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Original Article http://dx.doi.org/10.12997/jla.2014.3.1.21 pissn 2287-2892 eissn 2288-2561 JLA Cholesterol Lowering Effects of Low-dose Statins in Korean Patients Jee Eun Kwon, Young Kim, Seonghyup Hyun, Hoyoun Won, Seung Yong Shin, Kwang Je Lee, Sang-Wook Kim, Tae Ho Kim, Chee Jeong Kim Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea 한국인에서저용량스타틴의종류에따른콜레스테롤저하효과 권지은, 김영, 현성업, 원호연, 신승용, 이광제, 김상욱, 김태호, 김치정 중앙대학교의과대학내과학교실 Objective: The aim of this study is to compare cholesterol lowering effects of low dose 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in Korean patients. Methods: A total of 909 consecutive patients were enrolled prospectively according to the criteria of National Cholesterol Education Program guidelines. Lipid profiles were obtained before and 2 months after statin therapy. Results: Atorvastatin 10 mg (n=260), lovastatin 20 mg (n=145), pitavastatin 2 mg (n=80), pravastatin 20 mg (n=28), rosuvastatin 5 mg (n=145), and simvastatin 20 mg (n=208) reduced low density lipoprotein (LDL) cholesterol by -41.8±11.0%, -33.8±12.8%, -39.3±10.8%, -31.5±8.9%, -48.8±12.3%, and -42.8±13.5%, respectively. LDL cholesterol less than 130 mg/dl was achieved in 90.3%, 76.9%, 88.5%, 85.2%, 97.2%, and 94.2%, respectively. The reduction of LDL cholesterol by 30% or more was obtained in 84.4%, 60.7%, 81.6%, 63.0%, 93.0%, and 83.5%, respectively. LDL cholesterol less than 70 mg/dl or the reduction by 50% or more was observed in a small portion of patients and was variable according to the different types of statins. Conclusion: A low dose statin was enough to manage dyslipidemia in most Korean patients with low to moderate risks and was even effective in a subpopulation of high risk patients. Key Words: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, Hypercholesterolemia, LDL Cholesterol 서론 고콜레스테롤혈증환자, 심장혈관계질환위험군환자및심장혈관계질환환자에서 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor( 스타틴 ) 의콜레스테롤저하효과와이에의한심장혈관계질환의예방효과는많은연구에서증명되었으며이에대한이견은없다. 1-3 스타틴의콜레스테롤저하효과의정도는약제의종류와용량에따라다양하며, 역시많은연구에서직접및간접적으로비교보고되었으나거의대부분의연구들이서양인을대상으로시행되었다. 