The Effect of Atorvastatin on Serum Lipoproteins in Acromegaly
The Effect of Atorvastatin on Serum Lipoproteins in Acromegaly
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 (0·210·47) mmol vs. 0·23 (0·130·30) 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 (3·317·9) vs. 2·8 (1·55·7)% over next 10 years; P < 0·01). Serum triglyceride was 1·34 (1·061·71) mmol/l on placebo and 1·14 (0·881·48) 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.
Acromegaly reduces life expectancy significantly, largely due to an excess of cardiovascular deaths. 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. Currently, most patients with acromegaly undergo hypophysectomy followed by radiotherapy and/or medical treatment, depending upon the residual growth hormone levels postoperatively. 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. 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.
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. 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. 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. Serum total cholesterol decreased following a reduction in growth hormone concentrations in one study in acromegaly, but increased as a consequence of pegvisomant therapy in a more recent study. This was despite pegvisomant, a growth hormone analogue that acts as a growth hormone receptor antagonist, being more effective than long-acting somatostatin analogues at decreasing serum IGF-1 in patients with active acromegaly. 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, which contributes little to total serum choleterol. Lipoprotein (a) (Lp(a)) has also been reported to be increased in acromegaly. Serum 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. 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. Furthermore, there is evidence of impaired endothelial function and there may be additional, direct effects on the heart muscle, reviewed by Clayton.
Here we report the effects of low-dose atorvastatin on lipoprotein metabolism and on calculated potential coronary heart disease risk in patients with acromegaly.
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 (0·210·47) mmol vs. 0·23 (0·130·30) 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 (3·317·9) vs. 2·8 (1·55·7)% over next 10 years; P < 0·01). Serum triglyceride was 1·34 (1·061·71) mmol/l on placebo and 1·14 (0·881·48) 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.
Acromegaly reduces life expectancy significantly, largely due to an excess of cardiovascular deaths. 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. Currently, most patients with acromegaly undergo hypophysectomy followed by radiotherapy and/or medical treatment, depending upon the residual growth hormone levels postoperatively. 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. 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.
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. 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. 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. Serum total cholesterol decreased following a reduction in growth hormone concentrations in one study in acromegaly, but increased as a consequence of pegvisomant therapy in a more recent study. This was despite pegvisomant, a growth hormone analogue that acts as a growth hormone receptor antagonist, being more effective than long-acting somatostatin analogues at decreasing serum IGF-1 in patients with active acromegaly. 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, which contributes little to total serum choleterol. Lipoprotein (a) (Lp(a)) has also been reported to be increased in acromegaly. Serum 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. 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. Furthermore, there is evidence of impaired endothelial function and there may be additional, direct effects on the heart muscle, reviewed by Clayton.
Here we report the effects of low-dose atorvastatin on lipoprotein metabolism and on calculated potential coronary heart disease risk in patients with acromegaly.