Jyh-Gang Leu
1,2,4,* Mei-Mei Huang
3Jung-Kuei Pai
1Wey-Wen Jiang
4Background and purpose: We attempted to study the efficacy of 20 mg/day simvastatin as monotherapy in patients with renal impairment combined with hyperlipidemia. Methods:
Thirty patients with impaired renal function (serum creatinine of > 1.3 mg/dl, 17 of whom were dialysis patients) were studied. Twenty patients with normal renal function (serum creatinine of
£ 1.3 mg/dl) were used as a control group. Once-daily 20 mg simvastatin was administered to all patients for 16 weeks in the absence of other lipid-lowering agents. Results: Serum total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein-cholesterol (LDL-C) in both patient groups significantly decreased after simvastatin treatment (TC from 258 ± 33 to 199 ± 36 mg/dl, TGs from 383 ± 171 to 273 ± 107 mg/dl, and LDL-C from 150 ± 36 to 101 ± 33 mg/dl in patients with impaired renal function; TC from 262 ± 54 to 194 ± 35 mg/dl, TG from 485 ± 201 to 274 ± 210 mg/dl, and LDL-C from 118 ± 41 to 101 ± 27 mg/dl in patients with normal renal function, all p < 0.01).
An increase in the serum high-density lipoprotein-cholesterol (HDL-C) also occurred in both patient groups (from 39 ± 11 to 44 ± 17 mg/dl, p < 0.05 in patients with renal impairment), however, the change in patients with normal renal function was not significant (from 38 ± 8 to 43 ± 10 mg/
dl, p = 0.064). Conclusion: Monotherapy with 20 mg/day simvastatin has similar safety and effectiveness in patients with normal and those with impaired renal function.
(FJJM 2005; 3 (1): 43-47 )
Keywords: Simvastatin, Hyperlipidemia, Renal impairment
School of Medicine, Fu-Jen Catholic University,Taipei,Taiwan1 Division of Nephrology, Department of Medicine2 Department of Pathology and Laboratory Medicine3, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan National Taipei College of Nursing, Taipei, Taiwan4 Submitted December, 03, 2003; final version accepted March, 26, 2005.
* Correspondence author: M004224@ms.skh.org.tw
Jyh-Gang Le Mei-Mei Huang Jung-Kuei Pai Wey-Wen Jiang
44 Fu Jen Journal of Medicine Vol.3 No.1 2005
of active fibrate metabolites may induce myotoxicity and increase serum creatinine levels in patients with renal impairment[3]. Previous reports showed a 3%~5% risk of myopathy with fibrate-statin combination therapy [4].
Recently, monotherapy with high doses (40 and 80 mg/day) of simvastatin was shown to be efficacious for combined hyperlipidemia [5]. In addition to a reduction in LDL-C, reductions in TG levels of 27.8% and 33% were noted after 6 weeks of treatment with 40 and 80 mg/day simvastatin, respectively. Such single-agent therapy may be useful for the management of patients with hyperlipidemia combined with renal impairment because no dosage adjustment of statins is needed in patients with renal impairment. The therapeutic role of statins in hyperlipidemia has been well established in subjects without renal function impairment, but few studies have been done on patients with renal impairment. In this study, the safety and efficacy of monotherapy with a low dose of simvastatin (20 mg/day) were measured and compared in patients with and those without renal impairment.
METHODS
Fifty patients with combined hyperlipidemia (serum TC of > 200 mg/dl and TGs of 250~1000 mg/dl) were enrolled in this study. Thirty patients (12 men and 18 women, with a mean (± standard deviation) age of 56 ±13 years) had impaired renal function (serum creatinine of > 1.3 mg/dl, including 17 dialysis patients, 13 on hemodialysis, and 4 in continuous ambulatory peritoneal dialysis), 20 patients (9 men and 11 women, with a mean age of 54 ±12 years) had normal renal function and were used as a control group (serum creatinine of
£ 1.3 mg/dl). None of these patients had received any lipid-lowering agents in the preceding 3 months
before entering this study. Once-daily 20 mg of simvastatin was administered to all patients for 16 weeks in the absence of any other lipid-lowering agents. All patients were informed of the possible side effects of simvastatin. Maintenance of individual dietary habits was supervised throughout the trial, and assessed by measurement of patients’ blood hemoglobin and serum glucose concentrations.
There were no significant changes in body weight during the study.