4,5 하지만인종에따라일부약제의혈중농도의차이가있다는보고도있어동양인에서는콜레스테롤저하효과의정도가서양인과차이가있을가능성이있으나이에대해알려진바가없다. 6 Received: Revised: Accepted: April 28, 2014 May 12, 2014 May 16, 2014 Corresponding Author: Chee Jeong Kim, Division of Cardiology, Department of Internal Medicine, Chung-Ang University Hospital. 224-1 Heukseokdong, Dongjakku, Seoul 156-755, Korea Tel: +82-2-6299-1398, Fax: +82-2-822-2769, E-mail: cjkim@cau.ac.kr This is an Open Access article distributed under the terms of the creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.lipid.or.kr Copyright c 2014 The Korean Society of Lipidology and Atherosclerosis 21

J Lipid Atheroscler 2014;3(1):21-28 JOURNAL OF LIPID AND ATHEROSCLEROSIS 국내연구에서는대부분일개약제의콜레스테롤저하효과를관찰하거나, 일부약제의일정용량을비교하거나, 일개약제의용량에따른효과를비교한연구들은있으나, 다수약제의효과를비교한연구는없다. 심장혈관계질환의예방연구에서도서양인을대상으로한연구에서는대부분기본용량보다많은양의약제를투여하여예방효과를관찰한반면에, 7-9 일부동양인을대상으로한연구에서는저용량의스타틴이일차및이차예방에효과가있다는보고도있어역시동서양인사이에스타틴의효과가차이가있을가능성이제시되었다. 10 따라서본연구에서는한국인에서여러종류의스타틴을기본용량으로투여하였을때에약제에따른콜레스테롤저하효과를비교하고, 서양인의결과들과간접적으로차이를알아보고자하였다. 대상및방법 미국 National cholesterol education program의 Adult treatment panel III (ATP III) 의치료지침에의해스타틴의투여가필요한환자 909명을대상으로하였다. 11,12 치료여부는추적중인경우에는반복적으로측정한저밀도지단백 (low density lipoprotein, LDL) 콜레스테롤농도, 처음고콜레스테롤혈증이발견된경우에는 2개월이상의식이요법후에측정한 LDL 콜레스테롤농도가약물요법을필요로할정도로높은경우에대상환자로하였다. 아스파르테이트아미노전이효소와알라닌아미노전이효소가정상치의 3배이상증가된환자는제외하였다. 이중에 37명 (4.1%) 은추적되지않았고, 6명 (0.7%) 은부작용으로투약을중단하여이들을제외한 866명의결과를분석하였다. 일부환자 (n=19) 에서중성지방의농도가 400 mg/dl 이상이어서 LDL 콜레스테롤변화의분석에서는제외되었다. 본연구대상환자의일부는이전의보고에포함되었다. 13 이들에게 atorvastatin 10 mg (n=260), lovastatin 20 mg (n=145), pitavastatin 2 mg (n=80), pravastatin 20 mg (n=28), rosuvastatin 5 mg (n=145) 및 simvastatin 20 mg (n=208) 을투여하였다. 지질농도를치료전과치료후 2개월에측정하였으며, 이를전향적으로기록하고, 후향적으로분석하였다. 혈액은 12시간이상금식후에채취하였다. 콜레스테롤 (Olympus Diagnostica, Hamburg, Germany) 과중성지방 (Wako Pure Chemical Industries, Ltd, Osaka, Japan) 의농도는자동분석기 (AU5400, Olympus Corporation, Tokyo, Japan) 로효소법을이용하였다. 고밀도지단백 (high density lipoprotein, HDL) 콜레스테롤농도는면역억제방법을사용한직접법을이용하여측정하였다 (Wako Pure Chemical Industries, Ltd, Osaka, Japan). LDL 콜레스테롤농도는중성지방농도가 400 mg/dl 미만의환자에서 Friedewald 공식을이용하여계산하였다. 모든수치는평균과표준편차로표시하였다. 통계분석은 Social Package for Social Science (SPSS V9.0K, SPSS Inc., Chicago, IL, USA) 방법을이용하였다. 