Short-term effect of atorvastatin in hypercholesterolaemic renal-transplant patients unresponsive to other statins

Rafael Romero1, Jesus Calviño1,, Javier Rodriguez2 and Domingo Sánchez-Guisande1

1 Division of Nephrology, Department of Medicine, and 2 Central Laboratory Department, Hospital Clínico Universitario, Santiago de Compostela, Spain



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Atherosclerosis associated with hyperlipidaemia is a major cause of morbidity and mortality after renal transplantation. Atorvastatin is a new HMG-CoA reductase inhibitor that has shown a favourable profile of lipid reduction when compared with other statins. The aim of the study was to assess the efficacy and safety of atorvastatin in hypercholesterolaemic renal transplant patients who had previously been on statins with little or no effect.

Methods. Atorvastatin, 10 mg/day, was administered to 10 renal transplant recipients with persistent hypercholesterolaemia (total cholesterol >240 mg/dl) for a period of 3 months. All of them had already been on statins for at least 3 months.

Results. Atorvastatin exerted a satisfactory lipid-lowering effect in seven of 10 patients. On average, serum total cholesterol (311±36.2 vs 253±48.8 mg/dl; P<0.05) and serum LDL cholesterol (184±30.9 vs 136±22.9 mg/dl; P<0.05) significantly decreased after atorvastatin therapy, whereas serum HDL cholesterol (86±14.6 vs 84±22.1 mg/dl) remained unchanged. In five subjects with a baseline serum triglyceride level above 150 mg/dl, a marked reduction in triglycerides was also observed (261±80.3 vs 193±53.3 mg/dl; P<0.05). Lp(a) did not significantly change (13±16.3 vs 15±23.9 mg/dl, P=NS). Serum creatinine, transaminases, creatinine phosphokinase (55±21.3 vs 56±29.4 IU/l) and fasting cyclosporin A levels were unaffected. The drug was generally well tolerated and neither myositis nor rhabdomyolysis was reported.

Conclusion. Short-term therapy with the new HMG-CoA reductase inhibitor, atorvastatin, appears to be effective in lowering atherogenic lipids in renal transplant patients who had had little or no response to other statins.

Keywords: atorvastatin; HMG-CoA reductase inhibitor; hyperlipidaemia; renal transplantation



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Abnormalities in lipoproteins are common after renal transplantation and, in this population, they may contribute to the high incidence of cardiovascular events as well as to the progression of chronic allograft dysfunction [13]. Several risk factors may lead to hyperlipidaemia in these patients including proteinuria, decreased renal function, immunosuppressive therapy with steroids and cyclosporin A (CsA), concurrent medical conditions such as age, obesity, diabetes, and treatment with ß-blockers or diuretics [13].

Renal transplant recipients with hyperlipidaemia can be treated with diet and various medications [14]. As diet alone is not usually enough for the control of this complication [5], several lipid-lowering agents have been advocated in these patients. Among them, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (‘statins’) are probably the most widely used since they are generally better tolerated than bile acid sequestrants, fibrates, and niacin [1,2]. However, these drugs should be carefully monitored in patients who are taking CsA, since they may cause myopathy and rhabdomyolysis, which may lead to myoglobinuria, hyperkalaemia, and acute renal failure [1,2,6]. This is, in fact, probably the main argument that explains why these drugs may have little or no effect in some patients, since maximal doses are usually avoided.

Atorvastatin is a new synthetic HMG-CoA reductase inhibitor that has shown a more marked effect on serum LDL cholesterol and triglycerides than other statins in non-uraemic patients [79]. This greater efficacy is probably due to a high first-pass effect in the liver, resulting in a long half-life HMG-CoA reductase inhibition [9]. The aim of this study was to evaluate the effect of atorvastatin in a group of renal transplant patients on CsA who were previously on statins with little or no serum lipid reduction.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Ten renal transplant recipients (two males and eight females, aged 51±11.5 years) were recruited. Despite dietary control with a cholesterol intake of less than 300 mg/day and at least 3-months therapy with statins (either simvastatin or pravastatin), all of them had hypercholesterolaemia according to the recommendations of the National Cholesterol Education Program (serum cholesterol >240 mg/dl) [10]. Time from renal transplantation ranged from 12 to 111 months. Immunosuppressive maintenance regimen included steroids (5 mg/day) and CsA in all cases. Three patients were concurrently treated with ß-blockers. None of the patients was on diuretics. Exclusion criteria were uncontrolled diabetes, concomitant liver disease, myopathy, pregnancy, and severe renal function impairment assessed by a serum creatinine level above 2 mg/dl or a creatinine clearance below 30 ml/min. Proteinuria (>0.3 g/l) was not present in any of the cases.