Fasting blood samples were taken at the start of the study and at the end of the 16-week period of simvastatin administration. Serum TC, TGs, LDL-C, high-density lipoprotein-cholesterol (HDL-C), glucose, urea nitrogen, creatinine, creatine kinase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase concentrations, a white blood cell count, platelet count, and hemoglobin level were analyzed by standard methods. All values are expressed as the mean ± standard deviation (SD).
Changes in each parameter were analyzed using SPSS for Windowsä. A p value of less than 0.05 was considered statistically significant.
RESULTS
Serum TC, TGs, and LDL-C in both patient groups significantly decreased after simvastatin treatment (TC from 258 ± 33 to 199 ± 36 mg/dl, TGs from 383 ± 171 to 273 ± 107 mg/dl, and LDL-C from 150 ± 36 to 101 ± 33 mg/dl in patients with impaired renal function; TC from 262 ± 54 to 194
± 35 mg/dl, TGs from 485 ± 201 to 274 ± 210 mg/
dl, and LDL-C from 118 ± 41 to 101 ± 27 mg/dl in patients with normal renal function, all p < 0.01).
Increases of HDL-C also occurred in both patient groups (from 39 ± 11 to 44 ± 17 mg/dl, p < 0.05 in patients with renal impairment), however, the change in patients with normal renal function was
Simvastatin in Patients with Renal Impairment
not significant (from 38 ± 8 to 43 ± 10 mg/dl, p = 0.064). All diabetic patients had stable blood sugar control (145 ± 37 mg/dl at the start of the study to 133 ± 35 mg/dl after the 16-week treatment, p >
0.1, n = 21), no hypoglycemic agent showed any change during the study period. There were no significant changes in body weight, white blood cell count, platelet count, hemoglobin, hematocrit, serum glucose, creatinine, creatine kinase, alanine aminotransferase, aspartate aminotransferase, or total bilirubinconcentrations during the studyperiod.
DISCUSSION
The decreases in TC and LDL-C in this study were compatible to those in previous studies on patients with[6]and without[7]dialysis; however, a more-significant decrease in TGs and increase in HDL-C were noted in our study, although we used a lower dosage of simvastatin. Higher TG levels which appeared in our patients may have been the major cause for this difference. Most patients in this study had achieved the National Cholesterol Education Program (NCEP) [8] cholesterol (< 200 mg/dl) and LDL-C (< 100 mg/dl) goals by the study end, but TG levels were still high after the 16-week simvastatin treatment. Combination therapy with other lipid-lowering agents is needed for those patients. Recently, simvastatin plus niacin was shownto provide markedclinicaland angiographically measurable benefits in patients with coronary disease and low HDL levels [9]. Long-term large-scale studies are needed to evaluate the efficacy and safety of niacin or simvastatin-fibratecombinationsinpatientswithrenalimpairment.
Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency [10]. There was no change in serum creatinine levels in our patients with chronic renal insufficiency during the study period. This
renal protection effect of statins is compatible with the results of previous studies [11]. Experimental studiessuggest thatstatinsmay influence intracellular pathwaysinvolvedin the inflammatory andfibrogenic responses of chronic renal injury[12], inhibit DNA synthesis in mesangial cells [13], and attenuate neointimal thickening andmesangial cell proliferation in animal models of atherosclerosis and nephritis independent of lipid levels[14]. Combination therapy using statins and angiotensin-converting enzyme inhibitors may be considered in the treatment of chronic renal disease.
The contribution of lipid abnormalities to atherosclerosis in patients with renal impairment remains controversial, although dialysis patients with clinical evidence of vascular disease were found to have high plasma triglyceride and low plasma high-density lipoprotein-cholesterol levels
[15]. Our study shows that monotherapy with a low dose (20 mg/day) of simvastatin is effective and safe for a lipid-lowering effect in patients with renal impairment. Recent studies also showed that statinsreduce cytokinesecretion,inhibitinflammation, and ameliorate angiotensin II-induced end organ damage[16]. It remains to be clarified whether such an intervention reduces the risk of atherosclerotic vascular complications in the uremic population.
REFERENCES
1. Oda H, Keane WF. Lipid abnormalities in end stage renal disease. Nephrol Dial Transplant 1998;
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2. MillerM,DolinarC, Cromwell W,et al.Effectiveness of high doses of simvastatin as monotherapy in mixedhyperlipidemia. AmJ Cardiol2001;87:232-234.