치료전후의중성지방변화를비교하기위해서는 Wilcoxon signed-rank test를이용하였고, 두군간의차이를비교하기위해서는 Mann-Whitney U test를이용하였다. 치료전후의다른변수의변화를비교하기위해서는 paired t-test 를사용하였고, 두군간차이를비교하기위해서는 the Student t-test를이용하였다. 다수군의비교는분포에따라 ANOVA나 Kruskal-Wallis test 를사용하였다. 이산변수의비교는 χ 2 test를이용하였다. 인자들사이의연관은일부정규분포를하지않는인자는로그형태로변형하여 Pearson 상관관계분석을이용하였다. 독립인자를찾기위해서는통계적으로의미있는변수를대입하여다변수단계적선형회귀분석을사용하였다. 통계에서 p값이 0.05 미만일때의미가있는것으로하였다. 결과 각군들사이에임상적인자들은의미있는차이가별로없었으나, 지질농도에서 LDL 콜레스테롤 (p) 과 HDL 콜레스테롤 (p) 은차이가있었다 (Table 1). Atorvastatin 10 mg, lovastatin 20 mg, pitavastatin 2 mg, pravastatin 20 mg, rosuvastatin 5 mg, 및 simvastatin 20 mg은 LDL 콜레스테롤을각각 41.8±11.0% (p), 33.8±12.8% (p), 39.3±10.8% (p), 31.5±8.9% (p), 48.8±12.3% (p), 42.8±13.5% (p) 감소시켰으며 (Table 2), 군간의 LDL 콜레스테롤저하효과도차이가있었다 (p). 이외에 HDL 콜레스테롤 (p<0.005), 중성지방 (p< 0.001) 및총콜레스테롤 (p) 의변화도약제군사이에차이가있었다 (Table 2). 22 www.lipid.or.kr

Jee Eun Kwon, et al.: Statin and Cholesterol Table 1. Comparisons of baseline clinical and laboratory characteristics among statin groups Number Sex (Male/Female) Age (years) Height (cm) Weight (kg) BMI (kg/m 2 ) Alcohol (%) Smoking (%) Hypertension (%) Diabetes mellitus (%) Ischemic heart disease (%) Cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglyceride (mg/dl) AST (U/L) ALT (U/L) Creatine kinase (IU/L) Atorvastatin (10 mg) 260 119/141 57.9±11.7 161.5±8.8 65.5±11.7 25.0±3.4 28.5 14.5 77.3 10.4 12.7 253.1±32.2 53.9±12.0 167.3±28.7 161.7±89.2 23.8±7.5 24.0±13.0 105.1±54.4 Lovastatin 145 60/85 61.3±9.4 158.1±8.2 61.6±8.9 24.6±2.9 18.9 12.2 86.9 11.0 20.0 254.4±34.1 53.5±11.7 166.6±27.3 169.8±85.7 22.4±6.4 22.5±10.5 93.0±44.7 Pitavastatin (2 mg) 80 32/48 58.7±12.0 160.4±9.4 64.7±9.6 25.1±2.7 32.1 15.4 80.0 7.5 8.8 248.8±32.1 52.3±11.4 162.4±29.4 173.0±94.0 24.0±5.5 22.6±10.9 104.3±41.7 Pravastatin 28 12/16 60.3±11.1 160.5±8.7 64.1±12.3 24.8±3.1 32.1 10.7 50.0 7.1 17.9 237.4±37.6 51.0±11.3 157.3±29.2 145.1±68.5 23.6±4.6 19.4±6.5 90.7±42.1 Rosuvastatin (5 mg) 145 70/75 59.6±12.0 161.6±8.7 66.1±12.4 25.2±3.0 31.7 15.9 80.7 8.3 13.8 240.2±26.3 50.6±9.1 157.5±22.3 166.1±98.0 25.2±7.3 24.2±12.6 124.2±69.5 Simvastatin 208 80/128 59.9±9.4 160.2±8.4 64.5±11.4 25.0±3.2 23.4 11.7 76.0 9.1 10.1 238.2±30.1 