Patients were studied for a period of 3 months. Atorvastatin, 10 mg daily, was given at a single dose at any time of the day with or without food. As patients were previously on statins a washout period of 4 weeks was established. During the study period, patients were advised to keep their diet under careful control and concurrent medications were not modified.

Variables were obtained at the outpatient clinic initially and after 3 months. Fasting haematological and biochemical analysis were measured by conventional laboratory techniques. These included blood count, creatinine, total cholesterol, triglyceride, aminotransferases, alkaline phosphatase, creatine phosphokinase, potassium, calcium and phosphate levels, as well as proteinuria. High-density lipoprotein (HDL), low-density lipoprotein (LDL), and lipoprotein (a) (Lp(a)) were determined by an agarose gel electrophoresis procedure (Helena Laboratories, UK). CsA concentrations were measured by fluorescence polarization assay (Abbott Laboratories). All patients were asked about any side-effect including nausea, headache, allergic reactions, abdominal pain, muscle pain or cramps, insomnia, and others. Treatment failure was considered as a lack of LDL-cholesterol reduction and/or total cholesterol remaining above 240 mg/dl at the end of the follow up.

Statistics
Wilcoxon signed rank test was used to determine whether values of specific variables differed from the baseline. Data are presented as mean±SEM unless stated. We considered P<0.05 as statistically significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Baseline patients details including age, gender, body weight, graft follow-up, creatinine, CsA doses and serum levels, as well as variables concerning prior statin therapy are shown in Table 1Go. Six patients were previously on simvastatin (10–20 mg/day) and four on pravastatin (10–40 mg/day), doses that are known to be safe and effective in renal transplant patients on CsA [6].


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Table 1. Patient demographics

 
All the patients were able to complete the 3-month study period. After 3 months on atorvastatin, lipid profile failed to improve in three of the 10 patients (nos 3, 9 and 10). Table 2Go summarizes total triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol at baseline and at the end of the follow-up, as well as LDL cholesterol/HDL cholesterol ratio and Lp(a) outcome.


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Table 2. Lipid outcome after 3 months on atorvastatin

 
On average, a significant reduction of total cholesterol (from 311±36.2 to 266±39.0 mg/dl, P<0.01) was observed after only 4 weeks on atorvastatin. After 3 months, total cholesterol had decreased by 19% (to 253±48.8 mg/dl, P<0.05), whereas LDL cholesterol had decreased by 26% (from 184±30.9 to 136±22.9 mg/dl, P<0.05). HDL cholesterol did not significantly change (from 86±14.6 to 84±22.1 mg/dl, P=NS). Lp(a) levels remained unchanged (from 13±16.3 to 15±23.9 mg/dl, P=NS). To estimate the atherosclerotic risk, we calculated the LDL cholesterol/HDL cholesterol ratio, which fell by an average of 23% (from 2.2±0.59 to 1.7±0.50, P=0.05) after 3 months.

Although not reaching statistical significance, a triglyceride-lowering effect was also observed (from 195±88.8 to 177±49.1 mg/dl, P=NS). When we excluded from the analysis five patients who had normal serum triglyceride levels (<150 mg/dl) at baseline, triglyceride reduction became statistically significant, reaching a 26% fall at 3 months (from 261±80.3 to 193±53.3 mg/dl, P<0.05). Therefore atorvastatin significantly modified serum triglyceride level in the hypertriglyceridaemic patients.

Adverse effects were reported in three cases (patients 1, 2 and 3). All events were mild and treatment did not need to be discontinued in any of the cases. Effects included headache (patient no. 1), and nausea, diarrhoea, and abdominal discomfort in two cases. Skin rashes were not reported. There was no evidence of myopathy, including myalgia. Moreover, creatine kinase did not rise significantly throughout the study period (from 55±21.3 at baseline to 56±29.4 IU/l, P=NS). Aminotransferases (ALT, AST) were also unaffected during the period on atorvastatin. Graft function, assessed by serum creatinine concentration, remained stable in all cases (1.3±0.17 vs 1.4±0.15 mg/dl, P=NS). CsA concentration was also unchanged throughout this period (197±33.6 vs 184±39.4 ng/ml, P=NS). All other findings for vital signs, haematology, blood chemistries including bilirubin, alkaline phosphatase, calcium, phosphate and potassium, and urinalysis, were unremarkable.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Cardiovascular disease has emerged as the most common cause of morbidity and mortality in renal transplant recipients [13]. In this population, the incidence of hyperlipidaemia is high, ranging from 50 to 80% and is considered to be al least to some extent responsible for the development of atherosclerosis and cardiovascular events [3]. Moreover, lipid abnormalities may persist for the life of the allograft and thus contribute to the progression of chronic graft dysfunction. In fact, plasma cholesterol concentration has been shown to predict long-term renal graft survival in some studies [2,11].

