 2 diabetic patients in the Collaborative 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 population44 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 cardiovascular 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 © 2005 Blackwell Publishing Ltd, Clinical Endocrinology, 62, 650– 655

be considered, including management of hypertension, smoking, and circulating lipid profile. Elevated concentrations of Lp(a) independently predict cardiovascular 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 consequence 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 GlaxoSmithKline Fellowship.

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