54.0±11.8 154.9±30.4 149.1±71.1 25.0±7.0 23.7±10.5 104.8±62.4 p value 0.460 0.063 0.046 0.100 0.860 0.210 0.860 0.006 0.910 0.290 0.063 0.200 0.005 0.310 Data are presented as the Mean±SD, BMI; body mass index, HDL-C; high density lipoprotein cholesterol, LDL-C; low density lipoprotein cholesterol, AST; aspartate aminotransferase, ALT; alanine aminotransferase Table 2. Percent changes of lipid profiles among statin groups Cholesterol (%) HDL-C (%) LDL-C (%) Triglyceride (%) Atorvastatin (10 mg) -30.3±8.2* -0.3±14.1-41.8±11.0* -12.7±38.4* Lovastatin -22.9±9.2* -0.6±18.2-33.8±12.8* 3.9±48.0 Pitavastatin (2 mg) -27.3±8.8* 3.1±13.0-39.3±10.8* -14.5±29.7* Pravastatin -22.2±6.9* -0.4±10.5-31.5±8.9* -2.6±32.2 Rosuvastatin (5 mg) -32.7±8.6* 5.3±11.9* -48.8±12.3* -10.3±34.9* Simvastatin -29.8±9.7* 2.4±13.2-42.8±13.5* -11.7±38.7* p value 0.001 Data are presented as the Mean±SD, *; p<0.05, HDL-C; high density lipoprotein cholesterol, LDL-C; low density lipoprotein cholesterol LDL 콜레스테롤의백분율변화는체중이더많이감소할수록 (r=0.11, p<0.005), 중성지방의농도가낮을수록 (r=0.12, p< 0.005), 스타틴의종류에의해더많이감소하였으며, 이중에스타틴의종류와중성지방농도가독립인자였다. 이외에 HDL 콜레스테롤, 중성지방및총콜레스테롤농도의백분율변화도여러인자들의영향을받았으며, 일관되게스타틴의종류가독립인자로작용하였다 (Table 3). ATP III 치료지침에서중등도위험군의 LDL 콜레스테롤목표농도중에하나인 130 mg/dl 미만에도달하는빈도는각각 90.3%, 76.9%, 88.5%, 85.2%, 97.2%, 94.2% 였으며, 특히고효능약제의경우 90% 이상에서목표농도에도달하였다 (Table 4). ATP III 치료지침에서고위험군의 LDL 콜레스테롤목표농도중에하나인 100 mg/dl 미만에도달하는빈도는각각 58.8%, 36.6%, 60.3%, 42.3%, 82.6%, 72.5% 로상당부분의환자에서기본용량으로목표농도에도달하였고, 특히고효능약제의경우 60% 이상에서효과가있었다. 또한 LDL 콜레스테롤농도가 70 mg/dl 미만으로떨어지는비율도고효능약제의경우기본용량을투여하였을때에 20-30% 에서달성되었다 (Table 4). 유럽의치료지침에서중등도위험군의치료목표인 115 mg/dl 미만도많은비율에서기본용량의스타틴으로달성할수있었다 (Table 4). www.lipid.or.kr 23

J Lipid Atheroscler 2014;3(1):21-28 JOURNAL OF LIPID AND ATHEROSCLEROSIS Table 3. Parameters associated with percent changes of lipid profiles Sex (Male/Female) Age (years) Height (cm) Weight (kg) BMI (kg/m 2 ) Changes in weight (%) Alcohol (%) Smoking (%) Hypertension (%) Diabetes mellitus (%) Ischemic heart disease (%) Cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglyceride (mg/dl) AST (U/L) ALT (U/L) Creatine kinase (IU/L) Statins -0.05 0.07 0.07 0.13 0.11 0.00-0.10-0.18 