3. Bruce R, Daniel A, Cundy T. Renal function changes in diabetic nephropathy induced by bezafibrate. Nephron 1996;73:490.
4. Ellen RLB, McPherson R. Long-term efficacy and
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safety of fenofibrates and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 1998;
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5. Stein E, Plotkin D, Bays H, et al. Effects of simvastatin (40 and 80 mg/day) in patients with mixedhyperlipidemia.AmJCardiol2000;86:406-441.
6. Saltissi D, Morgan C, Rigby RJ, et al. Safety and efficacy of simvastatin in hypercholesterolemic patients undergoing chronic renal dialysis. Am J Kidney Dis 2002;39:283-290.
7. Branchi A, Fiorenza AM, Torri A, et al. Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients withhypercholesterolemia.ClinTher2001;23:851-857.
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Lipoprotein abnormalities are associated with
increased rate of progression of human chronic renal insufficiency. Nephrol Dial Transplant 1997;
12:1908-1915.
11. Johnson DW, Saunders HJ, Field MJ, et al. In vitro effects of simvastatin on tubulointerstitial cellsinahumanmodelof cyclosporinnephrotoxicity.
Am J Physiol 1999;276:F467-F475.
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Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Kidney Int 1993;44:503-508.
14. Massy ZA, Guijarro C. Statins: effects beyond cholesterol lowering. Nephrol Dial Transplant 2001;16:1738-1741.
15. Yukawa S, Mune M, Yamada Y, et al. Ongoing clinical trials of lipid reduction therapy in patients with renal disease. Kidney Int 1999;56(Suppl 71):
S141-S143.
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Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effects. Kidney Int 2000;58:
1420-1430.
Simvastatin in Patients with Renal Impairment
每天使用 20 毫克 Simvastatin 於合併有混合型 高脂血症的腎功能異常病人之效果評估
呂至剛
1,2,4,* 黃美美
3白榮貴
2江蔚文
4目標： 探討以 simvastatin 治療合併有混合型高血脂症的腎功能異常病人之效果。
方法： 將病人分為兩組，第一組為腎功能異常病人，共有三十位，其中十七位正接受
腎臟透析治療，其餘十三位的血清肌肝酸濃度均大於1.3 mg/dl。第二組為腎功能正常
的控制組病人，共有二十位，每位血清肌肝酸濃度均小於或等於1.3 mg/dl。兩組病人
均接受十六週口服 simvastatin 的治療，每天口服一次，劑量為 20 毫克。所有病人皆 未使用其他的降血脂藥物。結果： 經過十六週治療之後，兩組病人血清中總膽固醇、
三酸甘油脂及低密度脂蛋白內膽固醇濃度均顯著的降低。第一組腎功能異常病人的血 清中總膽固醇由治療前258 ± 33 降至治療後 199 ± 36 mg/dl；三酸甘油脂由 383 ± 171 降 至273 ±107 mg/dl；低密度脂蛋白內膽固醇由 150 ± 36 降至 101 ± 33 mg/dl (p < 0.01)；而第 二組腎功能正常的病人的血清中總膽固醇由262 ± 54 降至 194 ± 35 mg/dl；三酸甘油脂 由485 ± 201 降至 274 ± 210 mg/dl；低密度脂蛋白內膽固醇由 118 ± 41 降至 101 ± 27 mg/dl (p < 0.01)。兩組病人血清中高密度脂蛋白內膽固醇濃度均升高，第一組腎功能異常的病 人由39 ± 11 升高至 44 ± 17 mg/dl ( p < 0.05)；第二組腎功能正常的病人由 38 ± 8 升高至 43
± 10 mg/dl，但統計學上無顯著意義( p = 0.064)。結論：每天以口服一次 20 毫克 simvastatin 治療混合型高血脂症，無論是用在腎功能正常或異常的病人身上，其治療 效果及安全性均極為相似。(輔仁醫學期刊2005；3 (1) ：43-47 )
關鍵詞：降血脂藥物，高血脂症，腎功能不足
天主教輔仁大學醫學系1 財團法人新光吳火獅紀念醫院內科部腎臟科2 財團法人新光吳火獅紀念醫院病理檢驗科3 國立台北護
理學院4
投搞日期：2003 年 12 月 3 日；接受日期：2005 年 3 月 26 日
* 通訊聯絡作者：電子郵件：M004224@ms.skh.org.tw
輔仁醫學期刊歡迎各醫學專業領域的同仁投