For this reason, several lipid-lowering agents have been used in these patients. HMG-CoA reductase inhibitors suppress hepatic cholesterol biosynthesis, thereby promoting an increase in hepatic LDL receptors and reducing LDL cholesterol concentration [6,12]. These drugs are the most effective cholesterol-lowering agents available and have emerged as the first-line drugs in the treatment of post-transplant hypercholesterolaemia [2,4]. However, these agents have been avoided for some time because of reports of severe rhabdomyolysis. This adverse effect may result from higher HMG-CoA reductase inhibitor levels when combined with CsA, since the P-450 system metabolizes both drugs at the liver [1,6]. Although the lipid-lowering effect of statins is known to be dose dependent, clinical trials have shown that low doses of statins reduce atherogenic lipids in renal transplant patients on CsA without significantly increasing muscle toxicity [1,2,6]. However, in some cases, the lipid-lowering effect of these drugs is undeniable limited by its ‘maximum’ doses that in some cases may result in little or no impact on lipid profiles.

Data from studies in non-transplant patients with hypercholesterolaemia indicate that low doses of atorvastatin (10 mg/day), a new synthetic HMG-CoA reductase inhibitor, has a more significant effect on LDL cholesterol and triglyceride reduction than other statins with a comparable rate of adverse effects [79]. The present study is probably the first report on the effectiveness and safety of this agent in treating hypercholesterolaemic renal transplant recipients on CsA who had previously failed to improve with other statins.

After a 3-month period, atorvastatin reduced the mean serum total cholesterol and LDL cholesterol concentration by 19 and 26% respectively. On average, cholesterol LDL was shifted into the range that is considered to carry only a slight atherosclerotic risk in the normal population. These results are in line with those obtained in primary hypercholesterolaemic subjects [8]. However, treatment failure occurred in three of the 10 patients studied. Although we cannot exclude the possibility of these patients' inability to comply with diet and/or with the medication, this suggests that the factors increasing total and LDL cholesterol in these patients and atorvastatin-induced lipid lowering may have reached equilibrium. In fact, doses up to 80 mg/day have been successfully used for primary hypercholesterolaemic subjects [79]. However, our experience with renal transplant patients may limit the maximum dose to 20 mg/day.

HDL cholesterol did not significantly change throughout the study period. However, mean HDL cholesterol level at baseline was above 60 mg/dl, which is considered to be a negative risk factor for coronary artery disease. Unfortunately we did not measured HDL2 subfraction, which is inversely related with the atherosclerotic risk and has been thought to decrease after renal transplantation [13]. In order to estimate the atherogenic risk we analysed the LDL/HDL cholesterol ratio; this fell by 23%.

Lp(a) is a plasma fraction that consists of LDL covalently linked to apoprotein (a) [14]. Although its physiological function is unclear, elevated serum Lp(a) is an independent risk factor for atherogenesis and is often refractary to lipid-lowering therapies. Our study is in agreement with those published with other statins that report little reduction or no effect on Lp(a) concentration [15].

Regarding serum triglyceride levels, atorvastatin has shown better reductions than other statins when treating non-transplant patients requiring both cholesterol and triglyceride lowering. In our study, this effect was observed in the hypertriglyceridaemic patients who reached an average 26% reduction. Therefore, as with other statins, the effect on triglycerides seems to be related with baseline levels [16].

Adverse effects occurred in three cases. These were mild and transient, mainly involving the gastrointestinal tract as described for other groups of patients [79]. CsA blood levels, mean liver enzymes, creatine phosphokinase, and creatinine were unaffected. None of the patients reported myalgias, and neither myositis nor rhabdomyolysis was documented. However, short-term analysis of data cannot exclude the risk of rhabdomyolysis, which has been previously reported by other investigators in three non-transplant patients between 5 and 7 months on atorvastatin (two of them receiving 10 mg/day and one receiving 20 mg/day) [9]. Therefore, as when using other statins, regular check up of creatine phosphokinase is recommended.

In summary, short-term therapy with atorvastatin seems to be safe and effective in hypercholesterolaemic renal transplant patients on CsA who had not previously responded to other statins. However, randomized control trials, with longer follow-up and cardiovascular end-points are necessary to evaluate this agent.



   Notes
 
Correspondence and offprint requests to: Dr Jesus Calviño, Division of Nephrology, Hospital Clínico Universitario, A Choupana s/n, E-15706 Santiago de Compostela, Spain. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 16.10.99
Revision received 25. 4.00.