0.07-0.05-0.08-0.05 0.34 Cholesterol HDL-C LDL-C Triglyceride r p r p r p r p 0.480 0.130 0.051 0.044 0.530 0.002 0.450 0.420 0.600 0.970 0.002 0.380 8 0.130 6 0.130 - - 0.05 0.05-0.05-0.07-0.32-0.07 0.16-0.08-0.07 0.07 0.690 0.870 0.740 0.870 0.780 0.140 0.200 0.880 0.860 0.780 0.180 5 5 9 0.900 4-0.06 0.04 0.05 0.11 0.00-0.00 0.00 - -0.06 0.12-0.06-0.05-0.09 0.34 0.410 0.110 0.340 0.190 0.530 0.004 0.480 0.970 0.980 0.490 0.840 0.980 0.810 0.110 0.001 0.100 0.140 0.008 - - -0.00 - -0.00 0.00 0.13 0.12-0.33-0.11 0.11 0.690 0.650 0.340 0.670 0.760 0.580 0.920 0.580 0.910 0.630 0.890 0.990 0.670 0.320 0.002 0.002 HDL-C; high density lipoprotein cholesterol, LDL-C; low density lipoprotein cholesterol, BMI; body mass index, AST; aspartate aminotransferase, ALT; alanine aminotransferase Table 4. Percent of patients achieving LDL-C targets recommended by major guidelines for lipid management among statin groups 30% or more 50% or more LDL-C <130 mg/dl (%) LDL-C <100 mg/dl (%) LDL-C <70 mg/dl (%) LDL-C <115 mg/dl (%) Atorvastatin (10 mg) 84.4 20.3 90.3 58.8 9.3 80.8 Lovastatin 60.7 11.4 76.9 36.6 7.0 56.3 Pitavastatin (2 mg) 81.6 18.4 88.5 60.3 8.0 78.2 Pravastatin 63.0 0 85.2 42.3 0 73.1 HDL-C; high density lipoprotein cholesterol, LDL-C; low density lipoprotein cholesterol Rosuvastatin (5 mg) 93.0 47.9 97.2 82.6 30.8 93.7 Simvastatin 83.5 28.6 94.2 72.5 22.2 85.9 p value 최근 American College of Cardiology/American Heart Association (ACC/AHA) 치료지침에서치료목표로제시한 LDL 콜레스테롤을 30% 이상감소시키는비율은각각 84.4%, 60.7%, 81.7%, 63.0%, 93.0%, 83.5% 로상당부분의환자에서기본용량으로목표농도에도달하였다. 또한 50% 이상감소시키는비율도고효능약제의경우기본용량으로 20-50% 에서도달하였다 (Table 4). 부작용으로 6예에서약물을중단하였는데이는소화장애, 피부병변등의심하지않은것이었다. 전체환자에서아스파르테이트아미노전이효소 (p) 와알라닌아미노전이효소 (p< 0.001) 는전체에서증가하였으며, 아스파르테이트아미노전이효소변화량은스타틴종류에따라차이가없었으나 (p=0.11), 알라닌아미노전이효소의변화량은차이가있었다 (p=5). Atovastatin (p=0.006), pitavastatin (p=0.004), rosuvastatin (p=0.005), simvastatin (p) 은알라닌아미노전이효소를증가시켰으나, lovastatin (p=0.33) 과 pravastatin 24 www.lipid.or.kr

Jee Eun Kwon, et al.: Statin and Cholesterol (p=0.15) 은증가가관찰되지않았다. 하지만이러한상승은수치상의결과이고실제아스파르테이트아미노전이효소나알라닌아미노전이효소가정상치의 3배이상증가한경우는 2예에불과하였으며, 이는 rosuvastatin 을사용한환자였다. Creatine kinase (CK) 도전체환자에서투약후에수치상으로증가하였으나 (p=5), 스타틴종류에따른차이는없었다 (p=0.72). Rosuvastatin을사용한 1예에서 CK가정상의 10배이상증가하였는데증상은없었으며, 혈액검사직전의심한운동과연관이있을것으로생각되었다. 고찰 본연구에서는기본용량의스타틴이중등도위험군에서는대부분의경우에서, 고위험군에서는상당부분의환자에서, 최고위험군의환자에서도일부환자에서치료목표를성취하는데효과적임을관찰하였다. 따라서한국인에서는외국의경우와달리저용량의스타틴이매우효과적일수있음을제시하고있다. 본연구에서는치료여부결정을일시적인지질이상승한경우를배제하기위해추적중인경우에는반복적으로측정한 LDL 콜레스테롤농도, 처음고콜레스테롤혈증이발견된경우에는 2개월이상의식이요법후에측정한 LDL 콜레스테롤농도가약물요법을필요로할정도로높은경우에만대상환자로하였다. 따라서지질저하효과를이전의무작위연구와비교하는데무리는없을것으로생각된다. 실제투약전식이요법을하였던군 (n=370) 과지속적으로추적중이라식이요법을하지않았던군 (n=496) 사이에 LDL 콜레스테롤저하효과는각각 41.9±12.4% 와 41.0± 13.4% 로차이가없었다 (p=0.32). 이외다른지질의변화에도차이가없었다. 본연구에서사용한 atorvastatin 10 mg, lovastatin 20 mg, pravastatin 20 mg 및 simvastatin 20 mg의 LDL 콜레스테롤에대한효과는각각 41.8±11.0%, 33.8±12.8%, 31.5±8.9%, 42.8±13.5% 로서서양에서스타틴종류와용량에따른효과를직접비교한연구의 38%, 29%, 24%, 35% 보다감소폭이더컸다. 4 또다른서양의연구에서도 atorvastatin 10 mg, pravastatin 20 mg 및 simvastatin 20 mg은 LDL 콜레스테롤을각각 36.8%, 24.4% 및 35.0% 감소시켜역시본연구의효과보다낮았다. 또한 rosuvastatin 10 mg은 LDL 콜레스테롤을 45.8% 감소시켜본연구에서 5 mg이 48.8±12.3% 감소시킨 것과비교하여효과가적었다. 5 서양의대단위무작위일차예방연구에서 lovastatin 20-40 mg은 1년후에 LDL 콜레스테롤을 25% 감소시켜역시본연구의 33.8±12.8% 보다감소폭이적었다. 7 다른연구에서 pravastatin 40 mg은 LDL 콜레스테롤을 26% 감소시켜본연구에서 20 mg이 31.5±8.9% 를감소시킨것과비교하여고용량임에도불구하고 LDL 콜레스테롤저하효과는적었다. 8 대단위무작위이차예방연구에서 simvastatin 40 mg은 LDL 콜레스테롤을 35% 감소시켜본연구의 20 mg 이 42.8±13.5% 감소시킨것과비교하여효과가적었다. 9 LDL 콜레스테롤이많이높지않은환자를대상으로 1년간 atorvastatin 을투여하였을때에 LDL 콜레스테롤이 35% 감소하여역시본연구의 41.8±11.0% 보다효과가적었다. 14 LDL 콜레스테롤이 130 mg/dl 미만으로많이높지않으면서 C reactive protein이 2 mg/l 이상인환자에서 rosuvastatin 20 mg은 LDL 콜레스테롤을 50% 감소시켜본연구의 5 mg이 48.8±12.3% 감소시킨것과비교하여효과가비슷하였다. 15 ATP III에서중등도위험군에서는 LDL 콜레스테롤을 130 mg/dl 미만으로유지할것을권장하였는데본연구에서는저효능스타틴인 lovastatin 과 pravastatin의기본용량인 20 mg도 60% 전후에서이목표에도달하였으며, 고효능스타틴의기본용량인 atorvastatin 10 mg, pitavastatin 2 mg, rosuvastatin 5 mg 및 simvastatin 20 mg 의경우에는 80% 이상에서효과가충분하여한국인에서중등도위험군의경우에는대부분기본용량의스타틴이사용되는것이적당할것으로생각된다. 뿐만아니라고효능스타틴의경우에기본용량으로 60-80% 에서 LDL 콜레스테롤을 100 mg/dl 미만으로감소시켜이들군에서도기본용량이우선시도되어야할것으로생각된다. 11 초고위험군에서권장되는 LDL 콜레스테롤 70 mg/dl 미만도고효능스타틴의경우에기본용량으로 20-30% 에서목표에도달할수있어, 외국에서권장되었던고용량의스타틴의처방도한국인에서는기본용량으로시작하여조정이필요할것으로생각된다. 12 최근 ACC/AHA 치료지침에서는이전에있던약물요법이필요한 LDL 콜레스테롤농도나목표농도의개념을없애고환자의위험도나여러임상인자를고려하여 LDL 콜레스테롤을 30% 이상혹은 50% 이상감소시킬것을권장하였다. 16 치료지침에서 pravastatin 20 mg과 lovastatin 20 mg은저강도스타틴치료로 LDL 콜레스테롤을 30% 미만감소시키는것으로정리하였으 www.lipid.or.kr 25

J Lipid Atheroscler 2014;3(1):21-28 JOURNAL OF LIPID AND ATHEROSCLEROSIS 나본연구에서는 60% 이상에서 LDL 콜레스테롤을 30% 이상감소시켜한국인에서는초기약제로이들을사용할수있을것으로생각된다. 치료지침에서중강도스타틴치료로 LDL 콜레스테롤을 30-50% 감소시키기위해권장되는약제의용량은본연구에서는 80% 이상에서효과가있었다. 50% 이상감소시키기위해서는 atorvastatin 80 mg이나 rosuvastatin 20 mg을권장하였는데본연구에서는고효능의스타틴기본용량을사용하여도 20% 이상에서이기준에만족하였다. 이상의 LDL 콜레스테롤감소율의비교, 목표농도에도달하는비율및 LDL 콜레스테롤을 30% 혹은 50% 감소시키는비율을서양인과비교해본결과를바탕으로한국인에서는각각의스타틴의효과가서양인에비해감소비율이매우크므로환자의치료방침의결정에서외국의권장과달리저효능의스타틴을사용할수도있으며, 고효능의스타틴의경우에는용량을줄여사용할수있을것으로생각된다. 특히 rosuvastatin의경우동양인에서약물의혈중농도가서양인에비해높은것으로보고되어용량의조절이필요할것으로생각된다. 6 동양인을대상으로한대단위무작위연구에서는 pravastatin 을 5-20 mg 사용하였을때에 LDL 콜레스테롤을 18% 감소시켜관상동맥질환을 30% 이상감소시킴을보고하였다. 하지만이연구에서는대상의 2/3 이상에서 5-10 mg 의용량을사용하였기때문에본연구와직접적인비교는어렵다. 10 본연구에서 pravastatin 20 mg을투여하였을때에 31.5±8.9% 감소시킨것에비해효과가작았다. 국내의연구는대부분약제발매초기에약의효능과안전성을확인하거나 2개약제사이의효과를비교한연구가대부분이다. 약제의효능과안전성을관찰한연구에서 lovastatin 20 mg을 4-12주간투여하였을때에 LDL 콜레스테롤이 21-34% 감소하였다. 17-20 이들중에한연구에서 20 LDL 콜레스테롤이 21% 로타연구에비해저하정도가낮았으나, 이는스타틴이처음발매되었을때에시행된연구로콜레스테롤이아주높은환자만을대상으로하였기때문에대상군의치료전의평균 LDL 콜레스테롤이 229±53 mg/dl 로아마다수의가족형고콜레스테롤혈증환자가포함되어저하효과가적었을가능성이있다. 이를제외하고는본연구의 33.8±12.8% 와효과가비슷하였다. Pravastatin 10 mg 을 2-3개월간투여하였을때에 LDL 콜레스테롤을 19-34% 감소시킴이보고되었다. 21-23 20 mg을투여한연구결과가없어본연구의결과를이전의연구와비교하는데에는 한계가있으나, 본연구에서 pravastatin 20 mg을투여하였을때에 31.5±8.9% 감소한것과큰차이는없을것으로생각된다. Simvastatin 10 mg 을 4주간투여하였을때에 LDL 콜레스테롤을 34% 감소시켰다. 또한 10-40 mg 을 12주간투여하였을때에 41% 감소시켰는데이중 61% 의환자는 12주에 10 mg, 28% 는 20 mg 을복용중이었고, 오직 7% 만이 40 mg 을복용하였다. 24 본연구에서 20 mg이 42.8±13.5% 감소시켰는데비록용량이다양하나저하효과에는큰차이가없는것으로생각된다. 이전의보고에서 atorvastatin 10 mg을 4-6주간투여하였을때에 LDL 콜레스테롤은 39-45% 감소하였는데 25,26 이는본연구의 41.8±11.0% 와잘일치하는소견이다. Pitavastatin 2-4 mg 은 LDL 콜레스테롤을 41.1% 감소시켰다. 27 약반수의환자가 4 mg을복용한것을감안하면본연구에서 2 mg을사용하였을때에 39.3±10.8% 감소시킨것과역시잘일치하는것으로생각된다. Rosuvastatin의효과에대한연구는한국인을대상으로한보고가미약하여비교할수는없다. Rosuvastatin의경우약물의혈중농도가서양인과비교하여동양인에서높다고알려져있으며, 따라서용량을줄여서사용할것을권장하였다. 6 본연구에서 5 mg 이다른고효능스타틴의기본용량과비교하여 LDL 콜레스테롤저하효과가거의비슷하거나오히려더효과적이어서한국인에서용량을줄여서사용하는것이합당할것으로생각된다. 한국인에서약제간에효과를비교한연구결과를분석해보면, pitavastatin 2 mg과 atorvastatin 10 mg의효과를 8주동안투약한연구에서 LDL 콜레스테롤을각각 42.9% 와 44.1% 감소시켰다. 28 급성관상동맥증후군이나급성허혈성뇌졸중환자에서 atorvastatin 20 mg과 rosuvastatin 10 mg을비교한연구에서 LDL 콜레스테롤을각각 40.1% 과 46.8% 를감소시켰다. 29 대사증후군환자를대상으로 atorvastatin 10 mg과 rosuvastatin 10 mg 을 6주간투여한후에비교한연구에서 LDL 콜레스테롤을각각 39.5% 와 46.8% 를감소시켰다. 30 이상의연구결과는본연구의 LDL 콜레스테롤저하효과와비슷하였다. 최근미국의식약청에서스타틴사용시에간기능의지속적인관찰이필요없다고권장하였다. 본연구에서스타틴의사용은수치상통계적으로유의하게간기능의악화가관찰되었으나실제간기능지수가정상의 3배이상증가하는경우는매우드물었다. 또한간기능의변화는스타틴의종류와연관이있어저효능약제의경우에는치료전후에차이가없는반면에고효능약제의경우에는 26 www.lipid.or.kr

Jee Eun Kwon, et al.: Statin and Cholesterol 악화가관찰되었다. 따라서가능하면치료기준에맞게적은용량의스타틴을사용하는것이적당해보이며특히한국인에서서양인에비해콜레스테롤저하효과가크므로이를감안하여치료하는것이필요할것으로생각된다. 반면에 creatine kinase는전체에서통계적으로유의하게증가하였으나약제간에차이가없었다. 본연구의한계로는무작위연구가아니라는것이다. 우선약제사이에지질의농도가차이가있다. 본연구에서일부약제의효과판정에있어백분율변화는비슷하나목표농도의도달정도는낮았는데, 이는대상환자의치료전콜레스테롤농도가상대적으로높았기때문이다. 또한약제의발매시기에따라각군의대상자로선정되는데에시간적차이가있었다. 본연구에서는외국인과는달리한국인에서는기본용량의스타틴이매우효과적이어서중등도위험군에서는대부분의경우에서, 고위험군에서는상당부분의환자에서, 최고위험군의환자에서도일부환자에서치료목표를성취하는데효과적임을관찰하였다. 따라서한국인에서는대부분의경우에저용량의스타틴으로시작하여필요에따라용량을증가시키는접근이필요할것으로생각된다. 참고문헌 1. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278. 2. Kim CJ, Lee KJ. Hypercholesterolemia; management of Korean patients in new millennium. Korean J Med 2007; 72:580-592. 3. Kim CJ. In the shadow of the "Statin Festival". Korean Circ J 2006;36:77-83. 4. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582-587. 5. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92:152-160. 6. Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005; 78:330-341. 7. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622. 8. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-1307. 9. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389. 10. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368:1155-1163. 11. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. 12. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227-239. 13. Cho JH, Kim KJ, Lee WS, Lee KJ, Kim SW, Kim TH, et al. Effect of statins on C-reactive protein, lipoprotein(a) and fibrinogen in hypercholesterolemic patients. J Lipid Atheroscler 2012;1:21-28. 14. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol con- www.lipid.or.kr 27

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